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11 | https://www.bhf.org.uk/informationsupport/heart-matters-magazine/news/coronavirus-and-your-health/astrazeneca-covid-vaccine | "The AstraZeneca vaccine is no longer available in the UK.
No, the UK government stopped using the AstraZeneca Covid-19 vaccine in winter 2021. In May 2024, AstraZeneca withdrew the vaccine, now called Vaxzevria, from sale in other countries.
The AstraZeneca vaccine played an important role in the UK's life-saving vaccine programme during the early stages of the pandemic, but evidence shows that mRNA vaccines, Pfizer and Moderna, are more effective at boosting protection from Covid-19. These vaccines have also been updated to tackle more recent Covid-19 variants, and these are the vaccines now used in the UK's seasonal booster programmes.
While the Oxford/AstraZeneca vaccine is no longer being offered in the UK, the Medicines and Healthcare products Regulatory Agency (MHRA) still monitors potential side effects from this vaccine.
Most side effects that have been reported for the Oxford/AstraZeneca vaccine are mild and short-term. The most common side effects are: discomfort at the injection site, or feeling generally unwell, tired, or feverish, or a headache, feeling sick or having joint or muscle pain.
Blood clots in combination with low platelet levels (thrombocytopenia) are listed as a very rare side effect of the AstraZeneca vaccine. Most cases were observed in the first 3-4 weeks after vaccination.
In April 2021, the Medicines and Healthcare products Regulatory Agency (MHRA) confirmed a possible link between the AstraZeneca Covid-19 vaccine and these rare blood clots, but emphasised that the benefits of the vaccine continued to outweigh the risks for the vast majority of people.
The cases of blood clots that the MHRA reviewed were accompanied by abnormally low levels of platelets in the blood. Platelets are involved in blood clotting, and these abnormally low levels can be a sign that your body’s normal clotting mechanisms are not working properly. Some of the blood clots were an unusual type of blood clot in blood vessels that drain blood from the brain called a cerebral venous sinus thrombosis (CVST).
Research from Cardiff University and Arizona State University, published in December 2021, found a possible explanation of the link between the AstraZeneca vaccine and rare blood clots. They discovered that the adenovirus in the vaccine (which is used to deliver genetic instructions to the cells) can bind with a protein found in the blood, called platelet factor 4. They think that in extremely rare cases, this may trigger a chain reaction in the immune system, which could result in blood clots developing.
More research still needs to be done in this area. The study authors hope that scientists will be able to build on these findings to reduce the risk of these extremely rare side effects, as well as informing the development of future vaccines.
Read the article" |
12 | https://www.yalemedicine.org/news/covid-19-vaccine-comparison | "Comparing the COVID-19 Vaccines: How Are They Different?
BY KATHY KATELLA August 29, 2024
[Originally published: February 24, 2021. Updated: August 29, 2024.]
Note: The Johnson & Johnson (Janssen) COVID-19 vaccine expired as of May 6, 2023, and is no longer available in the U.S. Those who did get the J&J shot are considered up-to-date when they get one updated (2023–2024 formula) COVID vaccine.
Information in this article was accurate at the time of original publication. Because information about COVID changes rapidly, we encourage you to visit the websites of the Centers for Disease Control & Prevention (CDC), World Health Organization (WHO), and your state and local government.
COVID-19 is now in its fifth year, and the subvariants of the Omicron strain continue to drive infections in the United States. The good news is that vaccines, which have been updated each year since 2022, are still expected to be effective at preventing severe disease, hospitalization, and death from COVID.
In the U.S., infants, children, and adults ages 6 months and older are eligible to be vaccinated, according to the Centers for Disease Control and Prevention (CDC).
As the SARS-CoV-2 virus mutates and new variants continue to emerge, it’s important to keep up with how well the updated vaccines are performing.
We mapped out a comparison of the COVID vaccines in the United States.
The Pfizer-BioNTech vaccine (brand name: Comirnaty) was granted full Food and Drug Administration (FDA) approval in August 2021 for people ages 16 and older. Before that, it was the first COVID vaccine to receive FDA Emergency Use Authorization (EUA) back in December 2020, after the company reported that its vaccine was highly effective at preventing symptomatic disease. This is a messenger RNA (mRNA) vaccine, which uses a relatively new technology. It must be stored in freezer-level temperatures, which can make it more difficult to distribute than some other vaccines.
Status: Pfizer’s vaccine has been updated over time to target new virus variants. First introduced in December 2020, the original COVID mRNA vaccines from both Pfizer and Moderna protected against the original SARS-CoV-2 virus. They have been replaced three times since then with shots targeting different iterations of the Omicron strain of the virus. In 2022, “bivalent” vaccines targeted both the original virus and Omicron variants BA.4 and BA.5; in 2023, a monovalent shot targeted the XBB lineage of the Omicron variant; and in 2024, a new updated shot aims to protect against KP.2, which circulated in the U.S. earlier in the year. The previous vaccines are no longer in use.
Who can get it: People 6 months and older. The CDC has specific recommendations for the following groups, noting that anyone who recently had COVID may need to consider delaying their vaccination by 3 months:
For adults ages 65 years and older, an additional COVID-19 vaccine dose—beyond what is listed here—is NOT currently recommended unless they are moderately or severely immunocompromised.
For people who are moderately or severely immunocompromised: Different recommendations can be found on the CDC website.
Possible side effects: Pain, redness, or swelling at the site where the shot was administered, and/or tiredness, headache, muscle pain, chills, fever, or nausea throughout the rest of the body. If these side effects occur, they should go away in a few days. A few side effects are serious, but rare. These include anaphylaxis, a severe reaction that is treatable with epinephrine (the drug in EPIPENs®).
FDA warnings: The FDA added a warning label on the mRNA vaccines regarding serious (but rare) cases of inflammation of the heart muscle (myocarditis) and of the outer lining of the heart (pericarditis) in adolescents and young adults, more often occurring after the second dose of an mRNA vaccine. The inflammation, in most cases, gets better on its own without treatment.
How it works: It uses mRNA technology, which is a way of sending instructions to host cells in the body for making copies of a spike protein (like the spikes you see sticking out of the coronavirus in pictures). Our cells recognize that this protein doesn’t belong, and the immune system reacts by activating immune cells and producing antibodies. This will prompt the body to recognize and attack the real SARS CoV-2 spike protein if you become exposed to the actual virus.
How well it works: The 2024-2025 updated vaccines were approved based on preclinical studies of their efficacy against circulating strains. Some people may still become infected even though they have been vaccinated, but the goal of the vaccines now is to prevent severe disease, hospitalization and death. Research has suggested that people who are infected after vaccination also are less likely to report Long COVID (defined as signs, symptoms, and conditions that continue or develop after acute COVID infection), compared to those who were not vaccinated.
In its recommendations for COVID vaccines, the CDC has cited a study showing the risk of cardiac complications, including myocarditis (an inflammation of the heart muscle), in males 12-17 years old was 1.8–5.6 times higher after a COVID infection compared to after COVID vaccination.
In December 2020, Pfizer-BioNTech’s Phase 3 clinical data for its original vaccine showed 95% efficacy for preventing symptomatic COVID. Later data on real-world effectiveness for adults showed that the protection from the mRNA two-dose primary series waned over time, suggesting that updated vaccines would be needed to bring the immune system back to robust levels.
The FDA granted the Moderna vaccine (brand name: Spikevax) full approval for people 18 and older in January 2022, upgrading the vaccine’s EUA, which was granted in December 2020 (a week after Pfizer-BioNTech). Moderna uses the same mRNA technology as Pfizer-BioNTech and had a similarly high efficacy at preventing symptomatic disease when the companies applied for authorization; it also needs to be stored in freezer-level temperatures.
Status: Moderna’s vaccine has been updated over time to target new virus variants. First introduced in December 2020, the original COVID mRNA vaccines from both Pfizer and Moderna protected against the original SARS-CoV-2 virus. They have been replaced three times since then with shots targeting different iterations of the Omicron strain. In 2022, “bivalent” vaccines targeted both the original virus and Omicron variants BA.4 and BA.5; in 2023, a monovalent shot targeted the XBB lineage of the Omicron variant; and in 2024, a new updated shot aims to protect against KP.2, which circulated in the U.S. earlier in the year. The previous vaccines are no longer in use.
Who can get it: People ages 6 months and older. The CDC has specific recommendations for the following groups, noting that anyone who recently had COVID may need to consider delaying their vaccination by 3 months:
For adults ages 65 years and older, an additional COVID-19 vaccine dose—beyond what is listed here—is NOT currently recommended unless they are moderately or severely immunocompromised.
For people who are moderately or severely immunocompromised: Different recommendations can be found on the CDC website.
Possible side effects: The side effects are similar to Pfizer-BioNTech’s vaccine: Pain, redness, or swelling at the site where the shot was administered—and/or tiredness, headache, muscle pain, chills, fever, or nausea throughout the rest of the body. If any of these side effects occur, they should go away in a few days. A few side effects are serious, but rare. These include anaphylaxis, a severe reaction that is treatable with epinephrine (the drug in EPIPENs®).
FDA warnings: The FDA placed a warning label on the Moderna vaccine regarding a “likely association” with reported cases of heart inflammation in young adults. This inflammation may occur in the heart muscle (myocarditis) or in the outer lining of the heart (pericarditis)—it more often occurs after the second dose of an mRNA vaccine. The inflammation, in most cases, gets better on its own without treatment.
How it works: Similar to the Pfizer vaccine, this is an mRNA vaccine that sends host cells in the body instructions for making a spike protein that will train the immune system to recognize it. The immune system will then attack the spike protein the next time it sees one (attached to the actual SARS CoV-2 virus).
How well it works: The 2024-2025 updated vaccines were approved based on preclinical studies of their efficacy against the latest circulating strains. Some people may still become infected even though they have been vaccinated, but the goal of the vaccines now is to prevent severe disease, hospitalization, and death. Research has suggested that people who are infected after vaccination also are less likely to report Long COVID compared to those who were not vaccinated.
In its recommendations for COVID vaccines, the CDC has cited a study showing the risk of cardiac complications, including myocarditis (an inflammation of the heart muscle), in males 12-17 years old was 1.8–5.6 times higher after a COVID infection compared to after COVID vaccination.
Moderna’s initial Phase 3 clinical data in December 2020 was similar to Pfizer-BioNTech’s—both vaccines showed about 95% efficacy for prevention of COVID. Later data on real-world effectiveness for adults showed that the protection from the mRNA two-dose primary series wanes over time, but booster doses brought the immune system back to robust levels.
The Novavax vaccine (brand names: Nuvaxovid and Covovax) was the fourth COVID vaccine to be administered in the U.S (after Johnson & Johnson, which is no longer available). The Novavax vaccine is the only non-mRNA updated COVID vaccine that has been available in the U.S. This vaccine is a protein adjuvant that had a 90% efficacy in its clinical trial, performing almost as well as the mRNA vaccines in their early trials. It is simpler to make than some of the other vaccines and can be stored in a refrigerator, making it easier to distribute.
Status: An updated 2024-2025 COVID vaccine from Novavax for children and adults ages 12 and older is not FDA-approved at this point. Novavax designed its updated shot to target JN.1, a predecessor of KP.2. Novavax’s 2023–2024 vaccine remains authorized but is no longer available in the United States, since all doses have expired, according to the CDC.
The CDC has currently removed its recommendations for use of the Novavax COVID vaccine from its website, and says it will provide updates if the FDA approves or authorizes the company’s latest vaccines.
As with previous COVID vaccines, the 2024-2025 updated mRNA COVID vaccines are available at participating pharmacies and provider offices. To find a location near you that carries the vaccine and to schedule an appointment, go to Vaccines.gov. You can also call 1-800-232-0233 (TTY 1-888-720-7489).
Note: None of the COVID vaccines change—or interact with—a recipient’s DNA.
Information provided in Yale Medicine articles is for general informational purposes only. No content in the articles should ever be used as a substitute for medical advice from your doctor or other qualified clinician. Always seek the individual advice of your health care provider with any question
Vaccines aren’t just for kids. Thousands of adults go to the hospital each year for a serious (sometimes even deadly) disease they might have avoided if they had received the vaccination to prevent it.
Vaccines activate the immune system, training it to fight off certain viral and bacterial infections.
Coronavirus is a term describes a family of viruses, common in both animals and humans." |
13 | https://www.nature.com/articles/s44298-024-00043-3 | "Beyond COVID-19: the promise of next-generation coronavirus vaccines
npj Viruses
volume 2, Article number: 39 (2024)
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Coronaviruses (CoVs) have caused three global outbreaks: severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) in 2003, Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, and SARS-CoV-2 in 2019, with significant mortality and morbidity. The impact of coronavirus disease 2019 (COVID-19) raised serious concerns about the global preparedness for a pandemic. Furthermore, the changing antigenic landscape of SARS-CoV-2 led to new variants with increased transmissibility and immune evasion. Thus, the development of broad-spectrum vaccines against current and future emerging variants of CoVs will be an essential tool in pandemic preparedness. Distinct phylogenetic features within CoVs complicate and limit the process of generating a pan-CoV vaccine capable of targeting the entire Coronaviridae family. In this review, we aim to provide a detailed overview of the features of CoVs, their phylogeny, current vaccines against various CoVs, the efforts in developing broad-spectrum coronavirus vaccines, and the future.
Vaccines are safe and effective biological formulations synthesized to protect the population from infectious diseases by preventing, limiting, or eradicating the infection and spread of a specific pathogen by inducing specific immune responses1. The design and development of an effective vaccine against infectious diseases requires considerable knowledge about the causative agent, including the nature of the infection, phenotypic characteristics, and infection-associated pathogenesis. The safety, broad-spectrum efficacy, ease of administration, induction of long-term immunity, minimal cost of production, and extended shelf life through improved thermostability are other factors of paramount importance in developing an ideal vaccine2. The medical, social, and economic burden caused by COVID-19 and the evolution and emergence of new variants has highlighted the urgent need for next-generation vaccines with increased breadth of protection, durability, and ability to block infection and transmission.
CoVs belong to the Coronaviridae family and are known to cause outbreaks on endemic and pandemic scales. These viruses are genetically diverse and distinct as demonstrated by phylogenetic analysis and their evolutionary origin. To date, seven human CoVs (HCoVs) have been identified, namely HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV-1, MERS-CoV, and SARS-CoV-23,4,5,6,7,8. Studies focused on the origin of these viruses have shown that bats, rodents, and domestic animals serve as the main reservoir species9. Concerns regarding the possibility of future spillovers with unknown CoVs and the emergence of SARS-CoV-2 variants of concern (VOCs) with unique mutations necessitate generating broad-spectrum vaccines. In addition, waning immunity and breakthrough infections within the population strongly advocate for developing improved vaccines with increased immunogenicity and durability. The first-generation vaccines designed to prevent disease with the ancestral SARS-CoV-2 were proven to be less effective against VOCs. For instance, multiple studies have shown that neutralizing antibody responses induced by the first-generation COVID-19 vaccines were limited against most of the Omicron variants10,11,12,13,14,15,16. Waning immunity against SARS-CoV-2 in the population necessitates the need for frequent boosters17,18,19.
Vaccine design and the delivery route are essential aspects to consider while developing a vaccine. SARS-CoV-2 vaccine design mainly focuses on two antigen targets: the spike (S) protein and the receptor binding domain (RBD) in the S protein. Both targets result in the induction of neutralizing antibody responses20,21. The S protein amino acid sequence similarity between SARS-CoV-1 and SARS-CoV-2 is 76%, and between SARS-CoV-2 and SARS-related CoVs (SARSr-CoVs) is ~80%22. Likewise, the RBDs of SARS-CoV-1 and ancestral SARS-CoV-2 have an amino acid sequence similarity of 73.5%23. Hence, in the design of pan-CoV vaccines, it is wise to consider S protein and RBDs from different CoVs.
Available COVID-19 vaccines are administered intramuscularly (IM) and provide robust systemic antibody responses. Since CoVs are respiratory pathogens and the primary route of virus entry is through the upper respiratory tract, inducing a local mucosal immune response could be an effective way to protect against CoV infection and transmission. Studies focusing on mucosal vaccines have shown induction of mucosal, cellular, and humoral immune responses24. Transmission still occurs from IM-vaccinated individuals25,26,27, and combining mucosal and IM vaccination routes could reduce or completely prevent virus transmission28,29,30.
Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses belonging to the order Nidovirales and the family Coronaviridae. The family Coronaviridae is further divided into three subfamilies: Letovirinae, Pitovirinae, and Orthocoronavirinae, the latter of which is the focus of this review. The subfamily Orthocoronavirinae is subdivided into four genera: Alpha, Beta, Gamma, and Deltacoronaviruses. SARS-CoV-1, SARS-CoV-2, and MERS-CoV belong to the Betacoronavirus genera31.
The general structure of the virus is spherical, with crown-like protrusions present on the outer surface of the virus, which are formed by the S protein, required for the attachment, fusion, and entry of the virus into the host cell. Besides S, CoVs are made of additional structural proteins: the membrane protein (M), the envelope protein (E), and the nucleocapsid protein (N). Both M and E proteins play major roles in viral assembly32,33. HCoV-OC43 and HCoV-HKU1 contain an additional structural protein called the hemagglutinin-esterase protein (HE)34. These proteins, together with the lipid bilayer, form the viral envelope seen surrounding the helical capsid formed by N. The large genome of CoVs, typically 22 to 36 kb, is packaged within the capsid32,35.
Coronaviruses can cause a myriad of diseases both in animal and human populations. Animal CoVs target various animals, including cows, pigs, dogs, cats, mice, and chickens, and can cause gastroenteritis, encephalitis, and bronchitis. For instance, murine hepatitis virus (MHV) causes respiratory, enteric, hepatic, and neurologic infections in mice36,37. Although there are multiple animal CoVs, we focus on HCoVs in this review. HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1 cause mild respiratory tract infections mainly in immunocompromised individuals, which are self-limiting4,5,6,38. However, infection with SARS-CoV-1, MERS-CoV, and SARS-CoV-2 can affect multiple organs, and patients can develop acute respiratory distress syndrome (ARDS), extrapulmonary manifestations, and multiple organ dysfunction syndrome (MODS)39.
The presentation of COVID-19 can either be asymptomatic or symptomatic, ranging from mild to moderate to severe40,41,42,43,44,45. Lung damage is directly proportional to the virus replication and the titer, immune cell infiltration, and elevated levels of various proinflammatory cytokines and chemokines46,47,48,49,50. The immunological response, including the induction of a cytokine storm, can lead to severe lung damage and increased mortality47,51. Several COVID-19 survivors have prolonged health complications associated with COVID-19, often referred to as long COVID52.
Acquisition of mutations and recombination within the virus genome are major driving forces that create genetic diversity, eventually aiding in increased virus survival, pathogenicity, transmissibility, and immune evasion53. CoVs have an internal proofreading mechanism: the 3′ exonuclease (nsp14 for SARS-CoV-2), which limits the mutation rate of CoVs54,55. It has been estimated that the mutation rate of CoVs is 10−6 per base per infection cycle56 and 10-3 per site per year57. Recombination events in conjunction with purifying selection result in the generation of new CoV variants58,59.
The comparative genomic analysis of MERS-CoV, SARS-CoV-1, and SARS-CoV-2 shows that SARS-CoV-2 is distinct and holds a different position on the phylogenetic tree (Fig. 1). Whole-genome sequence alignments of SARS-CoV-2 with other CoVs have revealed that SARS-CoV-2 is most related to certain SARS-related-CoVs including bat CoVs (96%) and pangolin CoVs (86%-92%)60. For example, the whole genome sequence identity of SARS-CoV-2 with BatCoV RaTG13 is 96%, with SARS-CoV-1 79.6%, and with MERS-CoV 50%61,62.
Full-length genomes were obtained from GenBank (https://www.ncbi.nlm.nih.gov/genbank/), and alignments were built with MAFFT (FFT-NS-1 algorithm181. Maximum likelihood phylogenetic tree was constructed using IG-TREE2182 with the best model for distance estimates identified with the ModelFinder function183 as the one with the lowest Bayesian information criterion (BIC). Branch support was assessed using both ultrafast bootstrap approximation (ufBoot, 1000 replicates)184 and SH-like approximate likelihood ratio test (SH-aLRT). The tree was visualized in FigTree (http://tree.bio.ed.ac.uk/software/figtree/), and midpoint rooted for purposes of clarity. Only bootstrap values greater than 70% are shown. Bars indicate nucleotide substitutions per site.
The S protein comprises three segments: a large ectodomain, a single-pass transmembrane anchor, and a short intracellular tail. The ectodomain consists of a receptor-binding subunit S1 and a membrane-fusion subunit S2. The S is a clove-shaped trimer with three S1 heads and a trimeric S2 stalk63,64,65.
The D614G mutation was the first notable substitution in the S protein of SARS-CoV-2 and quickly spread worldwide66. Hereafter, multiple VOCs, including Alpha, Beta, Gamma, Delta, and Omicron, emerged independently across the globe67. One of the variants, Omicron (BA.1), which first appeared in Nov 2021 in Botswana, was antigenically distinct from previous VOCs and became dominant within a short span of time68. Following Omicron BA.1, several subvariants have appeared in different regions all around the globe69,70,71. Recombination events resulted in the appearance of additional VOCs72. During evolution, Omicron lineages exhibited antigenic shifts, resulting in poor neutralization by antibodies induced by first-generation vaccines and pre-Omicron infection15,73.
In the initial stages of the pandemic, the evolution of SARS-CoV-2 appeared to select for VOCs with higher transmissibility and, in some cases, higher severity74,75,76,77. Mutations resulting in antigenic changes leading to immune escape were recognized during the later stages of the pandemic78. Now, it is postulated that the evolution of SARS-CoV-2 is shifting towards adapting to different tissue tropisms as well as immune evasion79. For example, Omicron BA.1 has evolved a preference for efficient replication in the nasopharynx, a better vantage point for entering aerosols80,81. These changes may have a notable impact on the development of a successful vaccine that can prevent virus infection and transmission.
HCoVs have been circulating in the population for decades, and no licensed CoV vaccine was available until December 2020 as a direct consequence of the COVID-19 pandemic. Before the pandemic, a few vaccine candidates against MERS-CoV, MVA-MERS-S, GLS-5300 DNA, and ChAdOx1-MERS were tested in phase I clinical trials82,83,84,85,86. Nevertheless, none were entered into phase II or III trials and approved for human use by the US FDA (United States Food and Drug Administration).
It has been 20 years since the scientific community has identified the potential of using S protein as a vaccine candidate against CoVs87,88,89. Multiple studies have demonstrated that S-specific antibodies can neutralize SARS-CoV-1 or MERS-CoV and protect animals90,91,92. Different variations on the S protein, including full-length, S1 domain only, or RBD, can be used to develop effective vaccines against SARS-CoV-220,93. Moreover, a multitude of vaccines and vaccine delivery platforms have been developed, including mRNA, DNA, protein subunits, whole virus in inactivated form, live-attenuated virus, viral vectors, and lipid nanoparticles94,95,96,97,98. Most of the first-generation vaccines against SARS-CoV-2 are based on the ancestral Wuhan virus strain and use a prefusion stabilized S. Two mutations in the S2 subunit between the central helix (CH) and heptad repeat 1 (HR1), K986P and V987P, stabilize the prefusion confirmation and were critical for the effectiveness of COVID-19 vaccines99. Substitution of these residues was initially described for SARS-CoV-1 and MERS-CoV100,101. Subsequent studies showed that the S could be further stabilized by substituting six prolines, resulting in improved neutralizing antibody responses and efficacy102,103.
Eleven vaccines are approved for human use (Table 1) and more than 5 billion people are vaccinated with at least one dose of vaccine104. During the initial COVID-19 waves, multiple vaccines were shown to provide partial protection from infection, severe disease, and death105,106,107. mRNA-1273 and BNT162b2 vaccines, both mRNA vaccines, showed more than 90% efficacy in preventing symptomatic infection and disease severity108,109. AZD1222, a replication-incompetent adenovirus vaccine, prevented disease severity to 100%110. The efficacy of preventing symptomatic infection by a single dose of Ad26.CO.2 was 52.4%, and disease severity was 74.6%108. The mean efficiency of inactivated SARS-CoV-2 vaccines, including Covaxin, Covilo and CoronaVac, in preventing severe disease was 61.80%, 73.78% and 70.96%, respectively111. The emergence of VOCs completely altered this picture. Omicron VOCs have at least 32 mutations in the S protein and can partially escape the neutralizing antibody response elicited by Wuhan strain-based vaccines15. For instance, omicron subvariant BA.2.75 appeared early 2022, a descendent from BA.2, had several distinct mutations in its S protein, including five substitutions in the N-terminal domain (NTD), K147E, W152R, F157L, I210V, and G257S, and four substitutions in the RBD, D339H, G446S, N460K, and R493Q. BA.2.75 exhibited higher resistance to vaccine- and infection-induced serum neutralizing activity than BA.2, and the resistance was largely attributed to the K147E and N460K mutations112. Similarly, major genetic drift within the Omicron genome has resulted in the emergence of a highly mutated variant BA.2.86 in 2023 and replaced the circulating XBB and EG.5.1 variants. L455S, F456L, R346T, and D339H mutations within the S of BA.2.86 caused the emergence of a newer variant JN1 with reduced ACE2 binding and increased immune evasion113,114,115. These newer variants exhibited reduced neutralizing capacity within the convalescent and vaccinated individuals116,117.
Breakthrough infections within vaccinated individuals by the Omicron variants substantiated that first-generation COVID-19 vaccines are inadequate in preventing transmission and the requirement of alternate strategies118. Despite the increase in antibody levels after breakthrough infection, neutralization titers against Omicron variants are significantly lower than the earlier variants119,120,121,122,123. To counteract the immunological imprinting effect of SARS-CoV-2, repeated Omicron boosting is required124. All these facts highlight the pressing need to develop next-generation vaccines that can broadly protect against novel variants and multiple related viruses from the same family.
It is important to emphasize that even though the neutralizing antibody response was reduced, all vaccine candidates continued to protect against severe disease caused by most of these VOCs. Protection could be via non-neutralizing antibodies125,126,127 or the induction of CD4+ and CD8 + T cells, for which epitopes are unaffected by S mutations128,129,130,131,132. S-specific CD4 + T cell memory responses induced by natural infection or mRNA vaccination are conserved against different VOCs, including Alpha, Beta, Gamma, and Omicron133. Despite partial escape of humoral immunity induced by SARS-CoV-2 infection or BNT162b2 vaccination by Alpha and Beta VOCs, S-specific CD4 + T-cell activation is not significantly affected by the mutations in these variants134. A similar study showed that SARS-CoV-2-specific memory CD4+ and CD8 + T cell recognition is not disrupted by the VOCs, including Alpha, Beta, and Gamma in COVID-19 convalescents and in recipients of the mRNA-1273 or BNT162b2 COVID-19 vaccines135. A study conducted in the BALB/c mouse model showed that T cell-based SARS-CoV-2 spike protein vaccine could provide significant protection against SARS-CoV-2 and Omicron BA.5 variant infection without inducing any specific antibodies. Moreover, the depletion of CD4+ or CD8 + T cells led to a significant loss of protection, indicating the role of T cells in limiting infection136. Patients with X-linked agammaglobulinemia without B cells can develop pneumonia and still recover from SARS-CoV-2 infection137. Computational tools have been developed to predict immunogenic and conserved T-cell epitopes, thus augmenting the precise selection of SARS-CoV-2 vaccine targets138. Thus, incorporating more T-cell epitopes while developing a vaccine would be able to provide more breadth and durability.
Organizations like the Coalition for Epidemic Preparedness Innovations (CEPI) and the National Institute of Allergy and Infectious Diseases (NIAID) have taken the initiative to provide funding for the development of advanced vaccines. These vaccines aim to offer protection against all current and future variants of CoVs by stimulating durable, broad-spectrum immunity. Researchers are updating available vaccines or considering an entirely new approach to achieve this goal.
Since developing a vaccine that protects against all CoVs is likely difficult to achieve due to its genetic variability, as discussed above, a tiered approach likely has a higher chance of success, beginning with COVID-19 vaccines, which can protect against all VOCs, to pan-sarbecovirus vaccines, to pan-betacoronavirus vaccines, to universal or pan-coronavirus vaccines139. Both Pfizer and Moderna have developed bivalent vaccines targeting ancestral SARS-CoV-2 and Omicron. Compared to the monovalent booster, these second-generation vaccines have moderately higher or similar effectiveness in inducing neutralizing antibody responses against Omicron variants in vaccinated infection-naïve cohorts140,141,142. However, immune imprinting and the antigenic variation within Omicron limit the induction of neutralizing antibody responses against newer variants143,144,145,146,147. A recent study carried out on serum samples obtained from participants who had received one or two monovalent boosters or the mRNA bivalent booster indicated that the neutralizing antibody responses are lower against BA.1, BA.5, BA.2.75.2, BQ.1.1, and XBB as that of the ancestral strain WA1 in all three cohorts148.
Other groups have focused on the development of broadly neutralizing sarbecoviruses vaccines by including multiple different antigens. Mosaic-8b, a multivalent spike receptor-binding domain nanoparticle vaccine displaying RBDs from SARS-CoV-2 and seven animal sarbecoviruses, was found to induce broadly neutralizing antibody responses and protected K18-hACE2 mice and non-human primates from SARS-CoV-1 and SARS-CoV-2 challenge, even though SARS-CoV-1 was not included in the vaccine. In contrast, nanoparticles with SARS-CoV-2 RBDs protected only against SARS-CoV-2 challenge. Compared to homotypic RBD nanoparticles expressing only SARS-CoV-2, immunization with mosaic-8b resulted in more robust binding and neutralizing antibody responses against SARS-CoV-1, SARS-CoV-2, and SARS-CoV-2 VOCs149. Another multivalent spike receptor-binding domain nanoparticle vaccine, GBP511, contains RBDs from SARS-CoV-2, SARS-CoV-1, and the bat CoVs WIV1 and RaTG13. This vaccine reduced SARS-CoV-1-MA15 virus replication in lung tissue of vaccinated mice. Furthermore, it elicited broad neutralizing antibody responses against multiple sarbecoviruses after a single immunization150. Likewise, a chimeric spike mRNA vaccine containing RBD, NTD, and S2 domains of various SARS-related CoVs could protect aged mice against SARS-CoV-1, SARS-CoV-2, SARS-CoV-2 Beta, bat CoVs RsSHC014, and a heterologous WIV-1 challenge151. Spike Ferritin Nanoparticle (SpFN) COVID-19 vaccine comprises S from multiple CoVs linked to the surface of a multifaceted ferritin nanoparticle and utilizes Army Liposome Formulation containing QS-21 (ALFQ) as an adjuvant. Upon vaccination, broadly neutralizing antibody responses against major SARS-CoV-2 VOCs and SARS-CoV-1 were induced, resulting in protection against ancestral SARS-CoV-2 in NHPs152,153. Finally, RBD-sortase-A-conjugated ferritin nanoparticle (RBD-scNP) vaccine protects both NHPs and mice from multiple CoV challenges154,155. RBD-scNP contains recombinant SARS-CoV-2 RBD with a C-terminal sortase A donor sequence and self-assembling Helicobacter pylori ferritin with an N-terminal sortase A acceptor sequence.
Antigen design may be important in inducing a broadly protective immune response. DIOSynVax is developing an mRNA vaccine, T2_17, based on the common viral structures on all sarbeco viruses reducing the need for synthesizing, processing, and manufacturing multiple components within one vaccine. A membrane-anchored form (T2_17_TM) mRNA immunogen was shown to be immunogenic against SARS-CoV-1, SARS-CoV-2, WIV16, and RaTG13 in BALB/c mice, guinea pigs, and outbred rabbits. Challenge studies on K18-hACE-2 mice primed with AZD1222 vaccine and boosted with either AZD1222 or T2_17 as an MVA-vectored immunogen showed induction of neutralizing antibody responses against pseudoviruses of SARS-CoV-1, SARS-CoV-2 and the Delta VOC156.
Several studies indicated that intranasally (IN) administered vaccines could induce comparable systemic humoral and cellular immunity as IM vaccination and protect the upper and lower respiratory tract of animals against SARS-CoV-2 infection (Fig. 2)24,157,158,159,160,161,162. Moreover, reduced nasal shedding of the virus was observed upon IN challenge, suggesting that mucosal vaccines could be better at reducing SARS-CoV-2 transmission163,164. Dimeric IgA in the nasopharynx has higher neutralizing capability than monomeric IgA and IgG165. A recent study conducted to evaluate the effectiveness of intranasal administration of sCPD9-ΔFCS, a replication-competent yet fully attenuated virus vaccine, showed induction of robust IgA in nasal washes, which neutralized Omicron BA.1 and BA.5, and limited virus transmission in hamsters models165,166.
Various delivery systems currently used to administer vaccines are shown on the far left. Vaccine delivery routes and devices are depicted in the middle, and the resulting immune pathway after intranasal inoculation is shown on the right. Intranasal delivery of vaccine is achieved by using an inhaler, nebulizer, or spray method. Vaccination via the mucosal route can mount an immune response both in the upper (URT) and lower (LRT) respiratory tract (indicated by green arrows). Microfold cells present on the nasal mucosa actively transport antigens to the dendritic cells (DCs) and macrophages in the subepithelial space. Additionally, DCs situated in the lamina propria or interspersed among epithelial cells sample the mucosal environment using extensions. Activated DCs and macrophages migrate to regional draining lymph nodes or tertiary lymphoid follicles and present antigens to T and B cells. Resulting effector T cells may traffic to the respiratory tract as tissue-resident memory T cells (TRM). Activated B cells either differentiate into low-affinity IgG or IgA-producing plasma cells, which traffic to the respiratory tract, or move to the germinal center, undergo class-switching and somatic hypermutation, and differentiate into long-lived plasma or memory B cells, secreting high-affinity immunoglobulins. These memory B cells may traffic to the respiratory tract. Here, IgA is mainly produced in its polymeric form (pIgA), predominantly dimeric, and transported across the epithelium of the respiratory tract by polymeric Immunoglobulin receptor (pIgR). The pIgR-pIgA complex is cleaved at the apical surface of the epithelium. Thereby, IgA gains part of the pIgR named the secretory component and is released as secretory IgA (sIgA). The secretory component increases the stability of sIgA. Intramuscular immunization can mount robust systemic and LRT immune responses (indicated by red arrows). Circulating IgG antibody levels are generally higher upon vaccination via the intramuscular route in comparison with the intranasal route. NALT Nasal-associated lymphoid tissue. Created with BioRender.com.
More than 20 mucosal vaccine candidates are in development and clinical trials, and two are approved for human use. iNCOVACC (BBV154) is an intranasal SARS-CoV-2 vaccine developed by Bharath Biotech, which was approved in India in early 2023 as a booster dose for those above 18 years of age167. iNCOVACC is a recombinant replication-deficient adenovirus-vectored vaccine encoding a pre-fusion stabilized SARS-CoV-2 S formulated as nasal drops to allow IN delivery. A preclinical study on mice expressing the hACE2 receptor indicated that a single IN dose of iNCOVACC induced high levels of neutralizing antibodies in serum and anti-SARS-CoV-2 IgG and IgA levels in serum and BAL fluid. Challenge studies confirmed complete protection against SARS-CoV-2 infection in the upper and lower respiratory tracts159. Further comparative clinical trial data on healthy adults showed that salivary IgA levels were higher in those who received two doses of iNCOVACC IN, 28 days apart, compared to the licensed intramuscular vaccine, Covaxin. Both vaccines induced significant serum-neutralizing antibody responses against ancestral SARS-CoV-2 and Omicron BA.5167.
A recombinant adenovirus type-5 vectored COVID-19 vaccine (Ad5-nCoV) has been authorized for use as a prime and booster dose in China168. This vaccine is administered via oral inhalation using a nebulizer to deliver the vaccine as aerosol particles into the lungs. Ad5-nCoV is highly immunogenic in clinical trials and efficacious in preventing severe COVID-19169,170,171,172.
IN administration of AZD1222, currently approved as an IM vaccine, can reduce viral shedding and protect hamsters and non-human primates from SARS-CoV-2 challenge163. A phase I clinical trial to investigate the mucosal and systemic immune responses elicited by intranasal AZD1222 as a booster was not encouraging, possibly due to the low number of participants and lack of proper control groups, and more studies have to be conducted to draw final conclusions173.
Two additional nasal vaccine candidates, NDV-HXP-S and CoviLiv, have completed phase I clinical trials174. NDV-HXP-S, a recombinant Newcastle disease virus-based vaccine, which expresses HexaPro S, has shown enhanced neutralizing and binding antibodies from serum samples obtained postvaccination in comparison with samples from mRNA BNT162b2 vaccinees175. A live-attenuated COVID-19 candidate, CoviLiv by Codagenix, expresses all SARS-CoV-2 proteins. IN administration of this vaccine in unvaccinated/uninfected volunteers induced mucosal immunity in a phase I clinical trial. Moreover, participants who received two doses of CoviLiv showed induction of both humoral and cellular immune responses176.
Most mucosal vaccine data comes from preclinical studies. IN vaccination with an N1-methyl-pseudouridine–modified mRNA-LNP results in decreased viral loads in the respiratory tract and reduced lung pathology in Syrian hamsters after the SARS-CoV-2 challenge compared to IM controls177. Vaccination of IFNAR1 − /− mice and hamsters using IN trivalent measles-mumps-SARS-CoV-2 spike protein vaccine induced robust neutralizing antibody responses, mucosal IgA, and systemic and lung resident T cell immune responses and resulted in protection against three different variants of SARS-CoV-2178. An alternate vaccine-boosting strategy, a primary IM vaccination with an mRNA vaccine (“prime”), and an intranasal dose of unadjuvanted SARS-CoV-2 S (“spike”) showed robust cellular and humoral mucosal immune responses in K18-hACE2 mice and protected the animals against SARS-CoV-2 infection. The same strategy reduced viral shedding and prevented transmission in the Syrian hamster model compared to naïve animals24. Finally, MigVax-101 is an orally administered disintegrating freeze-dried tablet vaccine that aims to provide mucosal and humoral immune responses and offers advantages, including ease of administration, low cost, and easy storage. MigVax-101 is a multi-antigen vaccine that contains the RBD and two domains of the N from SARS-CoV-2 and heat-labile enterotoxin B (LTB) as a potent mucosal adjuvant. Immunization studies performed in BALB/c mice and Sprague Dawley rats using MigVax-101 as a homologous oral vaccination of three doses and a heterologous subcutaneous prime and oral booster regimen indicated potent humoral, mucosal, and cell-mediated immune responses compared with the control animals179.
The continuous evolution of SARS-CoV-2 has posed several challenges and raised serious concerns about the effectiveness of currently available vaccines regarding virus infection and transmission. We posit that the development of broad vaccines with a mucosal immune activation component would be ideal for coronaviruses, along with other respiratory viruses.
Several challenges need to be addressed for both the development and clinical testing of vaccines. For example, the human population now exhibits extensive heterologous immunity, and it is not well understood how this affects subsequent vaccination. Furthermore, efficacy testing of novel vaccines in Phase III clinical trials is hindered by this existing immunity, as there will be no placebo group to compare infection rates to. Identifying correlates of protection is necessary to determine a vaccine’s effectiveness against SARS-CoV-2. Another intriguing question is how one can test the efficacy of a vaccine against an as-of-yet-unknown SARS-CoV-3, and likely fully hinges on understanding the correlates of protection.
As detailed above, mucosal vaccination is a promising and logical approach to induce immunity in the respiratory tract. However, more research is required to understand the specific correlates of protection in the respiratory tract, as these are currently unknown. Furthermore, due to previous issues with adjuvants, extra attention should be paid to the safety of mucosal vaccine candidates180. Factors to consider on the way to a successful mucosal vaccine include safe antigens and adjuvants, which vaccine platforms are best at inducing mucosal correlates of protection, what animal models can be used to test efficacy and safety, and what delivery devices are optimal. Another hurdle in developing a nasal vaccine is to address nasal clearing of the vaccine by mucus and cilia. Both mucus and cilia act as a protective barrier in the nasal mucosa and adversely affect antigen absorption. One way to address this issue would be by using virus-like particles and replication incompetent viral vectors that can infect the nasal epithelium or by using substances like gel that can remain in the nasal mucosa for a longer period to ensure proper antigen absorption.
In this review, we have highlighted the pressing need for pan-CoV vaccines against existing and novel emerging CoVs. Developing new tools and finding new vaccination strategies will be an effective way to achieve broad protection against existing and emerging coronaviruses. Multiple broad-spectrum vaccines are currently in various stages of development. Choosing alternative routes for vaccine delivery, along with proper immunogen design, are key approaches to move toward the development of broad-spectrum vaccines. Generating a vaccine against conserved epitopes within CoVs could provide a broader range of protection. The comparative effectiveness of IM and IN vaccination routes is debatable; however, designing and administering vaccines using both routes is an efficient way forward. Combining both routes can theoretically protect individuals from disease severity and virus transmission. Since the population has already received at least one dose of the IM vaccine, a potential IN booster in the form of a self-administrable nasal spray or inhaler would be an intriguing option. More must be addressed before moving into the next step of vaccination in humans.
The COVID-19 pandemic showcased the rigor and potential of the scientific community in developing, testing, and deploying multiple vaccine candidates within an unprecedented timeframe, achieving milestones in the history of vaccines. The COVID-19 pandemic also reminds us of the importance of global pandemic preparedness and the need to invest in research and development. Although COVID-19 is no longer considered a serious threat, the development of innovative vaccine formulations and delivery strategies resulting in improved immunogenicity, safety, and efficacy could make a significant impact on future pandemics.
Ghattas, M., Dwivedi, G., Lavertu, M. & Alameh, M. G. Vaccine Technologies and Platforms for Infectious Diseases: Current Progress, Challenges, and Opportunities. Vaccines (Basel) 9, https://doi.org/10.3390/vaccines9121490 (2021)." |
14 | https://www.tandfonline.com/doi/full/10.1080/21645515.2023.2273155#abstract | Coronavirus
Comparing the immune response and protective effect of COVID-19 vaccine under different vaccination strategies
Tianyi Zhao
, Xiaoping Huang
& Yuelong Shu
Article: 2273155 | Received 10 Jul 2023, Accepted 17 Oct 2023, Published online: 19 Dec 2023
Cite this article https://doi.org/10.1080/21645515.2023.2273155 CrossMark Logo
ABSTRACT
Although highly infectious respiratory viral infections spread rapidly, humans have evolved a precise and complex immune mechanism to deal with respiratory viruses, with strong intrinsic, highly adaptive and specific humoral and cellular immunity. At the same time, vaccination against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is one of the most cost-effective and efficient means of preventing morbidity, severe illness, and death from Coronavirus disease 2019 (COVID-19). As the global epidemic of COVID-19 continues to evolve and vaccines are being developed, it is important to conduct studies on immunization strategies to optimize vaccination strategies when appropriate. This review was conducted to investigate the relationship between the immune response and the protective effect of different vaccination scenarios (including booster, sequential and hybrid immunity), and to provide a basis for the optimization of vaccination strategies and the development of new vaccines in the future.
KEYWORDS:
COVID-19 vaccineimmunization strategiesimmune response
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Introduction
Since December 2019, COVID-19 has become a major public health event with the global transmission. According to public data from the World Health Organization (WHO) website, as of 3 May, 2023, there were 765,222,932 cumulative confirmed cases of COVID-19, 6,921,614 cumulative deaths, and 13,343,360,939 cumulative reported vaccination doses worldwide.Citation1 As the pandemic continues to spread and mutations continue to accumulate, the WHO has identified seven variants of concern (VOC), all of which are Omicron variants. The Omicron variant, with up to 40 mutations in the stinger protein alone, is highly transmissible and immune evasive and has rapidly replaced other strains as the dominant strain since 4 May, 2023.Citation2 The new Omicron subtypes are often the result of amino acid mutations in their ancestral Omicron subtypes that further evade the immune response.Citation3
Vaccines are essential for preventing and controlling infectious diseases, particularly viral infections. When it comes to SARS-CoV-2, the spike protein on its surface is the primary target for neutralizing antibodies. Many COVID-19 vaccines have been developed to specifically target this spike protein, as it plays a crucial role in the virus’s entry into host cells. (
) The immune response elicited by vaccines is not solely reliant on neutralizing antibodies. T cells, another component of the immune system, play a crucial role in recognizing and eliminating infected cells. T cells are less affected by changes in the spike protein and can provide protection against severe disease, even if the virus has evolved to partially evade neutral of existing vaccines against different variants. The COVID-19 vaccine is mainly divided into whole virus vaccines and virus component vaccines. Whole virus vaccines include attenuated and inactivated vaccines. Viral component vaccines include protein subunit vaccines, virus-like particle vaccines, DNA vaccines, RNA vaccines, non-replicating virus vector vaccines, replicating virus vector vaccines, etc. (
).
Figure 1. The whole process of SARS-CoV-2 life cycle. First step: after the S protein ACE2 of SARS-CoV-2 binding to the host cell’s receptor, the S protein ACE2 is cleaved by the protease TMPRSS2, which induces a change in the conformation of the S protein; after the virus is endocytized by the cell, the S protein ACE2 is further cleaved by the host protease, to be exposed the envelope fusion region of S2, thereby mediating fusion of viral outer envelope with host cell membrane. Second step: the protein precursor encoded by the gene ORF1ab of the virus undergoes a series of cleavage and modification to produce non-structural proteins (NSPs), which can rapidly inhibit the translation of host mRNA, and at the same time start to replicate and translate the virus’s own RNA. Third step: SARS-CoV-2 induces the formation of double membrane vesicles (DMVs) in the intracellular membrane system to provides a safe environment for viral RNA replication and to simultaneously translate viral structural proteins. Fourth step: the structural proteins and genomic RNA of the virus are assembled into a complete virus particle in ERGIC; and virus particles are secreted out of the cell by vesicles.
Figure 1. The whole process of SARS-CoV-2 life cycle. First step: after the S protein ACE2 of SARS-CoV-2 binding to the host cell’s receptor, the S protein ACE2 is cleaved by the protease TMPRSS2, which induces a change in the conformation of the S protein; after the virus is endocytized by the cell, the S protein ACE2 is further cleaved by the host protease, to be exposed the envelope fusion region of S2, thereby mediating fusion of viral outer envelope with host cell membrane. Second step: the protein precursor encoded by the gene ORF1ab of the virus undergoes a series of cleavage and modification to produce non-structural proteins (NSPs), which can rapidly inhibit the translation of host mRNA, and at the same time start to replicate and translate the virus’s own RNA. Third step: SARS-CoV-2 induces the formation of double membrane vesicles (DMVs) in the intracellular membrane system to provides a safe environment for viral RNA replication and to simultaneously translate viral structural proteins. Fourth step: the structural proteins and genomic RNA of the virus are assembled into a complete virus particle in ERGIC; and virus particles are secreted out of the cell by vesicles.
Table 1. Vaccines for SARS-COV-2.
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Neutralizing antibodies recognize and stop viruses in body fluids from invading cells, while killer T cells are responsible for attacking and clearing infected cells when a few have escaped the antibody-invading cells. Antibody levels in the serum will gradually decline over time, and T cells and memory B cells will play a long-term protective role in the future when antibody levels drop lower and viral invasion is encountered again.Citation4
Immunoglobulin G (IgG) is the most abundant antibody in the blood and is produced by B cells in response to an antigen. After vaccination, IgG antibodies are produced by plasma cells and can be detected in the blood. It has been shown that the half-life of IgG antibodies in people recovering from mild COVID-19 is approximately 73 days (52–120 days).Citation5 This phenomenon could potentially account for the continued occurrence of breakthrough infections following vaccination, considering the emergence of variants with enhanced immune evasion abilities that are engaged in a competitive relationship with the host’s immune system. Furthermore, a decline in human antibody levels over time, particularly in more vulnerable populations, increases the likelihood of falling below the protective threshold. However, it remains unclear why breakthrough infections among vaccinated individuals are generally less likely to progress to severe disease. One plausible explanation is the rapid activation of the body’s T cells and memory B cells. In light of this context, it becomes imperative to examine whether vaccination strategies can be effectively modified to align with the immune response conferred by the vaccine, ultimately achieving optimal prevention of Omicron infections. This paper will examine the relationship between the different immune responses and the protective effects of different vaccination strategies, namely booster, sequential, and hybrid immunity.
Booster immunity
It is a natural part of the immune response that the immune protection induced by either type of vaccine will fade over time after vaccination. Booster immunity is a vaccine dose that is administered after completion of the vaccination and supplemented according to the waning of antibodies to maintain the body’s immunity to SARS-CoV-2. A study tracking the prevalence of Omicron in the UK in November-December 2021 found that Omicron positivity rates were significantly lower in children who had received two doses of vaccine compared to unvaccinated children, and Omicron positivity rates were significantly lower in adults after the 3rd dose of vaccine. As a population-wide epidemiological study, this study confirms the public health significance of vaccination boosters for the prevention of Omicron.Citation6 The UK Department of Health HAS reported real-world vaccine efficacy (VE) of the vaccine three months after the 3rd dose of vaccine rollout, with no significant decrease in protection over the three months the study was conducted in the Delta and Omicron epidemics. Protection against hospitalization and death was 97–99% for the 3rd dose, suggesting the importance of a 3rd dose of highly protective vaccine to prevent infection and serious illness in high-risk countries.Citation7 A study reported an increase in immunogenicity after the 3rd dose of BNT162b2, they found a 1.7-fold increase in receptor-binding domain (RBD) specific IgG, an increase in affinity from 61.1% to 96.3% and a 6.1-fold increase in neutralizing titers after the 3rd dose compared to the 2nd dose. The 3rd dose of vaccination increased protection by 85.6% relative to the two doses of vaccine.Citation8 In addition, the Food and Drug Administration (FDA) reported a neutralizing effect of serum on Omicron after booster vaccination, and found that serum neutralized Omicron at a titer of only 22 after two BNT162b2 vaccinations and recovered to 70 after three vaccinations.Citation9 These studies suggest a high protective effect on Omicron after booster vaccination.
Previously, a study examined whether T-cell responses induced by different vaccine platforms (mRNA-1273, BNT162b2, Ad26.COV2.S, NVX-CoV2373) cross-recognized the SARS-CoV-2 mutant strain. It was found that T-cell recognition of the mutant strain was preserved, but that neutralizing antibodies significantly decreased recognition and response to the mutant strain. In subjects, approximately 6 months post-vaccination, an average of 90% of true CD4+ and 87% of CD8+ memory T cell responses to the mutant strain were preserved, with 84% of CD4+ and 85% of CD8+ responses to Omicron being preserved and T cell immunity being slightly affected by the mutant strain.Citation10 While vaccine-induced neutralizing antibody levels decreased over time, the frequency of SARS-CoV-2 memory B and T cells was stable, which could explain its longer-lasting effectiveness in preventing severe diseases. The above studies provide an important basis for understanding the vaccine-induced immune response.Citation11 Another study investigated the role of Spike-specific memory T cell responses induced by BNT162b2 inoculation against Omicron mutant strains. The study analyzed cells from health care workers following two or three doses of BNT162b2 inoculation or two doses of inoculation after infection. The study found that Spike-specific memory T cells induced by BNT162b2 inoculation had a significant functional response to Omicron and a response comparable to wild-type viral Spike, including IFN-γ, IL-2 and TNF secretion. This study demonstrates that BNT162b2-induced memory T cell pairs are persistently multifunctional and have a significant immune response to Omicron mutants.Citation12 A study found that the immunogenicity results of phase 2 clinical trial of the 4th dose of mRNA vaccination showed that the T cell response was also enhanced after the 4th dose, with a 7.32 and 6.22 fold increase in ELISpot SFU/million cells in the BNT162b2 and mRNA-1273 groups, respectively.Citation13 mRNA vaccination was also found to significantly enhance T-cell responses compared to natural infection, but additional boosters on top of this did not enhance T-cell responses any further. The application of mRNA homologous or heterologous vaccination significantly enhanced the Omicron Spike-specific T-cell response, and multifunctionality and specificity of T-cell interferon secretion were all significantly better than the T-cell response induced by natural infection. If a 3rd dose of vaccine is administered on top of this, antibody titers increase significantly, while T-cell responses remain stable.Citation14 This suggests that the immune response does not improve indefinitely and immune responses concentrated in one subunit and shifts to other subunits are suppressed after repeated doses of a particular vaccine. In a review, Duane Wesemann reported on the process of differentiation and maturation of human B cells and production of high-affinity antibodies after vaccination and concluded that antibody titers over time after vaccination. It is suggested that although antibody titers decrease over time after vaccination, B cells continue to differentiate after the second dose of vaccine and mature in antibody affinity using somatic hypermutation (SHM). This antibody affinity maturation process is actually the most important way in which humans mutate against viruses.Citation15 Nussenzweig’s group reported that three doses of vaccination based on the original wild-type design (BNT162b2 and mRNA-1273) remained effective against Omicron, in large part due to the role of memory B cells. The significant increase in the frequency of RBD-specific memory B-cell distribution after the 3rd dose of vaccine resulted from the continued expansion of RBD-specific memory B-cells induced after the 2nd dose of vaccine and the induction of new memory B-cell clones after the 3rd dose of vaccine. More importantly, the 3rd dose of vaccination resulted in a higher broad spectrum and neutralizing activity of the antibodies secreted by B cells; in particular, the newly induced B cell clones after the 3rd dose of vaccination had significantly higher neutralizing activity of the antibodies secreted by these B cells. Thus, the 3rd dose of vaccine resulted in a significant increase in B-cell repertoire (BCR) diversity, allowing for the rapid production of neutralizing antibodies to a broad spectrum of highly neutralize mutants. Their study explained why 3rd dose of BNT162b2 and mRNA-1273 provides better protection against Omicron infection.Citation16 Another study evaluating the response of memory B cells after three doses of vaccine was reported by John Wherry’s group, which found that after two doses of mRNA-1273 or BNT162b2 vaccine, antibody decay stabilized after 6–9 months, but antibody affinity maturation gradually increased. Spike and RBD-specific memory B cells remained stable over time, and 40–50% of RBD-specific memory B cells could bind the four mutant strains Alpha, Beta, Delta and Omicron. Spike and RBD-specific memory B cells remained stable over time, with 40–50% of RBD-specific memory B cells able to bind the four mutant strains Alpha, Beta, Delta and Omicron. After the 3rd dose of mRNA-1273 or BNT162b2 vaccine, Omicron RBD-specific memory B cells were activated in subjects, and this activation was closely associated with a significant increase in the neutralization titer to Omicron. A very important finding was that antibody titers before 3rd dose were negatively correlated with the fold change in antibody boosters, suggesting that high levels of circulating antibodies may limit the additional protection afforded by short-interval boosters. This suggests that antibody titers should be tested before booster vaccination to determine whether a booster is required. The above studies provide data on the quantity and quality of antibodies and B cells over time through three or more antigen exposures, and these data are important for the development of immunization strategies.Citation17 Longer vaccination intervals allow the human immune system to compensate for vaccine deficiencies: allowing more somatic hypermutation of B cells in secondary lymphoid organs.Citation18 Another study showed that longer vaccination intervals significantly increased antibody titers at the expense of T-cell response, suggesting that vaccination intervals should be somewhat flexible.Citation19
There is another key factor to pay extra attention to when studying the relationship between the immune response induced by a vaccine and its effectiveness: the length of incubation of the virus. By incubation period, we usually refer to the time between exposure to the pathogen and the onset of symptoms. The incubation period varies greatly from disease to disease and the activation of memory B cells is required for 3–5 days. An important meta-analysis showed that the incubation periods of the different strains of COVID-19 virus were: 6.65 days for the original strain; 5.00 days for Alpha; 4.50 days for Beta; 4.41 days for Delta; and 3.42 days for Omicron.Citation20 So on the one hand there is a gradual decline in antibody levels after vaccination, and on the other hand, when Omicron is encountered, the body’s immune memory cannot be fully activated before the virus replicates in large numbers, and this is when breakthrough infection occurs. However, compared to unvaccinated patients, vaccinated patients are much better off in terms of duration and severity of illness and are much less likely to become seriously ill. This is where the role of T cells and memory B cells comes into play. A current hypothesis is that an important mechanism for the prevention of severe illness and death by the COVID-19 vaccine is the induction of a long-lasting T-cell response, not just neutralizing antibodies. This may explain the current effectiveness of the three-dose inactivated vaccine in preventing severe illness and death in some real-world studies (e.g. the BA.2 outbreak in Hong Kong, China), despite its low protective power against infection. However, on the other hand, the priority of a vaccine should be to prevent infection, rather than being limited to preventing severe illness and death. Timely adjustment of booster strategies and the development of new vaccines are therefore essential for outbreak control.
Sequential immunity
Homogeneity and heterogeneity of COVID-19 vaccines refer to the similarity or difference in the vaccine components, such as the antigenic proteins or viral vectors used to stimulate the immune system. Homologous vaccines are those that use the same vaccine components for both the primary and booster doses, while heterologous vaccines are those that use different vaccine components for the primary and booster doses, i.e. sequential immunization. The WHO Interim recommendations for heterologous COVID-19 vaccine schedules: interim guidance, published on 16 December 2021, recommends that Sequential immunity studies be conducted using COVID-19 vaccines that have been authorized for emergency use and that the COVID-19 vaccine sequential vaccination should be attempted and studied based on various factors such as country epidemiology, epidemic variant, and vaccine safety.Citation21
Iwasaki’s group reported data from two doses of CoronaVac followed by booster vaccination with BNT162b2, applying the gold standard Plague Reduction Neutralization Test (PRNT) to assess serum neutralization titers following vaccination. It was found that serum neutralizing titers PRNT50 after two doses of CoronaVac were less than Plague Reduction Neutralization Test (PRNT),Citation12 but 28 days after booster vaccination with BNT162b2, serum neutralizing titers PRNT50 rose 10.1-fold against the original wild type and 6.3-fold against Delta in vaccinees, comparable to two doses of BNT162b2. In contrast, for the Omicron mutant strain, there was no neutralizing activity after two doses of CoronaVac, and enhanced inoculation with BNT162b2 increased the neutralizing titer PRNT50 by 7.3-fold.Citation22 The presence of a pool of SARS-CoV-2-specific B cells in BNT162b2 groups is prone to respond to restimulation, which asserts the long-term effectiveness of the BNT162b2 vaccine in contrasting the severe form of the pathology and prevent COVID-19-associated hospitalization. Another group also evaluated sera from subjects who received two doses of inactivated BBIBP-CorV and CoronoVac vaccines followed by mRNA vaccines. This level is close to or at the same level as three doses of inactivated virus vaccine. This level approached or reached the total RBD antibody level of three doses of mRNA vaccine, or mRNA vaccination after infection. The study also found that the inactivated + mRNA mix significantly increased the levels of multifunctional T cells compared to single-dose mRNA vaccination.Citation23 The above study suggests that two doses of inactivated and mRNA vaccine as a booster is a proven protocol for boosting antibody titers with good immune efficacy.Citation24 China National Pharmaceutical Group Corp reported preclinical data on a new Omicron Spike full-length mRNA vaccine. Two mRNA vaccines, Delta-specific ZSVG-02 and Omicron BA.1-specific ZSVG-02-O were designed and given to mice already vaccinated with the inactivated virus vaccine BBIBP-CorV. ZSVG-02-O induced high titers of broad-spectrum neutralizing antibodies in mice, with 3, 10 and 30 ug inducing high titers of neutralizing antibodies against Omicron BA.1, BA.2 and BA.4/5, with 10 and 30 ug inducing titers of neutralizing antibodies against BA.5 at 1105 and 2188 respectively. 1105 and 2188, respectively, and two doses of 30 ug ZSVG-02-O induced a highly effective and broad-spectrum multifunctional T-cell response. This vaccination strategy has implications for the response to Omicron in populations receiving a full course of inactivated virus vaccine.Citation25
Chen Wei’s team reported the safety and immunogenicity results of a phase 1/2 clinical trial of a nebulized oral version of the CanSino Ad5 adenovirus vector vaccine, administered as a third booster dose on top of two doses of the inactivated virus vaccine CoronaVac. The study was divided into three groups, a low-dose oral vaccination group, a high-dose oral vaccination group and a comparison group of homologous intramuscular vaccination with CoronaVac. The incidence of adverse reactions was found to be 19% in the low-dose group, 24% in the high-dose group and 39% in the CoronaVac group (p < .0001). The study applied neutralizing antibody titers to assess the immunogenicity and found that 14 days after vaccination, the NAb GMT against wild-type SARS-CoV-2 was 744.4 in the low-dose group, 714.1 in the high-dose group and only 78.5 in the CoronaVac group. Oral Ad5 vaccine was significantly higher than CoronaVac (p < .0001). Efficient Spike-specific T-cell responses were induced in both the high and low-dose CoronaVac groups, significantly higher than in the CoronaVac group (p < .0001).Citation26 Another team reported data from a phase 4 clinical trial of a mix of Ad5 adenovirus vector vaccine (Convidecia) and inactivated virus vaccine (CoronaVac). 198 people received a second dose of Convidecia 3–6 months after a single dose, and 102 people received a second dose of Convidecia or a mix of CoronaVac as a second dose booster vaccination. Another group of 101 received one dose of CoronaVac, 50 received a second dose of CoronaVac, and 51 received a mixed dose of Convidecia as a second dose. The study assessed the effect of vaccination with a wild-type live virus neutralization test. Although there were more adverse events in the Convidecia group, they were all mild to moderate reactions. It was found that of all combinations, the best induction of neutralizing antibodies was achieved by two doses of CoronaVac followed by vaccination with Convidecia for heterologous boosting. In addition, Convidecia followed by one dose of CoronaVac induced the most significant T-cell response. In conclusion, the primary vaccination with inactivated virus vaccine and the booster vaccination with the Ad5 adenovirus vector was the most effective and had a good safety profile. This means that a booster vaccination with an existing Ad5 linear virus vector vaccine or a recombinant protein subunit vaccine on top of an inactivated virus vaccine can be expected to have good results.Citation27
While the COVID-19 vaccine induces broad and efficient neutralizing antibodies and T-cell immunity, it has been less clear whether the vaccine induces a mucosal immune response in the respiratory tract, but this question is crucial and is directly related to the protective power of the vaccine against infection. A group found lower antibody titers to D614G, Delta, and Omicron in bronchoalveolar lavage fluid (BAL) from vaccinated patients, compared with higher BAL-neutralizing antibody titers from recovered patients. However, antibody responses in the peripheral blood of vaccinated patients were significant. In addition, there were few S-protein-specific T and B cells in the BAL of vaccinated patients compared to recovered patients. The study thus used a mouse model and found that the antibody response induced by vaccination alone was limited to the periphery and that it was difficult to induce an immune response in the respiratory mucosa; however, mRNA vaccination plus mucosal inoculation with adenoviral vector vaccine induced a broad spectrum and high titer of neutralizing antibodies against wild type and Omicron. This study first explains that one of the disadvantages of current vaccines for the prevention of infection is their inability to induce efficient mucosal immunity, and suggests a solution in the form of booster vaccines administered via the mucosal route.Citation28 Iwasaki’s group applied the Prime + Spike method, i.e. primary vaccination with an existing mRNA vaccine and booster with nasally inhaled Spike recombinant protein, and after booster vaccination, the method induced efficient virus-specific plasma IgG and IgA in mice, comparable to two doses of mRNA vaccination; this vaccination combination induced efficient nasal mucosal and lung IgA responses. The immune pathway also induced a virus-specific B-cell response and a mucosal memory T-cell response. In the attack virus model, the Prime + Spike method immunized mice survived 100% of the time and showed no weight loss. Viral titers in the lungs and nose were significantly lower than in the blank control and mRNA prime-immunized groups, and there was no pathological damage to the lungs. The method also provided good protection against the hamster attack model. Spike of SARS-CoV induced broad-spectrum peripheral blood and mucosal humoral and cellular immunity against SARS-CoV and SARS-CoV-2 if the mRNA vaccine was given to mice primed for immunization. This suggests that a single dose of mucosal vaccine can provide significant protection by applying existing vaccines and changing the route of immunization to the already widespread mRNA vaccination of the current population.Citation29
From the results of the available studies on Sequential immunity with COVID-19 vaccine, there is consensus that: (1) Sequential immunity with COVID-19 vaccine has been safe and effective in several countries, and no serious side effects have been observed; (2) Sequential immunity strategies have resulted in vaccine immunogenicity that meets or exceeds that of homologous vaccine boosters; (3) Sequential immunity is more effective than homologous booster immunization against some mutant strains; and (4) Given the safety of Sequential immunity and its effectiveness against some mutated strains, Sequential immunity is an exceptional tool to deal with severe epidemics, virus mutations and vaccine shortages, according to WHO guidelines.
Hybrid immunity
Hybrid immunity refers to the immune protection in individuals who have had one or more doses of a COVID-19 vaccine and experienced at least one SARS-CoV-2 infection before or after the initiation of vaccination. It appears to result in stronger protection than just infection or vaccination alone. Hybrid immunity is an exceptional tool to deal with severe epidemics, virus mutations and vaccine shortages, according to WHO guidelines.
A group reported on the neutralizing activity of inactivated booster sera against the four main Omicron subtypes BA.2, BA.2.12.1, BA.4 and BA.5 that are now prevalent throughout the world. The study applied a pseudovirus neutralization test to assess the effectiveness of the vaccine and found that the neutralizing activity of two doses of BBIBP-CorV against wild-type D614G was 89 NT50 and 274 NT50 for three doses. The neutralizing activity of ZF2001 booster after two doses of BBIBP-CorV was 255. 2 doses of BBIBP-CorV followed by Omicron BA.1 breakthrough infection resulted in a neutralizing activity of 1615 for D614G and 1712 for BA.2.2 breakthrough infection. The neutralizing activity of Omicron was 22 for BA.1, 35 for BA.2, 16 for BA.2.12.1 and 21 for BA.4/5 in three doses of BBIBP-CorV inoculated sera. 2 doses of BBIBP-CorV +1 dose of ZF2001 booster sera had a neutralizing activity of 36 for BA.1, 55 for BA.2 and 21 for BA.4/5. This suggests that the neutralizing activity against all subtypes of Omicron was low after the third dose of both vaccines. In contrast, the neutralizing activity was significantly higher in breakthrough infections. serum from those with BA.1 breakthrough infection after two doses of BBIBP-CorV had a neutralizing activity of 1360 against BA.1, 1059 against BA.2, 777 against BA.2.12.1 and 573 against BA.4/5. serum from those with BA.2 breakthrough infection after two doses of BBIBP-CorV had a neutralizing activity of 241 against BA.1. Thus, the highest titers of neutralizing antibodies and the broadest spectrum were produced after breakthrough BA.1 infection based on two doses of inactivated vaccine, which neutralized many of the currently prevalent Omicron subtypes, whereas the serum neutralizing activity after both vaccinations were lower. and activity after vaccination with both vaccines was lower.Citation30 In addition, it was found that serum activity and broad spectrum were significantly increased in breakthrough infections compared to vaccines without breakthrough infections (n = 47). In particular, breakthrough infections in three-dose vaccinees were associated with significant neutralizing activity against VOC mutants, and breakthrough infection with BA.1 triggered a strong immune recall response, rapidly promoting the expansion of memory B cells specific for conserved epitopes in various VOC mutants rather than inducing BA.1-specific B cells. Memory B cells are remarkably plastic and can be remodeled by different Spike(S antigen) exposures. This study confirms that memory B cells respond rapidly after breakthrough infection by amplifying conserved epitope-specific B cells, but not by increasing BA.1-specific responses.Citation31 A group reported on the B-cell response following Omicron infection in vaccine breakthrough-infected individuals, finding that early in the breakthrough infection, vaccinated individuals rapidly produced high levels of Spike antibodies and specific B-cell response. The antibodies had significant SHM but were specific for the original wild type used in the vaccine, suggesting that acute infection recalled the vaccination-induced memory B-cell response. Very interestingly, memory B cells primarily recognize the relatively conserved S2 subunit, but some time after breakthrough infection, the immunodominant antigen primarily recognized by the antibody shifts toward the RBD on S1, as evidenced by the tendency for RBD-specific neutralizing antibody clones isolated from Omicron breakthrough-infected individuals to become homogeneous. This finding is interesting in that it suggests that the immune memory established by vaccination tends to recognize the very conserved S2 subtype, but that there is a “clonal convergence” of antibodies to the most mutation-intensive RBD epitopes after breakthrough infection.Citation32 Other research group have reported that the magnitude and timing of recall immunity after breakthrough infection depends on the type of SARS-CoV-2 mutant strain. The study found different recall immunity in previously infected individuals vaccinated and in breakthrough infected individuals after vaccination, using a long-term observational cohort. While rapid and strong humoral and T-cell immunity was induced in previously infected individuals following vaccination, recall immunity in vaccine breakthrough infections was delayed and highly variable in magnitude, depending on the type of VOC mutant strain of the virus with which the individual was infected. In contrast, early recall response B-cell activation preceded the increase in neutralizing antibody titers in breakthrough-infected individuals. Omicron-binding memory B cells were efficiently reactivated by a 3rd dose of wild-type vaccine and correlated with the corresponding increase in neutralizing antibody titers. Although the delayed kinetics of immune recall provides a potential mechanism for the lack of complete prevention of viral infection by the vaccine in some patients, antibody recall occurs simultaneously with viral clearance, which may be the mechanism for the protective effect of the vaccine against severe diseases.Citation33 A group assessed the response of SARS-CoV-2 specific CD8+ T cells following antigenic stimulation based on single-cell sequencing in vaccinated, infected and breakthrough-infected individuals. It was found that the sequence of exposure determined the distribution of Spike-specific and non-Spike-specific responses, such that post-infection and post-vaccination resulted in the expansion and differentiation of Spike-specific T cells into CCR7-CD45RA+ effector cells. In contrast, individuals following breakthrough infection develop a strong non-Spike-specific response. Analysis of more than 4000 epitope-specific T cell antigen receptor TCR sequences in the study showed that all exposures triggered a broad spectrum of recognition of expanded TCRs. The findings of this study are important, namely that different sequences of infection and vaccination induce different specific CD8 T cell responses.Citation34
Veesler’s group reported on the immunological profile of breakthrough infections and assessed the serum-neutralizing activity of vaccinated and breakthrough-infected individuals. They also found that Omicron induced a very efficient and broad-spectrum neutralizing antibody response to SARS-CoV-2 VOC mutants including BA.5 and even SARS-CoV after breakthrough infection. The structure resolved by Cryo-em shows that the S2×324heavy chain binds to the open RBD K440-K444 region. Prophylactic administration of S2×324to hamsters prevented Omicron BA.2 and BA.5 infections. It was found that mucosal immunity was not induced locally in the respiratory tract by intramuscular vaccination, but that mucosal immunity was induced by vaccine breakthrough infection.Citation35 Humoral immunity is significantly enhanced by vaccination or hybrid immunity, but hybrid immunity (and natural infections) induces stronger mucosal immunity than vaccination alone, and mucosal immunity is an important shield against infection as the respiratory mucosa is the first point of entry for viruses into the body.Citation36 Individuals with hybrid immunity had the highest magnitude and durability of protection.
Conclusion
Vaccination providing long-lasting protection against SARS-CoV-2 is one of the most cost-effective and efficient options. Currently, humans have generally developed immunity to SARS-CoV-2, particularly antibody-mediated humoral immunity. This could lead to a situation similar to that of the 1918 H1N1 influenza, with each successive outbreak becoming weaker and weaker until it becomes a classic endemic. Due to viral evolution, it is important to evaluate the dynamic changes of humoral and cellular immune responses, protective effects and adverse reactions after different vaccination situations and to conduct studies on vaccination strategies in order to adapt and optimize vaccination strategies in a timely manner. Generally speaking, immune response, which dwindles in months, comes from B cells blocking SARS-CoV-2 from infecting cells via antibodies, and from T cells destroying infected cells and supporting other immune responses. This article provides a detailed framework for the above content, and these experiences will also provide important theoretical support for the development of universal vaccines by using new platforms and new generation vaccines with different technical routes. The development of pan-coronavirus vaccines targeting conserved antibody epitopes across coronaviruses and T-cell epitopes to prevent the emergence of new mutant strains and the development of transmucosal vaccines to induce respiratory mucosal immunity are the focus of the new COVID vaccine.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Additional information
Funding
This work was supported by National Key Research and Development Program of China (2021YFC2300100, 2021YFC2300102), CAMS Innovation fund for Medical Sciences (2022-I2M-1-021), +Shenzhen, and Special Funds for the Cultivation of Guangdong College Students’ Scientific and Technological Innovation. (“Climbing Program” Special Funds.) (No.58000-52910001).
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15 | https://www.sciencedirect.com/science/article/pii/S0264410X2400834X | Individual and familial factors associated with mRNA COVID-19 vaccine uptake in pregnancy: A large-scale registry-based linkage study
Author links open overlay panelJovan Elyass a b, Anteneh Desalegn a, Nhung T.H. Trinh a, Saima Orangzeb a, Mahmoud Zidan a, Hedvig Nordeng a c, Angela Lupattelli a
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Abstract
The association between maternal COVID-19 vaccination in pregnancy and factors such as high risk for severe COVID-19, pre-existing asthma, prior adverse reproductive history, or paternal COVID-19 vaccination during pregnancy, remains unclear. The aim of this study is two-fold: (i) to describe uptake of COVID-19 vaccine during pregnancy by maternal risk for severe COVID-19 and asthma, and (ii) to comprehensively examine individual and familial factors associated with vaccine uptake during pregnancy in Norway. Based on nation-wide registry-linkage data in Norway, we included 101,659 deliveries with gestational length ≥12 weeks, in 2021–2022. Our outcome measure was uptake of at least one dose of mRNA COVID-19 vaccine during pregnancy, using a narrow (first ever dose) and broad (any dose) definition. We fit univariate and multivariate modified Poisson regression models, clustered by county of residency and adjusted for calendar time, to estimate risk ratios (RR) with 95 % Confidence Intervals (CIs). Gestational uptake of any COVID-19 vaccine dose increased from <1 % before mid Aug-2021, to 38.8 % in the rest of 2021, and 48.9 % in 2022. Only 28.8 % and 33.9 % pregnant individuals with high risk for severe COVID-19 or asthma, respectively, received at least one COVID-19 vaccine dose. Paternal COVID-19 vaccination was strongly associated with greater vaccine uptake by pregnant individuals (adjusted RR: 7.2, 95 % CI: 6.8–7.5). Maternal SARS-CoV-2 infection pre-pregnancy (adjusted RR: 0.31, 95 % CI: 0.26, 0.37), familial and individual migrant status were associated with a considerable decreased likelihood of vaccine uptake in pregnancy. History of miscarriage or pregnancy with congenital anomaly were not associated with vaccine uptake. Despite rising COVID-19 vaccine rates in pregnancy, uptake remained low for high-risk individuals. Paternal vaccination, pre-pregnancy infection, migration status, and maternal citizenship were strongly associated with prenatal vaccine uptake. This knowledge can inform tailoring of future vaccination campaigns.
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Keywords
mRNA COVID-19 vaccine
Pregnancy
Prenatal vaccine uptake
Paternal vaccination
1. Introduction
Pregnant individuals have substantial higher risk of severe COVID-19 and death than non-pregnant counterparts, primarily if unvaccinated [1], [2], [3], [4]. Prenatal SARS-CoV-2 infection also increases the risk of multiple adverse pregnancy and child outcomes [5], [6], [7], [8], [9], [10]. With emerging reassuring data about the safety of mRNA COVID-19 vaccine in pregnancy [11], there is consensus that the benefit of prenatal vaccination outweighs any potential risk to both mother and child [12].
In Norway, adults of childbearing age working as healthcare professionals or having conditions associated with high risk of severe COVID-19 illness were prioritized for COVID-19 vaccination in the beginning of 2021 [13]. In May 2021, all people aged 18–24 or 40–44 years were offered the first COVID-19 vaccine dose, and individuals in the age band 25–39 years came next in the national vaccination roll-out [13]. In Norway, the vaccination coverage with at least one dose of the COVID-19 vaccine was high among people of fertile age (88–92 %) during 2021 [14], [15].
When it comes to pregnant individuals, national health authorities and professional medical organizations worldwide started recommending mRNA COVID-19 vaccination in this population, approximately in the second half of 2021 [12], [16], [17], [18]. In August 2021, the Norwegian authorities recommended mRNA COVID-19 vaccination during the second and third trimesters, while for the first trimester, the risk of severe illness in the woman or of high exposure to the virus had to be considered. By January 2022, vaccination was recommended at any trimester [19]. Although COVID-19 vaccination in pregnancy has increased following these recommendations, including in Norway [20], low uptake remains a challenge in individuals with lower education or younger age, living alone, and with migrant background [20], [21], [22], [23]. In addition, the extent of vaccine uptake among pregnant individuals with underlying health risk for severe COVID-19, remains insufficiently studied [24].
Studying vaccine uptake in pregnancy only in relation to maternal sociodemographic and broadly defined migrant status, is insufficient for informing targeted vaccination campaigns and clinical counselling. Multiple studies have confirmed that lack of knowledge [25], unrealistic risk perceptions [26], and fear of adverse vaccine effects on the child are major drivers of COVID-19 vaccine hesitancy among pregnant individuals [27], [28], [29]. Yet, the role of adverse reproductive history and prior lived experience of poorer delivery outcomes is unclear. Because having a family member vaccinated against COVID-19 is related to lower vaccine hesitancy in pregnant individuals [24], understanding the specific contribution of paternal COVID-19 vaccination is critical.
The aim of this study is two-fold: (i) to describe the uptake of mRNA COVID-19 vaccine during pregnancy in Norway during a two-years’ time span and according to maternal risk for severe COVID-19 and asthma; (ii) to examine the association of a broad set of individual and familial factors, including prior adverse pregnancy outcomes and paternal COVID-19 vaccination, with vaccine uptake during pregnancy. mRNA COVID-19 vaccine (hereafter, COVID-19 vaccine) uptake was examined as receipt of any dose (broad definition) and as first ever dose (narrow definition) during pregnancy.
2. Materials and methods
2.1. Data sources
This study is based on data from Medical Birth Registry of Norway (MBRN), the Norwegian Immunisation Registry (SYSVAK), the Norwegian Surveillance System for Communicable Diseases (MSIS), Statistics Norway (SSB), the Population Registry, the Norwegian Control and Payment of Health Reimbursements Database (KUHR), and the Norwegian Patient Registry (NPR). Linkage across these registries were facilitated using unique personal identification numbers.
The MBRN is a population-based registry containing information on all births in Norway since 1967 [30]. It is based on mandatory notification of all pregnancies lasting more than 12 weeks and contains various information on both mother and infant(s). The SYSVAK is a national electronic immunisation register based on mandatory records of individual vaccination since birth and includes the specific code and name of each vaccine, and date of vaccination [31]. The MSIS includes mandatory records of all polymerase chain reaction (PCR) SARS-CoV-2 tests and their results based on reports from municipal health officers and laboratories. SSB is a central agency that provides official statistics, including demographics, housing conditions, education and income [32]. The Population Registry collects information about residents in Norway and their citizenships. The KUHR provides comprehensive records of medical diagnoses given in primary and secondary outpatient care; the diagnosis classification follows the International Classification of Diseases, version 10 (ICD-10) and the International Classification of Primary Care (ICPC-2/ICPC-2B). The NPR contains information on specialist outpatient and inpatient care, and diagnostic codes follow the ICD-10 classification [33].
2.2. Study population
We included all singleton pregnancies with gestational length greater than 12 weeks as registered in the MBRN with delivery date between 1-Jan-2021 and 31-Dec-2022. We excluded records with missing maternal identification number or missing gestational age, and individuals who received a non-RNA COVID-19 vaccine (see Fig. S1). The latter exclusion criterion was applied since the mRNA based vaccines by Pfizer-BioNTech and Moderna were those administered in the national vaccine roll-out [13]. To achieve the final study population for examining first dose vaccine uptake during pregnancy, we further excluded individuals with uptake of at least one mRNA COVID-19 vaccine pre-pregnancy start (n = 12,951).
2.3. COVID-19 vaccine uptake
Vaccine uptake during pregnancy was defined as receipt of at least one dose (broad definition) and as first ever dose (narrow definition) of any mRNA COVID-19 vaccine, as recorded in the SYSVAK, between the estimated last menstrual period date (LMP) and date of delivery. The LMP date was calculated by subtracting gestational length in days, ascertained via ultrasound, from the date of delivery. We did not consider non-mRNA COVID-19 vaccines as these were not primarily used in the vaccination program in Norway.
2.4. Individual and familial factors
We examined three sets of individual and familial factors, as described in detail in Table S1: (i) sociodemographic and life-style characteristics; (ii) maternal health, vaccination, and reproductive history; (iii) familial migration status and paternal COVID-19 vaccination. Maternal sociodemographic and life-style factors included: age, parity, marital and employment status, body mass index (BMI) at pregnancy start, and smoking before pregnancy, as ascertained in the MBRN. The SSB provided information on maternal educational level. Maternal health, vaccination and reproductive history included pre-existing epilepsy, whether the pregnancy was secondary to in-vitro fertility treatment (as ascertained in the MBRN), human-papilloma virus (HPV) and influenza vaccination within the past 10 years, as well as influenza vaccination in prior pregnancy. We defined pregnant individuals as having “low”, “moderate” or “high” risk for severe COVID-19 according to the Norwegian Institute of Public Health (NIPH) classification for vaccine prioritization [34]. The definition is based on diagnosis codes from the NPR and KUHR with a look-back period of five years before LMP (see Table S2). Asthma was not included in the risk grouping as done by the NIPH, but considered as separate factor, due to the inability of identifying uncontrolled asthma. The MBRN provided information on maternal history of pregnancy loss (miscarriage or stillbirth), prior foetus/child with any major congenital anomaly, prior caesarean section, or premature delivery in the past 10 years. Familial factors included paternal COVID-19 vaccination during the pregnancy window, parental migration status, and granular information about maternal primary citizenship (grouped into regions). We separately examined associations with SARS-CoV-2 infection, defined as at least one positive PCR test in the MSIS during the six months before LMP.
Up to 36.5 % of observations had missing data on at least one of the examined factors, mainly maternal occupation, education, and smoking status. Incomplete data on prior pregnancy outcomes and reproductive history, occupation, education, smoking status, paternal age, and migration status, were imputed using multiple imputation with chained equation (ten replications), assuming data were missing at random. The imputation model included vaccine, sociodemographic- and health-related variables [35], [36].
2.5. Statistical analyses
We conducted descriptive statistics and then three sets of forward stepwise modified Poisson regression models, clustered by the individual’s county of residency and adjusted by calendar time of delivery, with COVID-19 vaccine uptake as binary outcome variable. We fit separate models for the narrow and broad definition of vaccine uptake during pregnancy [37], [38]. In the former analysis, individuals with at least one dose of COVID-19 vaccine pre-pregnancy were excluded. We assessed separately (i) sociodemographic and life-style characteristics; (ii) maternal health, vaccination and reproductive history; and (iii) familial migration status and paternal COVID-19 vaccination, to avoid multicollinearity and to better distinguish the role of each variable set. Candidate variables were first selected based on a p-value of <0.20 in the univariable regression model. Selected variables were then included in a unique multivariable model, and variables with no role (p > 0.05) or yielding a change less than 20 % in the beta coefficients of the retained variables were removed [37]. The final multiple regression model included only statistically significant factors and those influencing substantially the effect estimate of the retained factors [37]. Associations with SARS-CoV-2 infection pre-pregnancy were examined separately, and the multivariable regression models were adjusted for maternal education and age. Results are presented as risk ratios (RR) with the corresponding 95 % Confidence Intervals (CI) for each factor examined. Data analyses was performed using STATA MP v.18.
In sub-analyses, we replicated the regression models separately in pregnancies with delivery date before and after the 18-Aug-2021, to appraise whether factors were consistently associated with any dose vaccine uptake before and after the favourable national recommendation of vaccination in pregnancy. The date 18-Aug-2021 marks major revisions in national recommendations favouring COVID-19 vaccination during 2nd and 3rd trimesters, as well as 1st trimester if the benefit outweighs the risks [18]. To better appraise the associations of prior pregnancy outcomes with vaccine uptake by parity, we replicated the regression model of “Maternal health, vaccination, and reproductive history” factors among multiparous pregnancies.
3. Results
The study population included 101,659 pregnant individuals with delivery date between 1-Jan-2021 through 31-Dec-2022 (Fig. S1), whereof 30.0 % (30,518/101,659) received at least one dose of the COVID-19 vaccine during pregnancy. Of the 30,518 individuals who received COVID-19 vaccine during pregnancy, 41.4 % (12,951/30,518) had received at least one dose pre-pregnancy (Table S3). Among those individuals with no COVID-19 vaccination pre-pregnancy, 19.8 % (17,567/88,708) had uptake of their first dose of the COVID-19 vaccine specifically during gestation. Most pregnant individuals had one (15,164/30,518: 49.7 %) or two (14,474/30,518: 47.4 %) cumulative doses taken specifically during gestation (Table S3).
Fig. S2 shows vaccine uptake by calendar time and date of delivery. Before 18-Aug-2021, vaccine uptake in pregnancy was 0.9 % and mainly in the third trimester (92.0 % of vaccinations). This proportion increased to 38.8 % in the rest of 2021 and to 48.9 % in 2022 (Table S4). In 2021, any dose vaccine uptake generally coincided with first dose uptake, but not in 2022 (Table S4). Overall, the gestational timing of any dose vaccine uptake was 32.1 % (n = 9,780) in the first trimester, 57.2 % (n = 17,442) in the second, and 35.9 % (n = 10,947) in the third trimester.
Table 1 shows the distribution of baseline individual and familial factors by any and first dose COVID-19 vaccine uptake during pregnancy. As shown in Table 2, only 28.8 % and 13.8 % of pregnant individuals with high risk for severe COVID-19 received respectively any dose or the first vaccine dose during gestation. Vaccine uptake was about 2–4 % higher in women with pre-existing asthma than in their counterpart.
Table 1. Baseline characteristics by mRNA COVID-19 vaccine uptake during pregnancy, as any dose and first dose uptake. Numbers are presented as n with % unless otherwise specified.
Empty Cell Vaccine uptake
during pregnancy,
any dose Vaccine uptake during pregnancy, first dose*
No
N = 71,141 Yes
N = 30,518 Yes
N = 17, 567
Sociodemographic and life-style characteristics
Maternal age in years; mean & SD 30.9 4.7 31.5 4.5 31.4 4.5
Nulliparous (yes) 29,721 41.8 13,609 44.6 7,668 43.7
Married/cohabiting (yes) 66,790 93.9 29,131 95.5 16,714 95.1
Missing 17 0.0 <5 – <5 –
Occupation
Active working/employed 48,186 67.7 23,081 75.6 13,063 74.4
Not working 10,829 15.2 2,876 9.4 1,834 10.4
Missing 12,126 17.0 4,561 14.9 2,670 15.2
Education
High school 14,561 20.5 5,410 17.7 3,237 18.4
Higher than high school 38,387 54.0 20,668 67.7 11,470 65.3
Lower than high school 11,232 15.8 3,098 10.2 1,971 11.2
Missing 6,961 9.8 1,342 4.4 889 5.1
Preconception BMI; mean & SD 25.9 5.1 25.1 5.1 25.0 5.1
Smoking pre-pregnancy (yes) 3,477 4.9 1,070 3.5 687 3.9
Missing 9,320 13.1 3,620 11.9 1,850 10.5
Maternal health, other vaccinations, and reproductive history
Preexisting epilepsy (yes) 435 0.6 193 0.6 113 0.6
Pregnancy secondary to IVF (yes) 2,810 3.9 1,453 4.8 840 4.8
HPV vaccine within 10 years pre-pregnancy (yes) 19,456 27.3 10,137 33.2 5,542 31.5
Influenza vaccine within 10 years pre-pregnancy (yes) 18,509 26.0 11,029 36.1 5,423 30.9
Influenza vaccine in prior pregnancy (yes) 6,710 9.4 4,320 14.2 2,254 12.8
Risk for severe COVID-19
Low 70,421 99.0 30,192 98.9 17,410 99.1
Moderate 532 0.7 250 0.8 127 0.7
High 188 0.3 76 0.2 30 0.2
Pre-existing asthma (yes) 4,560 6.4 2,338 7.7 1,272 7.2
History of miscarriage or stillbirth (yes) 17,361 24.4 7,328 24.0 4,385 25.0
Missing 762 1.1 138 0.5 64 0.4
Prior cesarean section (yes) 7,153 10.1 2,771 9.1 1,625 9.3
Prior pregnancy with major congenital anomaly (yes) 437 0.6 196 0.6 113 0.6
Missing 3,834 5.4 1,012 3.3 660 3.8
Prior premature delivery (yes) 1,682 2.4 678 2.2 382 2.2
Missing 3,915 5.5 1,037 3.4 674 3.8
Positive Sars-CoV-2 6 months pre-pregnancy (yes) 1,810 2.5 351 1.2 192 1.1
Familial migration status and paternal COVID-19 vaccination
Maternal primary country of citizenship
Norway 52,618 74.0 26,146 85.7 14,888 84.7
Scandinavia 1,526 2.1 742 2.4 445 2.5
West/South Europe 1,158 1.6 560 1.8 310 1.8
Eastern Europe 6,912 9.7 979 3.2 608 3.5
Middle East 1,226 1.7 183 0.6 87 0.5
North America and Oceania 297 0.4 155 0.5 94 0.5
South and Central America 362 0.5 154 0.5 316 1.8
Africa 3,264 4.6 477 1.6 55 0.3
East and North-East Asia 230 0.3 96 0.3 55 0.3
North-Central Asia 537 0.8 82 0.3 285 1.6
South-East Asia 1,159 1.6 448 1.5 305 1.7
South and South-West Asia 1,852 2.6 496 1.6 119 0.7
Maternal migration status
Born in Norway, both parents from Norway 43,709 61.4 22,985 75.3 13,058 74.3
Born in Norway or abroad, at least one parent from Norway 3,785 5.3 1,972 6.5 1,129 6.4
Migrated to Norway 21,906 30.8 5,108 16.7 3,139 17.9
Born in Norway from migrant parents 1,739 2.4 453 1.5 241 1.4
Missing <5 − − − − −
Paternal migration status
Born in Norway, both parents from Norway 43,679 61.4 22,927 75.1 13,047 74.3
Born in Norway or abroad, at least one parent from Norway 3,538 5.0 1,828 6.0 1,054 6.0
Migrated to Norway 20,082 28.2 4,706 15.4 2,883 16.4
Born in Norway from migrant parents 1,457 2.0 439 1.4 238 1.4
Missing 2,385 3.4 618 2.0 345 2.0
Paternal COVID-19 vaccination during pregnancy (yes) 22,421 31.5 27,124 88.9 16,612 94.6
Paternal age; mean & SD 33.5 5.5 33.7 5.6 33.7 5.7
Abbreviations: SD = Standard deviation; IVF = in-vitro fertility treatment.
Table 2. Uptake of mRNA COVID-19 vaccine during pregnancy by maternal risk for severe COVID-19 or pre-existing asthma.
Empty Cell Risk for severe COVID-19
Low Moderate High
n (95 CI) n (95 CI) n (95 CI)
Any dose vaccine uptake during pregnancy (yes) 30,192 30.0 (29.7–30.3) 250 32.0 (28.8–35.3) 76 28.8 (23.6–34.5)
First dose vaccine uptake during pregnancy (yes) 17,410 19.8 (20.0–20.1) 127 19.3 (16.4–22.5) 30 13.8 (9.9–19.0)
Empty Cell Pre-existing asthma
No Yes
n (95 CI) n (95 CI)
Any dose vaccine uptake during pregnancy (yes) 28,180 29.7 (29.4–30.0) 2,338 33.9 (32.8–35.0)
First dose vaccine uptake during pregnancy (yes)* 16,295 19.7 (19.4–19.9) 1,272 21.8 (20.8–22.9)
Abbreviations: CI = Confidence Interval.
Fig. 1 shows which factors among sociodemographic and life-style characteristics (Panels A-B), and maternal health, vaccination, and reproductive history (Panels C-D) were associated with any dose and first dose vaccine uptake during pregnancy. Fig. 2 shows associations with familial migration status and paternal COVID-19 vaccination. Results of the univariate analyses are shown in Tables S5 and S6. Lower education and not working/unemployed status were consistently associated with a decreased likelihood of vaccine uptake in pregnancy, both as any and first dose. Maternal health risk for severe COVID-19, history of prior pregnancies with congenital anomaly or miscarriages were not associated with any dose vaccine uptake in pregnancy. Only history of caesarean section and premature delivery was consistently associated with a negligible lower likelihood of vaccine uptake, using both definitions. Paternal COVID-19 vaccination during the pregnancy window was strongly associated with greater vaccine uptake in pregnancy, and the magnitude of this association was larger for first dose uptake. As shown in Fig. 2, different familial migration and main citizenship statuses were strongly associated with vaccine uptake in pregnancy, using both definitions. Maternal SARS-CoV-2 infection in the six months pre-pregnancy was consistently associated with a substantial lower likelihood of uptake of any dose (RR: 0.31, 95 % CI: 0.26, 0.37) or first dose (RR: 0.32, 95 % CI: 0.26, 0.41).
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Fig. 1. Associations of sociodemographic and life-style characteristics (Panel A for any dose, Panel B first dose), maternal health, vaccination, and reproductive history (Panel C for any dose, Panel D for first dose) with COVID-19 vaccine uptake in pregnancy. Abbreviations: RR = Risk Ratio; CI = Confidence Interval. All multivariable models are adjusted by calendar time of childbirth, and for clustering by maternal region of residency. The reference categories in Panels A-B include: “high-school education” for educational level, and the counterparts of the other factors (e.g., “married/cohabiting” is reference group for “not married/cohabiting”). In Panels C-D, the reference categories are “no” for all factors (e.g. “No prior premature birth”). Non_COVID-19 vaccinations ever before and history of adverse outcomes are measured within ten years before pregnancy start.
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Fig. 2. Associations of familial migration status and paternal COVID-19 vaccination with vaccine uptake during pregnancy as any dose (Panel A) and first dose (Panel B) Abbreviations: RR = Risk Ratio; CI = Confidence Interval. The multivariable model is adjusted by calendar time of childbirth, and for clustering by maternal region of residency. The reference categories are “Norwegian primary citizenship”, “Born in Norway from two Norwegian parents”, and “No Paternal COVID-19 vaccine”. Paternal COVID-19 vaccine was measured during the pregnancy window.
Factors such as smoking before pregnancy, IVF, and uptake of other non-COVID-19 vaccines were not consistently associated with any vaccine dose uptake in terms of direction of the association and/or effect size, before and after the positive national recommendations towards COVID-19 vaccination in pregnancy (Table S7). Fig. S3 shows associations between maternal health, vaccination, and reproductive history factors and vaccine uptake, as ever and first dose, among multiparous pregnancies.
4. Discussion
This study reports increasing rates of COVID-19 any dose vaccine uptake in pregnancy, spanning from less than 1 % among deliveries before mid Aug-2021, to 38.8 % in the rest of 2021, and to 48.9 % in 2022. During the overall period, only three out of ten individuals with high risk for severe COVID-19 received at least one COVID-19 vaccine dose while being pregnant, and this estimate decreased to 14 % for first dose uptake. Being at high-risk for severe COVID-19 did not correlate with greater vaccine uptake in pregnancy, but maternal pre-existing asthma did so (9–10 % higher likelihood). We found no evidence that prior miscarriage or pregnancy with congenital anomaly were related to lower vaccine uptake. Only history of caesarean section and premature delivery were negatively associated with COVID-19 vaccine uptake, albeit the effect size of these associations was negligible, especially among multiparous individuals. Paternal COVID-19 vaccination during the pregnancy window emerged as major factor associated with vaccine uptake in pregnancy, and the magnitude of this association was exceptionally large for first dose uptake. Individual maternal factors such as smoking, being unemployed, multiparity, lower education, and younger age were only moderately associated with lower COVID-19 vaccine uptake during pregnancy, whilst the association magnitude was substantial for SARS-CoV-2 infection in the six months pre-pregnancy (68–69 % reduced likelihood). Familial and individual migrant status, and maternal main citizenship from the Middle East, Africa, Eastern Europe, or North-Central Asia, were associated with a considerable decreased likelihood of vaccine uptake while being pregnant.
This study extends prior literature by identifying multiple factors at individual and familial level associated with COVID-19 vaccine uptake during pregnancy and reports novel uptake rates by maternal underlying risk for severe COVID-19 during a two-years period. Our over time increasing rates of COVID-19 vaccine uptake by pregnant individuals align with prior research including data from Norway up to May 2022, and reflect trust in the national vaccine recommendations [20], [39], [40]. Any dose COVID-19 vaccine uptake largely coincided with first dose uptake by pregnant individuals in the period between 18-Aug-2021 and end of 2021, which is encouraging. The new emerging knowledge about the favourable reproductive safety of prenatal COVID-19 vaccine exposure may have favoured greater acceptance of COVID-19 vaccination in pregnancy over time [11], [41].
The observed low rate of vaccine uptake among pregnant individuals with high risk for severe COVID-19 was consistent for any and first dose vaccine uptake, which is somewhat worrisome. Pregnant individuals with high-risk also had lower likelihood of first dose vaccine uptake than their peers with no/low risk, which is an unexpected result. It is possible that the applied definition for severe COVID-19 risk group [34] may not be fully applicable to childbearing aged individuals as most of high-risk disorders, e.g. organ transplantation and cancer, are rare in this population. Prior research in Norway and Sweden [20] found individuals with pre-pregnancy comorbidities, as broad unique classification, to be more likely to get vaccinated during pregnancy than their peers, albeit the effect size was negligible (8–12 % higher likelihood). The disorders included in our high-risk classification do not fully coincide with those applied by Örtqvist et al. [20], which may explain the discrepant results. Furthermore, we considered pre-existing asthma as a stand-alone disorder, and this disorder was associated with greater vaccine uptake. Prioritizing high-risk individuals for vaccination is crucial due to their increased susceptibility to severe illness, and this also applies to pregnant individuals. In possible future pandemics, vaccination campaigns should better emphasize which specific high-risk disorders are critical for the pregnant and childbearing aged populations.
The substantial association between greater vaccine uptake in pregnancy and paternal COVID-19 vaccination during the pregnancy window deserves attention. A prior study [24] showed that pregnant individuals who had friend or family member vaccinated against COVID-19 had 84 % reduced odds of reporting vaccine hesitance than their counterparts, and partner support is critical in the context of pharmacotherapy in pregnancy [27], [42]. Paternal migration status was an additional familial factor associated with lower vaccine uptake. Taken together, these data highlight the importance of vaccine educational campaigns for couples, and call for an active involvement of fathers at the phase of clinical counselling, to facilitate the decision-making process regarding benefits and risks of prenatal vaccination.
Although maternal unrealistic risk perceptions of vaccine exposure and fears of adverse effects on the child [43], [26], [27], [28], [29] were identified as key factors associated with vaccination hesitancy, we found no evidence that prior lived experience of miscarriage or pregnancy with congenital anomaly led to lower vaccine uptake. This result could be attributable to trust towards national authorities and to the provided emerging knowledge about the safety of COVID-19 vaccination for maternal-child health. Only history of prior caesarean section or premature delivery were linked to lower COVID-19 vaccine uptake in our analyses, albeit the effect size was negligible, especially in the analysis restricted to multiparous women. It is possible that vaccine recommendations by policy makers and national authorities did not specifically address possible risk of vaccination in relation to these two outcomes, as they are more subtle than miscarriage or congenital anomaly [44]. Overall, these data suggest that maternal adverse pregnancy history is not strongly related to negative perceptions and attitudes towards vaccination in pregnancy, at least in Norway [43]. Efforts should be made to investigate whether this result also applies to other national and societal context, because this is critical knowledge for providing tailored vaccination counselling to couples who are most hesitant.
This study supports prior established associations between lower COVID-19 vaccine uptake in pregnancy among individuals being smokers, having lower education and income, younger age, multiparity, migrant status, and specific citizenships/ethnicities [20], [24], [45], [46]. Our granular findings by maternal main citizenship support the need of vaccination campaigns tailored specifically to pregnant individuals from African countries, the Middle East, Eastern Europe, or North-central Asia. In line with prior data [24], [46], this study shows that uptake of other vaccines, e.g. against influenza, is proxy of general positive attitude and trust towards vaccination, and this is linked to greater COVID-19 vaccine uptake rates even by pregnant individuals. Unlike other studies but also in line with other investigations [27], [47], SARS-CoV-2 infection in the six months pre-pregnancy appeared to be a major factor associated with lower vaccine uptake by pregnant individuals in Norway. This may be explained by uncertainties regarding durability of natural immunity [48] coupled to maternal safety concerns about prenatal exposure to the COVID-19 vaccine [27].
5. Strengths and limitations
The study is based on multiple, nation-wide health registry data in Norway linked to the MBRN, which covers all deliveries since gestational week 12. The mandatory registration of COVID-19 vaccination in the SYSVAK minimizes risk of misclassification of vaccine uptake; since the SYSVAK records all vaccine doses received independently of pregnancy, the study could differentiate between any dose and first vaccine uptake in pregnant individuals. The comprehensive availability of clinical diagnoses from primary and secondary healthcare, coupled to obstetric records from the MBRN, enabled us to adequately classify maternal risk groups for severe COVID-19 and asthma. Information on prospective fathers, and the availability of ten years historical data for mothers, allowed us to explore a vast array of familial and individual factors associated with vaccine uptake in pregnancy, including granular details on maternal main citizenship. Lastly, we used multiple imputation to minimize risk of bias due to missing data [49].
This study also has some limitations that need consideration when interpreting the results. We used receipt of a vaccine dose as proxy of vaccine acceptance, which may not fully measure attitude/beliefs toward vaccination. The study could not explore the role of emotional, social, and religious factors as these are not measured in our national registries, although these may be important determinants of vaccine uptake [27]. Political and logistical aspects related to the distribution of the COVID-19 vaccine in the various counties in Norway was not measured in the study; to address changes of vaccination recommendation, we repeated the association and descriptive analyses for the period before and after 18-Aug-2021 [34]. Vaccine doses given abroad need manual retrospective registration in SYSVAK, leading to uncertainty about how many pregnant individuals received vaccines overseas without official records in Norway. However, this risk is considered as minimal, given the necessity of vaccine registration during the study period. The MBRN does not provide granular information about the type of occupation in pregnant individuals, and thereby we could not examine the role of healthcare worker status on vaccine uptake in pregnancy. Although we examined separately three sets of individual and familial factors and their standard errors in the final multivariate models were assessed as satisfactory, we cannot rule out the risk for multicollinearity or for interaction effects.
6. Conclusion
In this registry-linkage study, we observed over time increasing rates of COVID-19 vaccine uptake during pregnancy, and any dose uptake largely coincided with first dose uptake in the period between 18-Aug-2021 through end of 2021. However, COVID-19 vaccination remained low among pregnant individuals with high risk for severe COVID-19. Paternal COVID-19 vaccination during the pregnancy window, SARS-CoV-2 infection pre-pregnancy, individual and familial migration status, and specific maternal main citizenships, emerged as important factors associated with COVID-19 vaccine uptake during pregnancy. We found no evidence that prior miscarriage or pregnancy with congenital anomaly were related to lower vaccine uptake. These findings are useful for the design of targeted intervention and educational vaccination campaigns for couples in possible future pandemics, to facilitate an informed, evidence-based vaccine uptake by pregnant populations.
Ethics approval
The Regional Committee for Medical and Health Ethics of South/East Norway (no. 285687) approved the study. The Norwegian Data Protection Services for research and the University of Oslo approved the Data Protection Impact Assessment – DPIA (no. 341884).
CRediT authorship contribution statement
Jovan Elyass: Writing – original draft, Formal analysis, Data curation. Anteneh Desalegn: . Nhung T.H. Trinh: Writing – review & editing, Supervision, Methodology, Data curation, Conceptualization. Saima Orangzeb: Writing – review & editing, Validation, Data curation. Mahmoud Zidan: Writing – review & editing, Validation, Data curation. Hedvig Nordeng: Writing – review & editing, Validation, Methodology. Angela Lupattelli: Writing – review & editing, Writing – original draft, Validation, Supervision, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization.
Declaration of competing interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Angela Lupattelli reports financial support was provided by European Union. This work is part of the VERDI project (101045989) which is funded by the European Union. Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union or the European Health and Digital Executive Agency. Neither the European Union nor the granting authority can be held responsible for them. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
This work is part of the VERDI project (101045989) which is funded by the European Union. We are grateful to all the participating families in Norway who are part of the health registries and made this research possible.
Funding
This work is part of the VERDI project (101045989) which is funded by the European Union. Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union or the European Health and Digital Executive Agency. Neither the European Union nor the granting authority can be held responsible for them.
Contributions of authors
AL, AD and NTHT conceived the study. AL applied for the study data. AL and JE performed the data analysis, and AD contributed to data curation. AL and JE wrote the initial draft. JE, AD, NTHT, SO, MZ, HN, and AL contributed to data interpretation and to writing the final manuscript. AL obtained funding. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.
Appendix A. Supplementary material
The following are the Supplementary data to this article:
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mmc1.
Data availability
All relevant data are within the paper and its Supporting Information files. No additional data are available.
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16 | https://www.nature.com/articles/s41392-022-00996-y | Signal Transduction and Targeted Therapy
volume 7, Article number: 146 (2022)
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With the constantly mutating of SARS-CoV-2 and the emergence of Variants of Concern (VOC), the implementation of vaccination is critically important. Existing SARS-CoV-2 vaccines mainly include inactivated, live attenuated, viral vector, protein subunit, RNA, DNA, and virus-like particle (VLP) vaccines. Viral vector vaccines, protein subunit vaccines, and mRNA vaccines may induce additional cellular or humoral immune regulations, including Th cell responses and germinal center responses, and form relevant memory cells, greatly improving their efficiency. However, some viral vector or mRNA vaccines may be associated with complications like thrombocytopenia and myocarditis, raising concerns about the safety of these COVID-19 vaccines. Here, we systemically assess the safety and efficacy of COVID-19 vaccines, including the possible complications and different effects on pregnant women, the elderly, people with immune diseases and acquired immunodeficiency syndrome (AIDS), transplant recipients, and cancer patients. Based on the current analysis, governments and relevant agencies are recommended to continue to advance the vaccine immunization process. Simultaneously, special attention should be paid to the health status of the vaccines, timely treatment of complications, vaccine development, and ensuring the lives and health of patients. In addition, available measures such as mix-and-match vaccination, developing new vaccines like nanoparticle vaccines, and optimizing immune adjuvant to improve vaccine safety and efficacy could be considered.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly infectious positive-sense, single-stranded RNA virus that spreads rapidly worldwide. The resulting infection, known as coronavirus disease 2019 (COVID-19), can cause several symptoms, such as cough, fever, chest discomfort, and even respiratory distress syndrome in severe cases.1,2 As of March 28, 2022, there were 480,905,839 confirmed cases of COVID-19 worldwide, and 6,123,493 patients died of viral infection or other related complications (https://coronavirus.jhu.edu/).
Effective and safe vaccines are essential to control the COVID-19 pandemic.3,4 Several studies have reported the progress in developing SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) vaccines.5,6,7,8 The preclinical data of these candidate vaccines partly saved the time for developing the current marketed SARS-CoV-2 vaccines and would provide platforms for the future widespread application of SARS-CoV-2 vaccines. The World Health Organization (WHO) classifies COVID-19 vaccines that have been analyzed or approved for clinical trials into the following categories: inactivated vaccine, live attenuated, vector, RNA, DNA, protein subunit, and virus-like particle (VLP) vaccines.
Animal experiments play a critical role in vaccine development, including evaluating the safety and protective efficacy, determining the injection schedule, and establishing the effective dosage. Small animals, especially rodents, are the foundation of biological and immunological studies in vaccine development.9,10 Generally, rats, mice, guinea pigs, rabbits, and other animals can be used as animal models to evaluate candidate vaccines’ immunogenicity, tolerance, and safety. However, due to species differences between these animals and humans, similar biological effects may not be produced after vaccination. The studies of non-human primates (NHPs) are helpful in understanding and illustrating human immune responses, owing to similar innate and adaptive immune responses.9 Many reagents used to identify human immune molecules also show similar effects on NHPs. In addition to preclinical trials (animal experiments), clinical trials are essential for developing vaccines. The safety, dosage, and tolerance of vaccines are assessed in the Phase I trial, efficacy and adverse effects are investigated in Phase II and III trials.
Vaccination is a pivotal means to prevent the spread of SARS-CoV-2 and ultimately quell the pandemic. However, vaccine performance is affected by the constant acquisition of viral mutations due to the inherent high error rate of virus RNA-dependent RNA polymerase (RdRp) and the existence of a highly variable receptor-binding motif in the spike (S) protein.11,12,13 We have previously noted that the B.1.351 (Beta) variant significantly reduces the neutralizing geometric mean antibody titers (GMT) in recipients14 of mRNA and inactivated vaccines and may cause breakthrough infections.15 The reduction in neutralization activity has raised concerns about vaccine efficacy. Thus, rapid virus sequence surveillance (e.g. the identification of E484 mutations in new SARS-CoV-2 variants16) and vaccine updates are crucial.
This review systematically introduces the existing COVID-19 vaccine platforms, analyzes the advantages and disadvantages of the vaccine routes, and compares the efficacy and safety of various vaccines, including the possible complications and different protective efficacies in special populations. Moreover, given the continuous mutation of SARS-CoV-2, we analyze the neutralization activities of various vaccines according to the latest research and propose ideas to improve and optimize existing vaccines, including changing the administration route, adopting more vaccination strategies, and applying more vaccine development methods (Fig. 1).
The milestones of COVID-19 vaccine development. With the maturity of vaccine platforms, more and more COVID-19 vaccines have entered clinical trials and been approved for emergency use in many countries. However, the appearance of VOCs has brought great challenges to existing COVID-19 vaccines. By changing the administration route, the protection provided by vaccines can be enhanced, and more vaccination strategies are applied to cope with VOCs. In addition, more vaccine development methods are applied, such as developing polyvalent vaccines and improving adjuvant and delivery systems. These enormous changes form a milestone in the COVID-19 vaccine progress compared with post-years
The immune response elicited by the body after vaccination is termed active immunity or acquired immunity. In this process, the immune system is activated. CD4+ T cells depend on antigen peptide (AP)-MHC (major histocompatibility complex) class II molecular complex to differentiate into helper T cells (Th cells). CD8+ T cells depend on AP-MHC class I molecular complex and differentiate into cytotoxic T lymphocytes (CTL). B cells are activated with the help of Th cells to produce antibodies. After antigen stimulation, B and T cells form corresponding memory cells to protect the body from invading by the same pathogen, typically for several years. The development of COVID-19 vaccines is mainly based on seven platforms, which can be classified into three modes according to the antigen category.17,18 The first mode is based on the protein produced in vitro, including inactivated vaccines (inactivated SARS-CoV-2), VLP vaccines (virus particles without nucleic acid), and subunit vaccines (S protein or receptor-binding domain (RBD) expressed in vitro). The second model is based on the antigen gene expressed in vivo, including viral vector vaccines (using replication-defective engineered viruses carrying the mRNA of S protein or RBD), DNA vaccines (DNA sequences of S protein or RBD), and mRNA vaccines (RNA sequences of S protein or RBD). The third mode is the live-attenuated vaccine. These vaccines can induce neutralizing antibodies to protect recipients from viral invasion. Moreover, some mRNA and viral vector vaccines can induce Th1 cell responses19,20 and persistent human germinal center responses,21,22 which provide more efficient protection. In addition, memory cells induced by COVID-19 vaccines play an important role in vaccine immunity.23,24,25
ChAdOx1 nCoV-19 (AZD1222, viral vector vaccine), NVX-CoV2373 (protein subunit vaccine), mRNA-1273(mRNA vaccine), BNT162 (including BNT162b1 and BNT162b2, mRNA vaccine), and other COVID-19-candidate vaccines were reported to induce Th1 cell responses.19,26,27,28 After recognition of the AP-MHC class II complex and T-cell receptor (TCR), CD4+ T cells distributed in peripheral lymphoid organs can differentiate into Th1 cells, which secrete various cytokines, such as interleukin 2 (IL-2), and simultaneously upregulate the expression of related receptors (IL-2R). After IL-2 binds to IL-2R, T-cell proliferation and CD8+ T-cell activation are promoted. Both CD4+ and CD8+ T-cell responses have been observed in Ad26.COV-2-S recipients.29,30 The activated CD8+ T cells differentiate into CTLs to further induce cellular immunity. In addition, Th1 cells can secrete interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α).31 The former also induces the differentiation of CD4+ T cells and enhances the intensity of the immune response (Fig. 2).
Vaccine-induced Th1 cell response. Some COVID-19 vaccines would induce Th1 cell responses. After recognition of the AP-MHC class II complex and T-cell receptor (TCR), CD4+ T cells distributed in peripheral lymphoid organs can differentiate into Th1 cells, which secrete various cytokines, such as interleukin 2 (IL-2), and simultaneously upregulate the expression of related receptors (IL-2R). Through IL-2 and IL-2R, T-cell proliferation and CD8+ T-cell activation are promoted, CD8+ T-cell can differentiate into cytotoxic T lymphocytes (CTLs) through the activation, producing perforin and other cytokines, which may improve the efficacy of vaccines
When the effector cells (Th cells and CTLs) clear the antigen, the signal maintaining the survival and proliferation of T cells no longer exists, the cell responses are reduced, and the immune system returns to homeostasis. However, antigen-specific memory T cells are crucial for long-term protection, typically formed during T-cell-mediated immunity.23
In addition to T-cell responses, follicular helper T cells (Tfh cells) induced by mRNA vaccines can trigger effective SARS-CoV-2 antigen-specific germinal center B-cell (GC B-cell) responses (Fig. 3).21,22,32 Upon the interaction of T cells and B cells, some activated Th cells move to the lymphatic follicles and then differentiate into Tfh cells. Activated B cells proliferate and divide in lymphatic follicles to form the germinal center. With the help of Tfh cells, high-frequency point mutations occur in the variable region of the antibody gene of GC B cells, and antibody category transformation occurs, finally forming memory B cells and plasma cells, which can produce high-affinity antibodies. In one study, the GC B-cell response of BALB/c mice peaks between 7 and 14 days after the injection of the mRNA vaccine based on full-length S protein. However, the ability of the RBD-based mRNA vaccine to induce GC B-cell response was poor, indicating that the full-length S protein may play an important role in vaccine-induced GC B-cell response.22 In addition, a strong SARS-CoV-2 S protein-binding GC B-cell response was detected in lymph node fine-needle aspirates of BNT162b2 (based on full-length S protein) vaccine recipients. The GC B-cell response was detected after the first dose and greatly enhanced after the second dose.21
Vaccine-induced germinal center response. Some COVID-19 vaccines would induce a germinal center response. Upon the interaction of T cells and B cells, some activated Th cells move to the lymphatic follicles and then differentiate into Tfh cells. Activated B cells proliferate and divide in lymphatic follicles to form the germinal center. With the help of Tfh cells, high-frequency point mutations occur in the variable region of the antibody gene of GC B cells, and antibody category transformation occurs, finally forming memory B cells and plasma cells, which can produce high-affinity antibodies
The continuous existence of GC B cells is the premise for inducing long-lived plasma cells.33 GC B cells that are not transformed into plasma cells will form memory B cells, and memory B cells are activated rapidly with the help of memory Th cells when encountering the same antigen and then produce plenty of antigen-specific antibodies. It can be concluded that the sustained GC B-cell response induced by the vaccine can secrete potent and persistent neutralizing antibodies and trigger strong humoral immunity.21
The COVID-19 vaccine-induced memory cell responses can induce Th1 and sustained germinal center responses, triggering strong cellular and humoral immunity. In this process, antigen-specific memory T cells and B cells are usually formed, significant for long-term protection (Fig. 4).23 Unlike initial T-cell activation, the activation of memory T cells no longer depends on antigen-presenting cells and can induce a stronger immune response. Most memory B cells enter the blood to participate in recycling and are rapidly activated to produce potent antibodies upon encountering the same antigen. The mRNA-1273 and BNT162b2 induced higher-level production of antibodies and stronger memory B-cell response.24 Moreover, memory B cells could also be detected in patients who have recovered from COVID-19, and a single dose of mRNA vaccine can induce the memory B-cell response to reach the peak in these patients,24,34 indicating that both previous infection and vaccination can induce memory cell responses.
Vaccine-induced memory cell response. In the Th1 and GC B-cell processes, antigen-specific memory T cells and memory B cells are usually formed. Unlike initial T-cell activation, the activation of memory T cells no longer depends on antigen-presenting cells and can induce a stronger immune response. Most memory B cells enter the blood to participate in recycling and are rapidly activated to produce potent antibodies upon encountering the same antigen
According to WHO data released on March 28, 2022, 153 vaccines have been approved for clinical trials, and 196 vaccines are in preclinical trials. These vaccines mainly include inactivated vaccines (accounting for 14% of the total), live attenuated vaccines (1%), viral vector vaccines (replication and non-replication; 17% of the total), RNA vaccines (18%), DNA vaccines (11%), protein subunit vaccines (34%), and VLP vaccines (4%) (https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines). As of March 28, 2022, a total of ten vaccines (including three India vaccines), including inactivated vaccines, viral vector vaccines, mRNA vaccines, and protein subunit vaccines, have been approved for emergency use by WHO (Fig. 5) (https://extranet.who.int/pqweb/vaccines/vaccinescovid-19-vaccine-eul-issued). The features, advantages, and disadvantages of different COVID-19 vaccines are shown in Tables 1, 2.
A timeline of critical events in the COVID-19 vaccine development progress. WHO has approved the emergency use of ten vaccines (including three India vaccines, COVISHIELD, COVAXIN, and COVOVAX). Vaccination plays a critical role in protecting people from SARS-CoV-2 infections. However, the appearance of VOCs brought big challenges to the efficacy of approved COVID-19 vaccines. These events were summarized and displayed in the form of a timeline
Inactivated vaccines are produced by inactivating the in vitro cultured viruses using chemical reagents.35 The vaccine can maintain the integrity of virus particles as immunogens.17 Wang et al. introduced the manufacturing process of the SARS-CoV-2 inactivated vaccine. In this process, SARS-CoV-2 from throat swabs of COVID-19 patients were used to infect Vero cells, and the HB02 strain with the strongest replication ability was selected from three isolated strains (HB02, CQ01, and QD01). After purification, the P1 library was obtained by subculturing in Vero cells with adaptive culturing, subculturing, and amplification. The seventh-generation virus, BJ-P-0207, was selected as the original strain of the COVID-19 inactivated vaccine,36,37 and then β-propiolactone was used to inactivate the virus.37
An advantage of inactivated vaccines is using the entire virus as an immunogen. Compared with vaccines based on the SARS-CoV-2 S protein or partial protein fragments, such as RBD, inactivated vaccines can induce a wider range of antibodies against more epitopes.17 In addition, the overall adverse reaction rate of inactivated vaccines in clinical trials is low, and no deaths have been reported in clinical trials, indicating their good safety.38,39,40 However, the production of inactivated vaccines are limited because the production of such vaccines must be carried out in biosafety level-3 laboratory or higher biosafety level.3
The BBIBP-CorV and CoronaVac inactivated vaccines approved by WHO are independently developed in China. A total of 21 candidate COVID-19 inactivated vaccines have been approved for clinical trials as of March 28, 2022 (https://www.who.int/publications/m/item/draft-landscape-of-COVID-19-candidate-vaccines).
Live attenuated vaccines are based on the virus obtained by reverse genetics or adaptation to reduce virulence and are used as non-pathogenic or weakly pathogenic antigens.17 Currently, the main manufacturing processes include codon pair deoptimization (CPD) and virulence gene knockout.3,41,42 Wang et al. and Trimpert et al. reported the CPD-based methods to modify SARS-CoV-2 genes genetically. In their studies, amino acid (aa) 283 deletion was introduced into the S protein, and the furin site was also deleted to attenuate the virulence of the virus but retain its replication ability.43,44
Through the CPD-based method, most of the viral amino acid sequences can be retained and induce extensive responses, including innate, humoral, and cellular immunity against viral structural and nonstructural proteins in the recipient.3,43 The extensive response is unlikely to diminish in efficacy due to antigen drift. In addition, live attenuated vaccines can induce mucosal immunity through nasal inhalation to protect the upper respiratory tract.3 In contrast, other types of vaccines, such as inactivated and mRNA vaccines, are usually administered intramuscularly and only protect the lower respiratory tract. However, after weakening the virulence gene of the virus, virulence may be restored during replication and proliferation in the host. Thus, the reverse genetic method remains challenging.
Currently, there is no WHO-approved COVID-19 live attenuated vaccine for emergency use. Two candidate COVID-19 live attenuated vaccines, COVI-VAC and MV-014-212, have been approved for clinical trials as of March 28, 2022 (https://www.who.int/publications/m/item/draft-landscape-of-COVID-19-candidate-vaccines).
Viral vector vaccines are based on replication-attenuated engineered viruses carrying genetic material of viral proteins or polypeptides.35 The particular antigen is produced by host cells after immune transduction.17 Zhu et al. reported the manufacturing process of a viral vector vaccine based on human adenovirus type-5 (Ad5). In this process, the signal peptide gene and optimized full-length S protein gene based on the Wuhan-Hu-1 strain were introduced into a human Ad5 engineering virus with E1 and E3 gene deletions to produce a vector expressing S protein.45 A recombinant chimpanzee Ad25 vector expressing full-length S protein was used to prepare the ChAdOx1 nCoV-19 vaccine.46 Recombinant vectors based on the combination of human Ad5 and Ad26 were also used to prepare the Sputnik V vaccine.47,48 In addition, the Ad26.COV-2-S vaccine developed by Janssen is based on the S protein modified by the Ad26 expression gene, with the deletion of the furin site and the introduction of aa986-987 mutations.48 Besides adenovirus, vesicular stomatitis virus can also be modified and used to produce the COVID-19 vaccine, inducing a stronger humoral immune response via intranasal and intramuscular routes.49
Except for inactivated vaccines and partially attenuated vaccines, there is no need to deal with live SARS-CoV-2 in manufacturing other types of vaccines (e.g., viral vector, protein subunit, mRNA, DNA, and VLP vaccines), so the manufacturing process of these vaccines is relatively safe.3 In addition, viral vector vaccines can induce Th1 cell responses,29,50 thus inducing strong protective effects. However, adenovirus-based viral vector vaccines can induce complications, especially thrombocytopenia. Thus, it is necessary to pay attention to the platelet levels of the relevant recipients in case of thrombocytopenia.51,52 Although adenovirus is not easily neutralized by pre-existing immunity, the pre-existing Ad5 antibodies (46.4, 80, 78, 67, 64, 60, 45% and less than 30% of the population with neutralizing antibodies titers for Ad5 of >1:200 in China, India, Kenya, Thailand, Uganda, South Africa, Sierra Leone, and America, respectively,26,53) these pre-existing adenoviruses antibodies in the serum may reduce the immunogenicity of such vaccines. Thus an additional flexible dose might be needed as a solution.26,54
The WHO has approved two viral vector vaccines (Ad26.COV-2-S and AZD1222). As of March 28, 2022, 25 candidates’ clinical trials for COVID-19 viral vector vaccines have been approved, with four using replicating vectors and 21 using non-replicating vectors. Moreover, 3 viral vectors (a type of nonreplicable vector and two types of replicable vectors) + antigen-presenting cells and a vaccine based on the bacterial antigen-spore expression vector are also approved for clinical trials (https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines).
Protein subunit vaccines are based on systemically expressed viral proteins or peptides using various cell-expressing systems, such as bacteria, yeasts, insects, and mammalian cells (such as human embryonic kidney cells).17,35,55,56,57 These vaccines can be divided into recombinant S protein and RBD vaccines.3 The ZF2001 vaccine adopts the dimer form of the S protein RBD of SARS-CoV-2 as an antigen.58 Another subunit vaccine (NVX-CoV2373) adopts a full-length S protein with a pre-fusion conformation containing a furin site mutation, and the modified S protein was produced by the Sf9 insect cell expression system. The S protein with a pre-fusion conformation is usually metastable and easily transformed into the post-fusion conformation. The pre-fusion conformation can be stabilized by mutating two residues (K986 and V987) to proline.17,59 In addition, a recombinant vaccine comprising residues 319–545 of the RBD was manufactured using insect cells and a baculovirus expression system, and the purity of the recombinant protein was more than 98% by adding a GP67 signal peptide in the expression system.60
The protein subunit can also induce Th1 cell responses.31 In addition, NVX-CoV2373 can induce higher titer neutralizing antibodies than inactivated and Ad5 viral vector vaccines.3 However, the S protein has a large molecular weight, and the expression efficiency of the S protein is relatively low compared with that of RBD. Although the RBD has a small molecular weight and is easy to express, it lacks other immune epitopes on the S protein and thus is prone to antigen drift.3
For emergency use, the WHO has authorized only one COVID-19 protein subunit vaccine (NVX-CoV2373). Furthermore, 51 candidate COVID-19 protein subunit vaccines were approved for clinical trials on March 28, 2022 (https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines).
DNA vaccines are based on viral antigens encoded by a recombinant plasmid. Viral proteins or polypeptides are produced by transcription and translation processes in host cells.17 Smith et al. synthesized the INO-4800 COVID-19 DNA vaccine based on a previously prepared MERS-CoV vaccine.61 The main steps are as follows: (1) acquisition of the S protein sequence from GISAID; (2) addition of the N-terminal IgE leading sequence; (3) optimization of the IgE-Spike sequence with algorithms to enhance its expression and immunogenicity and synthesize the optimized sequence; (4) ligation of the fragment into the expression vector pGX0001 after digestion.62,63 Brocato et al. constructed the DNA encoding SARS-CoV-2 S protein into the pWRG skeleton plasmid by cloning the gene with optimized human codons, and this skeleton plasmid was used to produce a DNA vaccine against hantavirus.64
Compared with mRNA vaccines, DNA vaccines have higher stability and can be stored for a long time.65 Escherichia coli can be used to prepare plasmids with high stability.3 However, the immunogenicity of the DNA vaccine is low. Furthermore, different injection methods, such as intramuscular or electroporation injection, also affect the vaccine’s efficacy.3
There is no COVID-19 DNA vaccine authorized by the WHO for emergency use. Sixteen candidate COVID-19 DNA vaccines have been approved for clinical trials on March 28, 2022 (https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines).
mRNA vaccines are based on mRNA encapsulated by vectors (usually lipid nanoparticles), viral proteins, or polypeptides produced during the translation process in the host cells.17,35 In addition to mRNA itself, the 5′ Cap and 3′ Poly (A) also play important roles in regulating the efficiency and stability of translation.66,67 At present, mRNA vaccines usually adopt the Cap 1 structure (m7GpppN1mp, with an additional 2′ methylated hydroxyl compared with Cap 0), improving translation efficiency.66 There are two ways of mRNA tailing: use traditional polyadenylate tails to add the 3′ tail of poly (A) or design the DNA template with a proper length of poly (A), and the latter can obtain a length-controlled poly (A) tail.67,68 Corbett et al. introduced a manufacturing process for the mRNA-1273 vaccine. The optimized mRNA encoding SARS-CoV-2 S-2P protein with stable pre-fusion conformation was synthesized (2 P represents double proline mutations of the K986 and V987 residues mentioned above). The synthesized mRNA sequence was purified by oligo-dT affinity purification, and encapsulated in lipid nanoparticles.69 The BNT162b2 vaccine also adopts a similar mRNA encoding S-2P,17,70 whereas the BNT162b1 vaccine adopts the mRNA encoding RBD and fuses the trimer domain of T4 fibrin to the C-terminus. Furthermore, a proper delivery system like LNP can protect mRNA against the degradation of nuclease71 and further enhance the efficacy of mRNA vaccines. The capsulation of mRNA with LNP can effectively transfer mRNA into cells and induce a strong immune response; thus is widely used in most mRNA vaccines, including BNT162b2 and mRNA-1273.71,72 In addition, other delivery systems like lipopolyplexes, polymer nanoparticles, cationic polypeptides, and polysaccharide particles also provide unlimited possibilities for the improvement of mRNA vaccine .72,73
The mechanism of mRNA vaccine-induced immunity is similar to that of the DNA vaccines. Both BNT162b1 and BNT162b2 vaccines transmit the genetic information of the antigen rather than the antigen itself,3 so they only need to synthesize the corresponding RNA of viral proteins, improving the production speed.35 In addition, mRNA vaccines can induce strong Th1 cell responses and GC B-cell responses and simultaneously produce long-lived plasma cells and memory cells, continuously eliciting SARS-CoV-2 neutralizing antibodies.21,24 However, mRNA vaccines may cause complications, especially myocarditis,54,74,75, and have a higher storage requirement due to the instability of mRNA.3
The WHO has approved two types of mRNA vaccines: mRNA-1273 and BNT162b2, and a total of 28 candidate COVID-19 mRNA vaccines have been approved for clinical trials as of March 28, 2022 (https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines).
VLP vaccines are based on noninfectious particles consisting of in vitro-expressed viral structural proteins and decorated viral polypeptides on the surface.74 Tan et al. used Spy Tag technology to modify the SARS-CoV-2 RBD on the surface of protein particles by forming covalent iso-peptide bonds based on the previous protein nanoparticle platform and obtained an RBD-Spy VLP.76 Moreover, a self-assembled VLP vaccine based on the expression of modified full-length S proteins, including R667G, R668S, R670S, K971P, and V972P mutations, has also been developed using a plant expression system.77
VLP vaccines do not contain viral genomes, and plant-based VLP vaccines have the potential of oral delivery vaccines.65 By loading a variety of antigens, such as the RBD from different variants on the protein particles, neutralizing antibodies against multi-immune epitopes can be induced to improve the neutralizing activity against SARS-CoV-2 variants. However, the manufacturing process of the VLP vaccine is more complex, and no relevant data was published for human clinical trials.
There is no COVID-19 VLP vaccine authorized by the WHO for emergency use. Six candidates' COVID-19 VLP vaccines have been approved for clinical trials as of March 28, 2022 (https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines).
Several SARS-CoV-2 animal models have been developed, including mice expressing human ACE2,78,79,80 SARS-CoV-2-adaptive mouse,81,82 ferret,83 hamster,84,85 and NHP models.86,87,88 Although mice can be infected with SARS-CoV-2 by transferring the human ACE2 gene or designing a virus-adapted mouse, no mouse model can simulate all the characteristics of human COVID-19, especially pulmonary vascular disease, hyperinflammatory syndrome, observed in adults and children, respectively.10 The hamster model can simulate serious COVID-19 diseases. Syrian hamsters show mild to severe symptoms 1–2 days after nasal infection,89,90 and progressive weight loss and dyspnea. The NHP model can reflect mild-to-moderate SARS-CoV-2 infection and can be used to test many candidate vaccines. However, due to different adjuvants and vaccine dosages, the use of serum-neutralizing antibody titer as a direct basis for comparing the efficacy of different vaccines is still limited. In addition, different analytical methods, such as 50% plaque reduction neutralization test (PRNT50), 80% plaque reduction neutralization test (PRNT80), and enzyme-linked immunosorbent assay (ELISA), may also affect the final experimental results. These data can objectively show the efficacy of each vaccine. Here, we summarize the immunogenicity, neutralizing activity, and cell response data from animal experiments for the BBIBP-CorV, CoronaVac, AZD1222, Ad26.COV-2-S, NVX-CoV2373, mRNA-1273, and BNT162b2 vaccines (Fig. 6).
A timeline of the preclinical and clinical trials of approved COVID-19 vaccines. Preclinical and clinical trials play important roles in evaluating the safety and protective efficacy of COVID-19 vaccines. The information of preclinical to clinical trials of several WHO-approved COVID-19 vaccines are provided in the form of a timeline, and partial Phase III clinical trials’ data were also displayed to show the total efficacy
Immunogenicity testing of BBIBP-CorV was performed in BALB/c mice, rabbits, and guinea pigs.36 The animals were classified into three groups according to the doses: high (8 μg), medium (4 μg), and low (2 μg). All dosages produced good immunogenicity, and the serum conversion rate reached 100% on day 21 after immunization. In different dosage groups of BALB/c mice, the immunogenicity of the three-dose group was significantly higher than the two- and single-dose groups. In the NHP experiment, after vaccination, the neutralizing GMTs in rhesus monkeys were 1:860 in the high-dose group and 1:512 in the low-dose group, respectively, indicating BBIBP-CorV can effectively prevent SARS-CoV-2 infection in rhesus monkeys.
The PiCoVacc inactivated vaccine, also known as CoronaVac, is highly immunogenic in BALB/c mice.37 After the injection of PiCoVacc, the serum S-specific antibody level of mice was ten times higher than that of convalescent serum obtained from COVID-19 patients. PiCoVacc could induce high RBD antibodies, 30 times higher than the induced NTD antibodies. The neutralizing antibody titer in rhesus monkeys was 1:50 in the third week after one dose of PiCoVacc, similar to the titers in the convalescent serum of COVID-19 patients. One week after the third dose of PiCoVacc, viral infection was induced through intranasal and organ routes. The viral load of all vaccinated animals decreased significantly 3–7 days after infection, indicating that PiCoVacc played an important anti-SARS-CoV-2 role in the NHP model.
Compared with BBIBP-CorV and CoronaVac, viral vector vaccines and mRNA vaccines can simultaneously induce T-cell responses,46,48,69,70 mainly a Th1 cell response, while Th2 responses are related to vaccine-induced respiratory diseases, and were not detected. Viral-specific neutralizing antibodies were detected in all BALB/c mice following inoculation with ChAdOx1 nCoV-19 (AZD1222). On day 14, after the first or second dose, the neutralizing antibody titers in rhesus monkey serum were 1:5 to 1:40 (single dose) and 1:10 to 1:160 (two doses). In addition, cytokines, including IL-4, IL-5, and IL-13, in rhesus monkey serum after a single dose or two doses injection were low, indicating the safety of ChAdOx1 nCoV-19 in NHPs.
Another viral vector vaccine, Ad26.COV-2-S (Ad26-S.PP) induced similar neutralizing antibody titers in the NHP model.48 RBD-specific neutralizing antibodies were detected in 31 of 32 rhesus monkeys (96.9%) 2 weeks after Ad26-S.PP inoculation and the induced titers were 1:53 to 1:233 (median 1:113) 4 weeks after vaccination. In addition, Ad26-S.PP also induced S-specific IgG and IgA responses in bronchoalveolar lavage (BAL) obtained from rhesus monkeys, indicating that Ad26-S.PP has a protective effect on rhesus monkeys’ upper and lower respiratory tracts. 6 weeks after vaccination, 1.0 × 105 50% tissue culture infectious dose (TCID50) of SARS-CoV-2 was challenged in intranasal and tracheal routes, and 17 of 32 rhesus monkeys inoculated with Ad26-S.PP were completely protected, and no viral RNA was detected in BAL or nasal swabs, indicating that Ad26-S.PP protects the upper and lower respiratory tracts in the NHP model.
Besides Ad26.COV-2-S, another protein subunit vaccine NVX-CoV2373, also showed the protection efficacy of both upper and lower respiratory tracts in the cynomolgus macaque model.91 The vaccine induced a remarkable level of anti-S IgG in mice with the titers of 1:84,000-1:139,000 on the 15th day after the single injection.59 Meanwhile, NVX-CoV2373 also elicits multifunctional CD4+ and CD8+ T-cell responses. In the NHP model, the serum neutralizing antibody titers produced after the second dose of 2.5, 5, 25 μg vaccine could achieve 1:17,920-1:23,040 CPE100, which was 7.1–10 times higher than those in convalescent serum. SARS-CoV-2 was challenged in the upper and lower respiratory tract routes after NVX-CoV2373 vaccination, and 91.6% (11 in 12) immunized animals were free of infection. No viral RNA was detected in the nasal swabs, indicating the broader protection of NVX-CoV2373.
The mRNA-1273 vaccine is most immunogenic in the NHP model. The GMTs of rhesus monkey serum obtained from injection dosages of 10 and 100 μg were 1:501 and 1:3,481, respectively, which were 12 times and 84 times higher than that of human convalescent serum.69 It has been shown that mRNA-1273 induces a strong S-specific neutralizing antibody response. Rhesus monkeys also showed a dose-dependent Th1 cell response after the injection of mRNA-1273, which was similar to the phenomenon observed after the injection of ChAdOx1 nCoV-19. Intranasal and tracheal routes administered all rhesus monkeys 1.0 × 106 TCID50 of SARS-CoV-2 in the 4th week after the second dose. Four days after infection, only low-level viral RNA in two of eight animals in the 10-μg-dose group and one of eight in the 100-μg-dose groups could be detected, indicating good antiviral activity of mRNA-1273 in the NHP model.
BNT162b1 and BNT162b2 (especially the former) also showed high immunogenicity in BALB/c mice while lower than mRNA-1273.70 On day 28, after single-dose injection, the serum neutralizing antibody titers of mice with BNT162b1 and BNT162b2 reached 1:1056 and 1:296, respectively. Additionally, both vaccines induced high CD4+ and CD8+ T-cell responses. In the NHP model, the neutralizing antibody titers of rhesus monkey serum obtained from 100 μg-dose 14 days after vaccination with the second dose of BNT162b1 and BNT162b2 were 1:1714 and 1:1689, respectively, which were significantly higher than those in the convalescent serum of COVID-19 patients (1:94). All rhesus monkeys were administered 1.05 × 106 plaque-forming units of SARS-CoV-2 by intranasal and tracheal routes on 41–55 days after the second dose of BNT162b1 or BNT162b2. On the third day after infection, viral RNA was detected in the BAL of two of the six rhesus monkeys injected with BNT162b1. Viral RNA was not detected in BAL of the BNT162b2 injected monkeys at any time point.
mRNA, viral vector, and protein subunit vaccines showed higher induced-antibody titers than inactivated vaccines and could induce Th1 cell responses. These vaccines mainly induced IgG production and showed a protective effect on the upper respiratory tract. However, the Ad26.S-PP and NVX-CoV2373 vaccines exerted a protective effect on both the upper and lower respiratory tracts. In addition, all injection groups showed significant virus clearance ability after the virus challenge, demonstrating the protection provided by these vaccines in NHPs. Furthermore, all experimental animals injected with the vaccine showed no pathological changes in the lungs and normal tissues, providing strong support for follow-up clinical trials.
The safety and effectiveness of vaccines are evaluated in preclinical trials. Clinical trials of candidate vaccines can be carried out only after the relevant data meet the standards for such trials. Ten candidate vaccines have been approved for Phase IV clinical trials. They include three inactivated vaccines (BBIBP-CorV, WIBP COVID-19 vaccine, and CoronaVac), three viral vector vaccines (AZD1222, Ad5-nCoV, and Ad26.COV-2-S), one protein subunit vaccine (MVC-COV1901), and three mRNA vaccines (mRNA-1273, BNT162b2, and mRNA-1273.351) (https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines). Data from Phase I, I/II, II, II/III, and III trials and some data from Phase IV clinical trials have been released (Fig. 6). Here, the neutralization efficacy, adverse reactions, and cell responses, mainly Th1 cell responses of some vaccines in different clinical trial stages, are discussed. Because of the different adjuvants used and different dosages of the vaccines, the titer of serum neutralizing antibodies cannot be used as a direct reflection of neutralization ability. Moreover, different analysis methods also affect the trial results.
Sinopharm announced the results of a randomized, double-blind, placebo-controlled Phase I/II clinical trial of the BBIBP-CorV vaccine (ChiCTR2000032459).38 The Phase I and Phase II trials included 192 and 448 healthy aged 18–80 participants, respectively. All participants were negative for serum-specific SARS-CoV-2 IgG or IgM. In the Phase I trial, the vaccine group was injected with 2–8 μg BBIBP-CorV on day 0 and day 28. The control group was injected with two doses of normal saline placebo containing aluminum hydroxide adjuvant. In the Phase II trial, the vaccine group was divided into single-dose (day 0, 8 μg) and two doses (day 0, day 14, 21, 28; 4 μg at each time). In the Phase II trial, on day 28, after the second dose in the two-dose group or after the single dose in the single-dose group, serum neutralizing antibody titers against SARS-CoV-2 were detected based on PRNT50. The antibody titer in the single-dose group was 1:14.7, and the titers range of the two-dose group were 1:169.5-1:282.7. The serum titers after two doses on days 0 and 21 were the highest, indicating that two doses of vaccination could induce a higher neutralizing antibody level. In addition, the Phase I trial showed that the serum titer of subjects >60 years old after 28 days of the second dose was less than that of subjects aged 18–59, indicating that the elderly may need higher doses or adjuvants with stronger immunogenicity. None of the subjects in Phase I/II trials displayed severe adverse reactions within 28 days after vaccination. BBIBP-CorV was demonstrated safe for humans. Currently, several Phase IV clinical trials of the vaccine are underway (NCT04863638, NCT05075070, NCT05075083, NCT05104333, NCT05105295, and NCT05104216) (https://clinicaltrials.gov).
Huang et al. showed that the neutralization ability of serum neutralizing antibody induced by both BBIBP-CorV inactivated vaccine and ZF2001 subunit vaccine to the Beta variant was reduced by 1.6 times.92 It is worth noting that serum neutralization activity obtained from BBIBP-CorV homologous booster group and BBIBP-CorV/ZF2001 heterologous booster group were increased, while 80% of samples still failed to neutralize B.1.1.529(Omicron) variant.93 The results showed that it is necessary to closely monitor the neutralization efficacy of the vaccine against variants, especially those with strong immune escape ability, such as Beta and Omicron, and update the sequence of seed strain in time.94
Sinovac conducted several randomized, double-blind, placebo-controlled Phase I/II clinical trials for the CoronaVac vaccine (NCT04551547, NCT04352608, NCT04383574).39,95,96 Two groups received 3–6 μg of the CoronaVac vaccine, and participants aged 3–17 years received 1.5–3 μg. The control group received the same amount of aluminum hydroxide diluent. None of the participants had a history of SARS-CoV-2 exposure or infection, their body temperature was <37 °C, and none was allergic to the vaccine components. The serum neutralizing antibody titer of the subjects was analyzed with a minimum quadruple dilution using microcytosis. The vaccine induced higher titers in children and adolescents groups in the Phase II trial (3 μg adolescent group, 1:142.2; 6 μg adult group, 1:65.4; 6 μg elderly group, 1:49.9). One case of severe pneumonia unrelated to the vaccine was reported in the placebo group in children and adolescents, one case of acute hypersensitivity after the first dose of injection was reported in the adult group, and seven cases of severe adverse reactions were reported in the elderly group. The remaining adverse events were mild or non-toxic. These findings indicated that CoronaVac could be used in children and adolescents, and it is safe for children, adolescents, and adults.
Furthermore, Sinovac performed Phase III (NCT04582344) and IV clinical trials of CoronaVac for patients with autoimmune diseases and rheumatism (NCT04754698).40,97 In the Phase III trial, 1413 participants, were analyzed for immunogenicity; 880 of 981 (89.7%) serum samples in the vaccine group were positive for RBD-specific antibodies, compared to 4.4% in the control group. The titer of neutralizing antibodies in 387 sera samples in the vaccine group ranged from 1:15–1:625 (1:15, 16%; 1:75, 38.7%; 1:375, 21%), indicating that most vaccine recipients could produce neutralizing antibodies after vaccination. No deaths or grade IV adverse events occurred in the Phase III trial. In the Phase IV clinical trial, using the above analysis based on microcytosis, the serum neutralizing antibody titer of vaccines with rheumatism was only 1:27 6 weeks after the second dose, which was lower than healthy subjects (1:67). These findings indicated that the dose should be increased for individuals with immune diseases, or the immune adjuvant should be replaced to improve protection. Seven Phase IV clinical trials of the vaccine are in progress (NCT04911790, NCT04953325, NCT04962308, NCT04993365, NCT05107557, NCT05165732, and NCT05148949) (https://clinicaltrials.gov).
According to the study of Chen Y and colleagues,98 serum-neutralizing activity against D614G, B.1.1.7(Alpha), and B.1.429 variants after inoculation with CoronaVac were equally effective, while B.1.526, P.1(Gamma) and Beta significantly reduced serum neutralization efficiency. Fernández et al. tested serum neutralization in 44 individuals after two doses of the CoronaVac vaccine. Alpha and Gamma variants could escape from the neutralization of antibodies induced by the vaccine, with escape rates of 31.8 and 59.1% in the subjects, respectively.99 Estofolete et al.100 reached a similar conclusion that although the CoronaVac vaccine cannot completely inhibit the infection caused by the Gamma variant, the vaccination can help to reduce patients’ clinical symptoms and the rate of death and hospitalization. The Omicron variant can escape neutralizing antibodies elicited by BNT162b2 or CoronaVac, bringing a challenge to existing vaccines.101
Phase I/II clinical trials of AZD1222 were divided into two stages (NCT04324606).50,102 In the first stage, 1077 healthy subjects aged 18–55 years with negative laboratory-confirmed SARS-CoV-2 infection or COVID-19 symptoms were recruited. Ten individuals were injected with two doses of 5 × 1010 viral particles (VPs), the remainders were injected with a single dose of 5 × 1010 VPs. Those in the placebo group were injected with a licensed meningococcal group A, C, W-135, and Y conjugate vaccine (MenACWY). Serum neutralizing antibody levels were evaluated using a standardized ELISA protocol. The median level of serum samples on day 28 after one dose was 157 ELISA units (EU). The median level of 10 individuals injected with the enhancer dose was 639 EU on day 28 after the second dose, indicating that two injection doses can induce higher neutralizing antibodies. In the second stage of the trial, 52 subjects who had been injected with the first dose received a full-dose (SD) or half-dose (LD) of AZD1222(ChAdOx1 nCoV-19) vaccine on days 28 and 56. The titers of 80% virus inhibition detected by the microneutralization assay (MNA80) were 1:274 (day 0, 28 SD), 1:170 (day 0, 56 LD), and 1:395 (day 0, 56 SD) respectively. The highest titer was produced after the full-second dose injection on day 56. In addition, the AZD1222 vaccine can also induce Th1 biased CD4+ and CD8+ T-cell responses and further promote cellular immunity. No serious adverse reactions were reported in any phase of the trial, and prophylactic paracetamol treatment reduced the rate of mild or moderate adverse reactions.103
In a single-blind, randomized, controlled Phase II/III trial of AZD1222 (NCT04400838),104 participants were divided into three groups based on age: 18–55, 56–69, and >70 years. The 18–55 years old group was allocated two low doses (2.2 × 1010 VPs)/two standard doses (3.5–6.5 × 1010 VPs) ChAdOx1 nCoV-19 and placebo at 1:1 and 5:1, respectively. The 56–69-year-old group was injected with a single dose of ChAdOx1 nCoV-19, a single dose of placebo, two doses of ChAdOx1 nCoV-19, and two doses of placebo (3:1:3:1, respectively). The >70-year-old group was administered a single dose of ChAdOx1 nCoV-19, a single dose of placebo, two doses of ChAdOx1 nCoV-19, and two doses of placebo (5:1:5:1, respectively). All placebo groups received the aforementioned MenACWY vaccine. MNA80 was used to evaluate the titer of serum neutralizing antibodies. The titer of the low-dose group ranged from 1:143 to 1:161, and that of the standard-dose group ranged from 1:144 to 1:193, indicating that ChAdOx1 nCoV-19 can induce high-level neutralizing antibody in all age groups and that two doses of injection can produce higher antibody levels. Thirteen serious adverse events were reported as of October 26, 2020, and none related to vaccine injection. Phase IV clinical trials of the vaccine are in progress (NCT04760132, NCT04914832, NCT05057897, and NCT05142488) (https://clinicaltrials.gov).
Supasa et al. tested the neutralizing effect of AZD1222 on the Alpha variant. GMTs of serum neutralizing antibody decreased by 2.5 times on day 14 and 2.1 times on day 28 after the second dose, while no immune escape was observed.105 Subsequently, the neutralization effect of AZD1222 on the Beta variant was tested. On day 14 or 28 after the second dose, the GMTs of the subjects’ serum neutralizing antibodies against the Beta variant were approximately nine times lower than that of the Victoria variant (an early Wuhan-related viral isolate).106 In addition, the serum neutralizing antibody GMTs of AZD1222 subjects against the Delta variant decreased by ~4 times compared with the wild type.107 On the 28th day after the booster dose, the neutralization ability against Omicron was reduced by about 12.7-fold compared with Victoria and 3.6-fold with B.1.617.2 (Delta).108 These findings indicate that the Omicron and Beta variants have stronger immune escape ability than the Alpha and Delta variants. Monitoring vaccine neutralization ability should be highlighted, and existing vaccines should be optimized or strengthened to maintain vaccine efficacy for emerging SARS-CoV-2 variants.
Janssen performed Phase I and Phase I-II clinical trials of Ad26.COV-2-S (NCT04436276).29,30 A total of 25 healthy adults aged 18–55 with negative nasopharyngeal PCR and serum IgG results participated in the Phase I trial. The participants were equally allocated to receive two doses of low-dose (5 × 1010 VPs) Ad26.COV-2-S (low-dose/low-dose, LL), one dose of low-dose vaccine and one dose of placebo (low-dose/placebo, LP), two doses of high-dose (1 × 1011 VPs) (high-dose/high-dose, HH), one dose of high-dose vaccine and one dose of placebo (high-dose/placebo, HP), or two doses of placebo (placebo/placebo, PP). The placebo group received a 0.9% sodium chloride solution. The GMTs of serum neutralizing antibody based on the inhibition of 50% of pseudovirus (ID50) were detected 14 days after the second dose. The ID50 values were 1:242 (LL), 1:375 (LP), 1:449 (HH), and 1:387 (HP) in the vaccine groups. Moreover, Ad26.COV-2-S induced CD4+ and CD8+ T-cell responses, simultaneously inducing cellular immunity. Adverse events after vaccination were not evaluated in this study.
In the Phase I-IIa clinical trial, 805 healthy adults aged 18–55 and >65 years were equally divided into LL, LP, HH, HP, and PP groups (low-dose: 5 × 1010 VPs, high-dose: 1 × 1011 VPs). On day 71 or 72 (2 weeks after the injection of the second dose), serum neutralizing antibody GMT based on 50% virus inhibition (IC50) of the 18–55-year-old group was 1:827 (LL, day 72), 1:1266 (HH, day 72), 1:321 (LP, day 71), and 1:388 (HP, day 71). On day 29, the serum GMT of the participants injected with a single dose of low-dose or high-dose vaccine in the >65-year-old group was 1:277 or 1:212, respectively. These findings indicated that two injection doses significantly improved antibody titers and enhanced protection. On day 15, 76–83% of the participants in the 18–55 age group and 60–67% of participants in the >65 age group had a Th1 biased CD4+ T-cell response, consistent with the results observed in the Phase I trial. After the first dose, most of the reported local adverse events were grade 1 or 2. The most common event was injection site pain. These collective findings indicated that Ad26.COV-2-S is safe. Four Phase IV clinical trials of the vaccine are ongoing (EUCTR2021-002327-38-NL, NCT05030974, NCT05037266, and NCT05075538) (https://www.ncbi.nlm.nih.gov, https://clinicaltrials.gov).
Alter et al. systematically evaluated the neutralization efficacy of the Ad26.COV-2-S vaccine against SARS-CoV-2 variants.109 Pseudovirus neutralization test results showed the neutralization titer of the antibody induced by the Ad26.COV-2-S to Gamma variant was 3.3 times lower than the wild type. The neutralization of the Beta variant was five times lower than that of the wild type. The live virus neutralization test showed that the neutralization activity of this variant (Beta) dropped approximately ten times in titers. Garcia Beltran et al. found the neutralization activity of serum samples from Ad26. COV-2 vaccinees against the Omicron variant was reduced by 17 times.110
NVX-CoV2373 is a protein subunit vaccine based on the full-length S protein of pre-fusion conformation (rSARS-CoV-2). Relevant Phase I-II clinical trial (NCT04368988) data has been released.31 A total of 131 healthy men and non-pregnant women aged 18–59 years were enrolled. All participants had no history of COVID-19 infection and had a low risk of COVID-19 exposure. Among them, six participants were assigned 5 μg/25 μg rSARS-CoV-2 + Matrix-M1 at a ratio of 1:1 as an initial safety measure and were observed for 48 h. The remaining 125 participants received 9% saline (placebo) as group A, two doses of 25 μg rSARS-CoV-2 without adjuvant Matrix-M1 as group B, two doses of 5 μg rSARS-CoV-2 + 50 μg Matrix-M1 as group C, two doses of 25 μg rSARS-CoV-2 + 50 μg Matrix-M1 as group D, and one dose of 25 μg rSARS-CoV-2 + 50 μg Matrix-M1 as group E, at a ratio of 1:1:1:1:1, respectively. ELISA-based neutralization test was used to detect the antibody titers on the 14th day after the second dose. Group C and D showed the most efficacy with the titers of 1:3906 and 1:3305, respectively, four to six times more than convalescent serum. In addition, T-cell responses were also induced and boosted by the adjuvant Matrix-M1. No serious adverse event was reported in this trial except a subject terminated the second dose due to mild cellulitis.
Results of the Phase III clinical trial of NVX-CoV2373 have also been released.111 This trial included 16,645 healthy men, non-pregnant women, and people with chronic diseases aged 18–84 without COVID-19 infection and immune disease history. The recipients received two doses of 5 μg NVX-CoV2373 or equivalent placebo (0.9% saline) at a ratio of 1:1. The rate of COVID-19 or SARS-CoV-2 infection 7 days after the vaccination was ~6.53 per thousand in the vaccine group versus 63.43 per thousand in the control group, indicating an overall efficacy of 89.7%. Based on the analysis of subgroups, the effectivity of NVX-CoV2373 in people aged over 65 was 88.9%, and the efficacy against the Alpha variant was 86.3%. The overall rate of adverse events among the recipients was higher in the vaccine group than in the placebo group (25.3 vs. 20.5%). The proportion of serious adverse events was similar in both groups, at about 1%, with one person in the vaccine group reporting severe myocarditis. The vaccine and placebo groups reported one death caused by respiratory failure and one sepsis caused by COVID-19 infection.
A clinical trial was further performed to evaluate the efficacy of NVX-CoV2373 in AIDS patients, in which the Beta variant infected most people. The results indicated that this vaccine showed 60.1% efficacy in HIV-negative participants, indicating that the NVX-CoV2373 vaccine was efficacious in preventing COVID-19.112
Similar to the viral vector vaccines, mRNA vaccines, especially mRNA-1273, also induced Th1 biased CD4+ T-cell responses in clinical trials.28,113 Moderna performed a Phase I clinical trial of mRNA-1273 (NCT04283461). In the first stage, 45 healthy adults aged 18–55 received two doses of 25, 100, and 250 μg mRNA-1273 at a ratio of 1:1:1. In the second stage, 40 subjects aged >56 years were injected with two doses of 25 and 100 μg vaccine at a ratio of 1:1. The interval between all injections was 28 days. There was no control group. PRNT50 was used to detect the titers of serum neutralizing antibodies in different age groups 14 days after the second dose, and the titers were 1:343.8 (100 μg, 18–55 years old), 1:878 (100 μg, 56–70 years old), and 1:317 (100 μg, >70 years old). The vaccine induced potent neutralizing antibodies in different age groups, and the highest titer was induced in the 56–70 age group. After the first dose, 23 participants aged 18–55 (51.1%) reported systemic adverse reactions. All the adverse reactions were mild or moderate. After the second dose, three subjects reported serious adverse reactions. No serious adverse events occurred in the group aged over 56 years.
Moderna also performed a Phase III clinical trial of the mRNA-1273 vaccine. The number of participants was 30,420, aged over 18 years and had no history of SARS-CoV-2 infection. Subjects were injected with two doses of mRNA-1273 vaccine (100 μg) at a 28-day interval or with normal saline at a 1:1.114 From the first day to November 25, 2020, 196 cases of COVID-19 were diagnosed by preliminary analysis, with 11 cases in the vaccine group and 185 cases in the placebo group, indicating a 94.1% effectiveness of mRNA-1273. After the first dose, adverse events occurred in 84.2% of the participants in the vaccine group, and 88.6% of the participants in the vaccine group reported adverse events after the second dose. The adverse events were mainly graded 1 or 2.
Furthermore, there were three deaths in the placebo group (one each from intraperitoneal perforation, cardiopulmonary arrest, and systemic inflammatory syndrome) and two deaths in the vaccine group (one from cardiopulmonary arrest and suicide). Although the death rate was low and unrelated to vaccination, the effects of nucleic acid vaccines on cardiopulmonary and other functions still need to be further studied. Phase IV clinical trials of the mRNA-1273 vaccine are currently underway (NCT04760132, NCT05060991, NCT04952402, NCT05030974, NCT05047718, NCT05075538, and NCT05075538) (https://clinicaltrials.gov).
The mRNA-1273 vaccine is still effective for the Alpha variant, but its neutralization effect on the Beta variant is reduced. The pseudovirus neutralization test showed that the antibody titers of mRNA-1273 against the Beta variant were 6.4 times lower than that of the D614G mutant.115 McCallum et al. tested the neutralization efficacy of mRNA-1273 against the B.1.427/B.1.429 variant and found that the neutralizing antibody GMTs induced by the vaccine decreased by 2–3.5 times compared to the wild type.116 Furthermore, more than 50% of mRNA-1273 recipients’ serum failed to neutralize the Omicron variant, with the GMTs reduced by about 43 times.110,117
Phase I and III clinical trials of the BNT162b2 mRNA vaccine have also been performed (NCT04368728).117 The Phase I clinical trial performed by Pfizer-BioNTech involved two candidate vaccines, BNT162b1 encoding RBD and BNT162b2 encoding the full-length of S protein. This trial included 185 healthy adults aged 18-55 and 65–85. With 15 individuals per group, they were divided into 13 groups (seven groups aged 18–55 and six groups aged 65–85) and inoculated with two doses of 10/20/30 μg BNT162b1 or BNT162b2, and an additional group aged 18–55 received a single dose of 100 μg BNT162b2. Twelve individuals in each group were vaccinated with BNT162b1/BNT162b2, and three were vaccinated with a placebo. The 50% neutralization titers were determined on the 14th day after the second dose, ranging from 1:33 to 1:437 (BNT162b1) and 1:81 to 1:292 (BNT162b2). BNT162b1 and BNT162b2 both induced high-level production of antibodies. The local adverse reactions caused by these two vaccines were similar, mainly pained at the injection site. However, the overall rate of adverse events of BNT162b2 was low, with less use of antipyretic analgesics and these findings indicated that BNT162b2 is safer.
The Phase III clinical trial involved 43,548 participants aged 16 years and over, who were injected with two doses of BNT162b2 (30 μg at an interval of 21 days) or placebo at a ratio of ~1:1.118 At least 7 days after the second dose, eight cases of COVID-19 were observed in the vaccine group, while 162 cases of COVID-19 were observed in the placebo group, indicating the effectiveness of 94.6%. Mild-to-moderate pain at the injection site within 7 days of the first dose of BNT162b2 was the most common local adverse reaction. Less than 1% of all subjects reported severe pain, and none of the participants reported grade 4 local adverse reactions. Two BNT162b2 vaccinees died (one from arteriosclerosis and one from cardiac arrest), four placebo subjects died (two from unknown causes, one from hemorrhagic stroke, and one from myocardial infarction). None of the deaths was related to the vaccine or placebo. Like the mRNA-1273 vaccine, heart disease also occurred in the BNT162b2 vaccine injection group, indicating that the mRNA vaccine needs to be strictly evaluated. Phase IV clinical trials of the BNT162b2 vaccine are currently underway (NCT04760132, NCT05060991, NCT04961229, NCT04775069, NCT04878211, NCT04952766, NCT04969250, NCT05047718, NCT05057169, NCT05057182, and NCT05075538) (https://clinicaltrials.gov).
Collier et al. tested the neutralization efficacy of the sera of single-dose BNT162b2 vaccine subjects against the Alpha variant.119 Ten of 23 samples showed a decrease in neutralization efficacy, with a maximum decrease of about six times. Supasa et al. showed that the neutralization activity of the BNT162b2 vaccine against the Alpha variant decreased by 3.3 times.105 Subsequently, the researchers further tested the neutralization activity of BNT162b2 against the Beta variant and found that the GMTs of neutralizing antibodies decreased by 7.6 times.106 In addition, the neutralization activity of the BNT162b2 vaccine against Kappa, Delta, B.1.427, and B.1.429 variants was reduced by at least two times (Kappa and Delta), 1.2 times (B.1.427), and 1.31 times (B.1.429).120 Although the Delta variant has high infectivity and can cause immune escape, Liu et al. reported that BNT162b2 retained neutralizing activity against the delta variant.121 In the study carried out by Cameroni E and colleagues, the neutralization activity of BNT162b2 booster-dose recipients’ serum significantly increased, but its neutralization capability against the Omicron variant still decreased by at least fourfold compared with the Wuhan-Hu-1 strain.122
Although clinical trials can reflect the effectiveness of vaccines, the outcomes are partly dependent on the status of participants. Thus, the data were not very objective. The real-world study can help to establish clinical trial evidence and provide information for adjusting the vaccination strategy. Here, we summarize several current real-world studies to support these vaccines’ efficacy further. A study on the effectiveness of mRNA vaccine in American healthcare workers (HCW) showed that the overall efficacy of BNT162b2 and mRNA-1273 vaccines were 88.8 and 88.9%, respectively.123 A study involving six locations in the United States, HCW, and the first responders also showed that after two doses of mRNA vaccine, the effective rate was about 90%.124 In addition, the 2nd dose of BNT162b2 was shown to reduce 94% of COVID-19 cases in a 1.2 million person dataset.125 A large-scale study in Scotland showed that the first BNT162b2 vaccination could achieve an efficacy of 91%, and the number of COVID-19 hospitalization decreased in 28–34 days after vaccination. The efficacy of AZD1222 in the same period was 88%, and these two vaccines showed a similar effect on preventing infection.126 There are limited real-world data on inactivated vaccines. The effectiveness of the CoronaVac vaccine was evaluated in a St. Paul study and showed more than 50% efficacy.127
These real-world studies showed that the approved COVID-19 vaccines effectively prevent SARS-CoV-2 infections, especially reducing the infection in susceptible people like healthcare workers.
As mentioned earlier, the emergence of VOC poses great challenges to the efficacy of existing vaccines. WHO has designated five VOCs, including Alpha, Beta, Gamma, Delta, and Omicron (Fig. 5), among which Alpha and Delta variants had strong contagious activity, while Beta and Gamma variants gained powerful immune escape ability. However, the Omicron variant obtained high infectivity and can evade most COVID-19 vaccines simultaneously. Understanding the relationship between the mutations and pathogenic characteristics (like infectivity and immune escape ability) is useful to analyze the efficacy of vaccines better and adjust the vaccination strategy properly. Here, the origin of these VOCs has been systematically reviewed, and the influence of mutations on the pathogenic characteristics is illustrated (Fig. 7). Furthermore, the effectiveness of approved vaccines on the Omicron variant was also discussed, given that the Omicron variant has caused large-scale infections worldwide and aroused people’s worries.
A systemic illustration of the mutation in the S protein of VOCs. VOCs were designated by WHO because of the enhanced infectivity or immune escape ability (or with both), the specific mutations in the S protein of VOC Alpha to Omicron are displayed, and the mutations related to enhanced immune escape ability were marked in green color, while the mutation related to decreased immune escape ability was marked into orange color
B.1.1.7 is the first variant circulating worldwide, which was first detected in the southeast of the UK in September 2020 and became the dominant variant in the UK during the following 3 months. On December 18, 2020, B.1.1.7 was designated as Variants of Concern (VOC) and labeled Alpha by WHO (https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/). Compared with other variants at that time, the Alpha variant had a stronger transmission ability, with a higher reproduction number.128 Interestingly, the variant lineage contained three subgroups initially, but the variant with Del69/70 in the S protein eventually occupied the mainstream, and 96.6% of all detected sequences of Alpha variants contained the mutation (https://outbreak.info/), which indicated the existence of selective advantage in the transmission of SARS-CoV-2.12 Apart from Del69/70, other mutations (like D614G in each VOC and E484K in Beta and Gamma) also proved the selective advantage. Variants with certain mutations gained stronger infectivity, fitness, or immune escape ability and are prone to survive and spread in the struggle between humans and COVID-19.
The analysis of these mutations with the selective advantage will further help to understand the pathogenic characteristics of these variants, such as infectivity, contagious ability, and immune escape ability. In addition to Del69/70, there are eight mutations in the S protein of Alpha variant: Del144 (contained in 95% of all detected sequences of Alpha variants), N501Y (97.6%), A570D (99.2%), D614G (99.3%), P681H (99%), T716I (98.7%), S982A (98.8%), and D1118H (99.2%) (https://outbreak.info/). Among these mutations, Del69/70 and Del144 can significantly reduce the neutralization of NTD targeted antibodies,105 because most of the immune epitopes of NTD antibodies are located in N3 (residues 141-156) and N5 (residues 246–260) loops, while Del144 can alter the N3 loop and cause the immune escape of such antibodies,129 Del69/70 can enhance the infectivity.130 The characteristic mutation N501Y can significantly increase the binding of S protein to ACE2,131 and further enhance the infectivity. In addition, N501Y was also related to the immune escape, in which the epitope of class A antibodies was located.129 This mutation was also in other VOCs like Beta, Gamma, and Omicron. Not only VOC, but almost all circulating variants also had a D614G mutation. Plante JA et al. found that D614G can alter the fitness and enhance the replication of SARS-CoV-2 in the lungs. However, D614G will reduce the immune escape ability of the virus and improve the sensitivity to neutralizing antibodies.131,132 The above studies suggested that this mutation may be essential to maintaining the survival of SARS-CoV-2. Thereby, it can be retained continuously. The P681H mutation near the furin-cleavage site may enhance the cleavage of S1 and S2 subunits and increase the Alpha variant’s entry. The P681R in VOC Delta may improve fitness compared with P681H in the Alpha variant.133
In general, the Del69/70, N501Y, D614G, and P681H of the Alpha variant were helpful to improve the infection, which can explain the high reproduction number of about 3.5–5.2 (https://aci.health.nsw.gov.au/covid-19/critical-intelligence-unit/sars-cov-2-variants). However, Del144 and N501Y affected the neutralization of antibodies, the vaccines approved by WHO showed strong neutralization ability to VOC Alpha, shown in Table 3.
B.1.351 (also known as 501Y.V2) was first detected in South Africa in May 2020 and firstly appeared after the first epidemic wave in Nelson Mandela Bay. This variant had different characteristics from the dominant variants B.1.154, B.1.1.56, and C.1 in the first wave of pandemic134 and had spread rapidly in Eastern Cape, Western Cape, and KwaZulu-Natal provinces in just a few weeks, causing the second wave of epidemic in South Africa (October 2020).135 On December 18, 2020, B.1.351 was designated as VOC by WHO and named Beta (https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/). Similar to the Alpha variant, B.1.351 lineage also included three subtypes 501Y.V2-1/-2/-3, and 501.Y.V2-1 occupied mainstream, then the 501Y.V2-2 with additional mutations of amino acid site 18 and 417 appeared, and finally Del241/243 mutation occurred in 501Y.V2-3.136 Among all detected sequences of VOC Beta, 89.6 and 93% had K417N and Del241/243 mutations, indicating that 501Y.V2-3 was the dominant subgroup of VOC Beta (https://outbreak.info/).
There were nine mutations in the S protein of Beta variant: L18F (found in 43.6% reported Beta variants), D80A (97.1%), D215G (94.6%), Del241/243 (89.6%), K417N (93%), E484K (86.5%), N501Y (87%), D614G (97.8%), and A701V (96.4%) (https://outbreak.info). The glycans of amino acid site 17, 174, 122, and 149 in the NTD region combined into seven targeted epitopes of NTD antibodies137 and L18F may interfere with the binding between antibodies, and residue 17 affect the neutralization of antibody. The Del241/243 map to the same surface as the Del144 in the Alpha variant,138 which may also interfere with the neutralization of antibodies. In addition, several studies have shown that K717N and E484K mutations (as well as the K417T in Gamma variant and E484A in Omicron variant) both contribute to the immune escape against group A-D antibodies,129,136,139,140 and K417N can enhance the infectivity at the same time.129,141
Overall, the L18F, Del241/243, K417N, E484K, and N501Y mutations all contribute to the immune escape ability of VOC Beta, while K417N, N501Y, and D614G can enhance the viral infection. Therefore, compared with the Alpha variant, the Beta variant has poor transmissibility, but a very strong immune escape ability and can reduce the neutralization efficacy of WHO-approved vaccines by more than 10 times.
P.1 was first detected in Brazil in November 2020 and caused the second wave of the epidemic in this country, causing more than 76% infection of the population,142 and the average number of daily-confirmed COVID-19 patients in Manaus increased by 180 from January 1 to 19, which was about 30 times of the average increased cases in December. On January 11, 2021, P.1 was designated as VOC by WHO and labeled Gamma.
There were 12 mutations in the S protein of Gamma variant: L18F (found in 97.9% reported P.1 strains), T20N (97.9%), P26S (97.6%), D138Y (95.5%), R190S (93.6%), K417T (95.5%), E484K (95.2%), N501Y (95.3%), D614G (99%), H655Y (98.5%), T1027I (97.2%), V1176F (98.1%) (https://outbreak.info). Since most of the mutations of interest like K417T, E484K, N501Y, and D614G have been introduced in the Alpha and Beta variants mentioned above, they will not be repeated here.
Among these mutations, L18F, K417T, E484K, and N501Y help to enhance the immune escape ability, while K417T, N501Y, and D614G can enhance the viral infection. Therefore, VOC Gamma showed a similar immune escape ability to VOC Beta, but less than the Beta variant, which may be caused by mutations outside the RBD region,143 the infectivity of both Beta and Gamma variants were less than the Alpha variant (https://aci.health.nsw.gov.au/covid-19/critical-intelligence-unit/sars-cov-2-variants).
B.1.617.2 was first detected in Maharashtra, India, in October 2020 and spread rapidly in a few months due to the relaxation of prevention and control measures for COVID-19, causing the death of more than 400,000 people.107 On May 11, 2021, this variant was designated as VOC by WHO and labeled Delta (https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/). VOC Delta was a worldwide circulating VOC after VOC Alpha and was detected by at least 169 countries (https://outbreak.info).
There were ten mutations in the S protein of Delta variant: T19R (found in 98.3% reported delta strains), T95I (38.3%), G142D (66.1%), E156G (92.1%), Del157/158 (92.2%), L452R (96.9%), T478K (97.2%), D614G (99.3%), P681R (99.2%), D950N (95.3%) (https://outbreak.info). G142D and E156G are located in the N3 loop, which NTD antibodies could target,129 thus may affect the neutralization activity of NTD antibodies. The Del157/158 map to the same surface as the Del144 in the Alpha variant and the Del241/243 in the Beta variant, respectively, which may affect the neutralization of antibodies.138 In addition, both L452R and T478K are located in immune epitopes targeted by group A-B antibodies, enhancing the immune escape ability of Delta variant,129,138,144 and L452R is related to a higher infectivity.145 The P681R mutation enhanced the infectivity of the virus and further improved the fitness compared with P681H,138 which explained the higher infectivity of VOC Delta than VOC Alpha.
Although the mutations like L452R, T478K have not been reported in previous VOC Alpha, Beta, and Gamma, these mutations gave VOC Delta a stronger transmission ability (with a reproduction number of 3.2–8, mean of 5) and immune escape ability than VOC Alpha, which made Delta variant quickly become a dominant variant and reduce the efficacy of approved vaccines (https://aci.health.nsw.gov.au/covid-19/critical-intelligence-unit/sars-cov-2-variants).
In November 2021, B.1.1.529 appeared in many countries. Since the S protein of this variant contains more than 30 mutation sites, and many of them coincide with the S protein mutations of previous VOCs, B.1.1.529 was designated as VOC by WHO on 26 November 2021 and labeled Omicron (https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/). Although the Omicron variant has more mutations, the severity of the Omicron infected patient was less than Delta. After infection with the Omicron variant, hamsters did not have progressive weight loss similar to that after infection with Alpha/Beta/Delta, and the number of virus copies in the lungs was lower,146 indicating that Omicron has less effect on the lower respiratory tract. By evaluating Omicron infection on different cells, Thomas P. Peacock et al. found that the infection degree of Omicron on Calu-3 (a lung cell line, whoseTMPRSS2 expression is normal, but lack of CTSL expression, hindering the nuclear endosome pathway of virus entry) is weaker than Delta, indicating that Omicron entry is more dependent on the nuclear endosome mediated endocytosis pathway147 rather than the membrane fusion pathway involved in TMPRSS2, and TMPRSS2 is mainly distributed in human lung epithelial cells. Therefore, Omicron has less infectivity to the lungs and causes mild symptoms, mainly causing upper respiratory tract infection.
The S protein of the Omicron variant contains 31 mutations: A67V, Del69/70, T95I, G142D, Del143/145, N211I, Del212-212, G339D, S371L, S373P, S375F, K417N, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y505H, T547K, D614G, H655Y, N679K, P681H, N764K, D796Y, N856K, Q954H, N969K, and L981F (since the proportion of mutations is constantly changing, it is not shown here) (https://outbreak.info). Cao Y and colleagues systematically analyzed the effect of these mutations on immune escape. Among them, 477/493/496/498/501/505 mutations affected the neutralization activity of group A antibodies, 477/478/484 mutations affected the neutralization activity of group B antibodies, while the neutralizing activity of group C/D/E antibodies was affected by 484, 440/446, and 346/440 mutations, respectively, Group F antibodies are disturbed by 373/375 mutations.94,129 However, group E and F antibodies showed effective neutralization of the Omicron variant among these antibodies. These two groups of antibodies were rarely used in the clinic and formed lower immune pressure on the virus, reducing the viral mutation of these antibodies and maintaining the binding of antibodies to corresponding epitopes.
Although the Del69/70, K417N, N501Y, D614G, and P681H mutations can enhance the viral infection (with a reproduction number of 2.6–4.0) and Del143/145, K417N, T478K, E484A, and N501Y are related to the immune escape, the infection of Omicron variant has less impact on the lung and is unlikely to cause serious diseases compared with VOC Delta. In addition, many vaccines serum almost lost the neutralization effect on the Omicron variant, indicating that new strategies (such as booster vaccination, sequential vaccination, and the development of new platforms such as nanoparticle vaccine) should be considered.
Pajon et al. and Nemet et al. evaluated the enhanced protection of the third dose of mRNA-1273 and BNT162b2 against the Omicron variant, respectively.148,149 Although a booster dose can enhance the response of memory cells and increase the antibody titers to produce stronger neutralization activity of 20 to100-fold, the enhanced immune response is still limited. An Israeli study showed that the fourth dose of the BNT162b2 or mRNA-1273 vaccine still could not prevent Omicron infection (https://www.shebaonline.org/). In addition, Wang J and colleagues evaluated the protection of the fourth BBIBP-CorV against the Omicron variant. Although the additional inoculation successfully recalled memory cell response in the 6th month after the third dose, the production of antibodies targeting the RBD region was suppressed due to the enhanced immune pressure and decreased peak level150 The suppression of RBD-targeted antibodies may induce the change of immune epitopes, and a vaccine inducing diverse epitopes antibodies (like a polyvalent vaccine) may decrease the immune pressure on certain epitopes and maintain the efficacy on different VOCs.
SCTV01E is a protein subunit vaccine under development that uses the S trimer of Alpha/ Beta/ Delta/ Omicron variants, and two clinical trials evaluating the safety and immunogenicity of SCTV01E are on the way (NCT05239806 and NCT05238441) (https://clinicaltrials.gov). In addition to the polyvalent vaccine, the mRNA vaccine used the VOC Beta sequence also showed better protection against Omicron in the hamster model than existing vaccines.151
According to the WHO data, as of March 28, 2022, 196 candidate vaccines are in the preclinical stage, and 153 candidate vaccines based on different vaccine platforms have been approved for clinical trials. Here, we present some data for each type of vaccine that the WHO has not approved.
As of March 28, 2022, 12 inactivated virus vaccines underwent Phase II/III and Phase IV clinical trials. Of these Phase III clinical trials, the QazCovid-in®-COVID-19 inactivated vaccine developed by the Research Institute for Biological Safety Problems, Republic of Kazakhstan, showed superiority in many aspects, including good immunogenicity and high seroconversion (https://clinicaltrials.gov/ct2/show/NCT04691908).
As of March 28, 2022, only one live attenuated vaccine-COVI-VAC has entered a Phase III clinical trial (ISRCTN15779782). The vaccine was developed by the Codagenix and Serum Institute of India. The study starts in August 2021 and runs until September 2023 to objectively evaluate the benefit and risk of COVI-VAC as a candidate vaccine, and relevant data have not been released (https://www.isrctn.com/ISRCTN15779782).
As of March 28, 2022, two replicating viral vector platform vaccines and eight non-replicating viral vector platform vaccines have been tested in Phase II/III and Phase IV clinical trials. The Gam-COVID-Vac aroused many concerns owing to its effectiveness of 91.6%.152 A Phase III trial was conducted in Moscow on September 7, 2020 (NCT04530396). 21,977 adults were randomly assigned to the vaccine and placebo groups in this trial. The vaccine group received 0.5 mL Gam-COVID-Vac. Only 0.1% of recipients were infected with SARS-CoV-2, while the percentage of the placebo group was 1.3%. No severe adverse events related to the vaccine were reported.
As of March 28, 2022, 22 candidate protein subunit vaccines were in Phase II/III and Phase IV clinical trials. The CpG 1018/Alum-adjuvanted SCB-2019 vaccine was developed by Clover Biopharmaceuticals Inc. and Dynavax. A Phase III clinical trial (NCT05012787), beginning on August 19, 2021, was conducted to evaluate the safety and immunogenicity of the investigational SCB-2019 in adult participants with stable chronic inflammatory immune-mediated diseases (IMDs) (https://clinicaltrials.gov/ct2/show/NCT05012787). Moreover, an RBD-based subunit vaccine developed by the West China Hospital, Sichuan University, and WestVac Biopharma Co., Ltd, showed strong induction of potent functional antibodies, as well as CD4+ T-cell responses in the preclinical trial,60 and the phase III clinical trial (NCT04887207) of this vaccine, has been completed (https://clinicaltrials.gov/ct2/show/results/NCT04887207).
As of March 28, 2022, nine RNA and four DNA vaccines have undergone Phase II/III and Phase IV clinical trials. An mRNA vaccine called mRNA ARCoV, developed by the Academy of Military Science, Walvax Biotechnology, and Suzhou Abogen Biosciences was conducted for a Phase III clinical trial of 28,000 subjects (NCT04847102). The subjects were inoculated with a vaccine or placebo in a 1:1 ratio with an interval of 28 days between two injections. It was reported that expected efficacy and good safety had been achieved. The effects of cross-injection will be assessed, including an immunogenic subgroup and a reactive subgroup, to evaluate the humoral immunity induced by the vaccine (https://clinicaltrials.gov/ct2/show/NCT04847102).
Although the currently approved COVID-19 vaccines were safe in clinical trials, the resulting adverse reactions are numerous, including fever, headache, fatigue, injection site pain, and nausea.3,153 As the vaccination campaign progressed, complications occurred in some subjects, and several patients died of cardiovascular diseases, such as arteriosclerosis. Furthermore, cardiac arrest occurred in Phase III clinical trials of the mRNA-1273 and BNT162b2 vaccines.114,118 The possible complications induced by COVID-19 vaccines mainly include the following categories: (1) coagulation dysfunction, such as thrombocytopenia;52,154 (2) heart diseases, such as myocarditis;74,75 (3) immune diseases, such as allergic reactions,155 autoimmune hepatitis,156 and autoimmune thyroid diseases;157 (4) nervous system diseases, such as facial paralysis158,159 and functional neurological disorders;153 (5) lymphatic system diseases;160 and (6) other diseases, such as Rowell’s syndrome,161 macular rash,162 and chilblain-like lesions163 (Fig. 8). Although the incidence of these complications is low, the relationship between vaccines and these diseases needs to be explored. Here, we describe related COVID-19 vaccine complications and analyze the factors.
A summary of some possible complications induced by COVID-19 vaccines. The possible complications induced by COVID-19 vaccines mainly include the following categories: (1) coagulation dysfunction, such as thrombocytopenia; (2) heart diseases, such as myocarditis; (3) immune diseases, such as allergic reactions, autoimmune hepatitis, and autoimmune thyroid diseases; (4) nervous system diseases, such as facial paralysis and functional neurological disorders; (5) lymphatic system diseases; and (6) other diseases, such as Rowell’s syndrome, macular rash, and chilblain-like lesions
Greinacher et al. and Lee et al. reported thrombocytopenia in an adenovirus vector vaccine and mRNA vaccine recipients.154,164 A large number of platelet factor 4 (PF4) antibodies were presented in the patients, and the antibody heparin PF4 complex acted on platelet FC γ receptors, activating platelets and further producing procoagulant substances.154 Adenoviruses can bind to platelets and activate them.165,166 However, trace adenoviruses in vaccines injected one or two weeks before onset seem unlikely to cause platelet activation. Further analysis of PF4 structure revealed that PF4 antibodies from vaccine-induced immune thrombocytopenia patients induced heparin-induced thrombocytopenia by binding eight surface amino acids on PF4.51 One study counted the cases of thrombosis sequelae voluntarily reported after vaccination, of which at least 169 cases of possible cerebral venous thrombosis and 53 cases of possible visceral venous thrombosis were reported among 34 million individuals vaccinated with ChAdOx1 nCoV-19 vaccine, and 35 cases of central nervous system thrombosis among 54 million individuals vaccinated with BioNTech mRNA vaccine. Among the 4 million subjects receiving the Moderna mRNA vaccine, cerebral venous sinus thrombosis may have developed in five cases. Among the more than 7 million subjects receiving Ad26.COV-2-S vaccine, cerebral venous thrombosis may have developed in six cases.52 Although the relevant pathogenesis is unclear, a possible trigger factor for these PF4 antibodies is free RNA or DNA in the vaccine.167
Moreover, platelet activation may also relate to the injury and inflammation induced by mast cell (MC) degranulation. Wu ML et al. found that SARS-CoV-2 can induce degranulation of MCs located in the mucosa, and a rapid MC degranulation could be recapitulated through the binding of RBD to ACE2, resulting in supra-alveolar dermatitis and lung injury.168 In addition, in the case of inflammation induction and lung epithelial injury, many plasminogen activators may be released.169 Thus, the increased D-dimer (one of the products formed when plasminase degrades fibrine) concentration was observed in many COVID-19 patients, with a decreased level of platelets.169 These pathological characteristics of patients were very similar to the thrombotic thrombocytopenia caused by the COVID-19 vaccination. Combined with the above studies, this mechanism may be explained as follows: after the SARS-CoV-2 infection or mRNA vaccine vaccination, S protein stimulated lung epithelial cells and induced MC degranulation, increasing the level of inflammatory mediators. These mediators increased the destructive effect of monocyte macrophages on erythrocytes and led to abnormal platelet levels. In addition, the injury of epithelial cells activated platelets and released coagulation factors, finally forming fibrin and forming extensive micro thrombosis. In this process, the over-consumed platelets and coagulation factors lead to the reduction of coagulation activity, further imbalance of coagulation and anticoagulation, secondary hyperfibrinolysis, and the release of a large number of plasminogen activators, eventually leaded to disseminated intravascular coagulation (DIC), which appeared in most COVID-19 patients.154,169,170 Compared with COVID-19 patients, fewer mRNA vaccine subjects reported DIC, which may be due to the lower amount of S protein produced after vaccination than natural infection, and the inflammation is also lower.
Relevant indexes (e.g., measuring prothrombin time, platelet count, and D-dimer concentrations of the receptors) should be tested within 2–3 days after vaccination to prevent the platelet abnormalities caused by COVID-19 vaccination.169 For patients with abnormal index, preventive treatment (usually heparin or low molecular weight heparin transfusion, the latter is safer) should be taken as soon as possible.169 In addition, degranulation inhibitors may also be a feasible means to inhibit the inflammatory response and prevent lung injury and platelet abnormalities.168
Myocarditis is a rare cardiac complication after COVID-19 vaccine injection.74,75 Rosner et al. reported seven patients hospitalized for acute cardiomyoid disease after vaccination with Pfizer-BioNTech/AstraZeneca (n = 6) and Janssen (n = 1) vaccines. Larson et al. reported eight patients hospitalized for chest pain within 2–4 days of vaccination with the BNT162b2 or mRNA-1273 vaccine. The laboratory diagnostic cardiac magnetic resonance imaging analysis revealed that these patients have myocarditis. All the subjects had left ventricular ejection dysfunction. The median ejection blood percentage was 48–59%.74,75 These two studies showed a significant temporal correlation between mRNA-based COVID-19 vaccines (including viral vector and mRNA vaccines) and myocarditis. Such systemic adverse events usually occur within 48 h after the second dose.114,118 There may be two potential mechanisms for COVID-19 mRNA vaccines causing heart diseases, such as myocarditis. The first is the nonspecific innate inflammatory responses induced by mRNA. The second is the interaction of the S protein produced by mRNA after the translation within the heart or blood vessels, resulting in cardiovascular injury.171 Since protein subunit vaccines like ZF2001 and NVX-CoV2373 have not been used widely, and the relevant data are still unreleased, it is not easy to judge whether the S protein causes myocarditis.
Immune diseases caused by the injection of the COVID-19 vaccine mainly include allergic reactions and autoimmune diseases that include autoimmune hepatitis and autoimmune thyroid diseases.155,156,157
From December 14 to 23, 2020, 175 of the first batch of 1,893,360 individuals vaccinated with BNT162b2 developed severe allergic reactions within 24 h. These cases were submitted to the vaccine adverse events reporting system (VAERS).155 Finally, 21 cases were identified as allergic reactions based on the Brighton Collaboration definition criteria.155,172,173 Between December 21, 2020, and January 10, 2021, ten of the 4,041,396 subjects vaccinated with the first batch of mRNA-1273 vaccine were identified as allergic reactions.155,173 Risma et al. analyzed the causes of allergic reactions induced by the COVID-19 vaccine. The reasons included nucleic acid of COVID-19 vaccine activated contact system; complement system that was directly activated by the nano lipid plasmid (LNP) vector of the vaccine, resulting in complement-related pseudoanaphylaxis;174 pre-existing antibodies to polyethylene glycol (PEG) that induced allergic reactions;175 and direct activation of mast cells leads to degranulation. Allergic reaction mainly includes classical pathway and non-classical pathway. The classical pathway is activated by mast cells and cross-linked IgE,176 which PEG IgE antibodies may activate in the inoculant. Non-classical pathways mainly involve complement antibody-dependent activation of mast cell activation.177 To further understand the causes of allergic reactions to the mRNA vaccine, Troelnikov et al. evaluated the ability of PEG, polysorbate 80, BNT162b2 vaccine, and AZD1222 vaccine to activate basophils and mast cells in patients with a previous allergic history of PEG. The authors clarified that PEG covalently modified on vaccine LNP carriers was a potential factor that triggered allergic reactions.178 For the allergic reaction caused by mRNA vaccines, molecules with better biocompatibility and lower immunogenicity should be considered vaccine carriers to reduce the rate of hypersensitivity reactions.
Vaccination can trigger a series of immune reactions and the production of neutralizing antibodies against antigens. An excessively strong immune response may simultaneously produce antibodies targeting normal organs or tissues, leading to autoimmune diseases like hepatitis and autoimmune thyroid diseases.
Lodato et al.156 reported that two days after the second dose of the BNT162b1 vaccine, a 43-year-old woman developed jaundice. A liver biopsy revealed moderate portal inflammatory infiltration, accompanied by bile duct injury and hepatic lobular punctate necrosis. After eight weeks of corticosteroid treatment, the clinical indices of the liver returned to normal. Given the beneficial effect of steroid treatment and the overall period from vaccination to onset consistent with the progress of the immune response, the patient was diagnosed with autoimmune hepatitis. Furthermore, the causal relationship between vaccine injection and autoimmune hepatitis has not yet been fully determined.
In addition to autoimmune hepatitis, cases of immune hypothyroidism caused by vaccination have been reported. Two female medical staff members showed increased thyroid hormone secretion and elevated thyroid antibody levels three days after receiving the COVID-19 vaccine, indicating inhibited thyroid functions.157
The relationship between autoimmune diseases and COVID-19 vaccines has not been clarified. However, the above cases emphasize the importance of regular follow-up and close observation of the physical condition of vaccines. While vaccination is an effective weapon in ending the COVID-19 epidemic, immune-related complications need to be considered.
Bell’s palsy, also known as acute peripheral facial paralysis of unknown cause, is usually characterized by sudden unilateral facial paralysis.159 This type of nerve paralysis is typically temporary. Most patients recover within 6–9 months without drug or steroid treatment,179 but a few patients may have facial dysfunction. Facial paralysis may occur after vaccination, such as the influenza vaccine, caused by viral reinfection.180 In a clinical trial of the COVID-19 mRNA-1273 vaccine, three of 15,210 subjects developed facial paralysis.114,118 Wan et al. used the reporting systems of medical institutions to evaluate the proportions of facial paralysis within 42 days after vaccination with BNT162b2 and CoronaVac vaccines and found that they were 66.9 cases/100,000 individuals/year in CoronaVac recipients and 42.8 cases/100,000 individuals/year in BNT162b2 recipients, respectively. A higher proportion of facial paralysis occurred in inactivated vaccine recipients,159 indicating that this complication may be related to the vaccine adjuvant as the inactivated vaccine is unlikely to cause virus reinfection and does not contain active viral nucleic acid. Renoud et al. conducted a disproportionate data analysis based on the WHO pharmacovigilance database and found that 844 cases among 133,883 mRNA vaccination cases had facial paralysis-related events.181 Although the COVID-19 vaccine may cause acute peripheral facial paralysis, the beneficial and protective effects outweigh the risk of this generally self-limiting adverse event. Adverse event monitoring and controlling should be improved and strengthened to ensure a timely treatment in case of complications.
FND is a nervous system disease that can produce neurological symptoms caused by biological, psychological, or environmental factors.153 The predisposing factors for FND include head injury, surgery, and vaccination. Currently, at least one vaccinated individual has been diagnosed with FND. Kim et al.153 described the potential relationship between FND and COVID-19 vaccination. Vaccine components are unlikely to be the main cause of FND because FND also occurs after normal saline injection.
Moreover, adverse events, such as local pain at the injection site or systemic muscle pain, may occur after vaccination, which may increase the sensitivity of the patient’s nerves. The reason for FND attacks caused by COVID-19 vaccines has not been determined. Close attention should be paid to the adverse events of vaccinated individuals. Improving the reporting of such events, the public’s confidence in the government and medical institutions will greatly reduce recipients’ psychological and mental pressure, reducing the incidence of FND.
Injection of the COVID-19 vaccine may lead to inhibition of thyroid function. Since the time window from vaccination to the disease is consistent with the immune process, such adverse reactions are classified as immune diseases, namely autoimmune diseases. In addition, lymphatic diseases, such as abnormal lymph nodes,160 may also occur after receiving the COVID-19 vaccine. For example, three days after receiving the first dose of the AZD1222 vaccine, eosinophils were detected in the left axillary lymph nodes of a 75-year-old male using [18 F] Choline positron emission tomography/computed tomography (PET/CT), demonstrating the mild uptake ability of choline. The choline uptake occurred in his left arm 3 days after AZD1222 vaccination, indicating the AZD1222 vaccine-induced abnormal lymph node exists. Eifer et al. also described that a 72-year-old woman vaccinated with BNT162b2 subsequently displayed the same phenomenon of increased choline uptake by lymph nodes.182 The vaccine recipients had tumors resected or treated by other means in both cases. [18 F] Choline PET/CT is an effective method to determine the location of tumor infiltration and the prognosis of tumor patients. Therefore, close follow-up of patients with tumors inoculated with the COVID-19 vaccine should be prudent to avoid incorrect interpretation of the imaging results and incorrect diagnoses of diseases.
In addition to the diseases mentioned above, some COVID-19 vaccines recipients may also have skin diseases, including Rowell syndrome,161 macula,162 and chilblain-like lesions.163
Gambichler T et al.161 found that a 74-year-old woman developed a severe rash one day after receiving the BNT162b2 vaccine. Clinical examinations showed that the patient had red cohesive spots and papules on the trunk and limbs but no mucosal infiltration. The patient was diagnosed with Rowell’s syndrome (RS), a relatively rare disease characterized by lupus erythematosus with pleomorphic erythematosus lesions and immunological manifestations through further skin biopsy.183 Subsequently, the patient received steroid treatment, and the symptoms were relieved. In this case, the BNT162b2 vaccine was considered a possible cause of RS, but the patient took pantoprazole for a long-time treatment of chronic gastrointestinal ulcers. Combining this drug and the COVID-19 vaccine may lead to the onset of RS. Some studies have pointed out that omeprazole, a proton pump inhibitor, may cause RS.184 Therefore, special vaccination groups, especially the elderly or patients with underlying diseases, should be paid attention to their post-vaccination status, and corresponding treatment should be given in time.
Jedlowski P et al.185 have reported a measles-like rash and papules caused by the BNT162b2 vaccine. After the first dose of the vaccine, a 30-year-old male had adverse reactions such as fever and pain at the injection site, followed by a measles-like rash. After the second dose of the vaccine, he had a recurrent measles-like rash and flesh-colored papules, which had subsided after corticosteroid treatment. Similarly, a 55-year-old man suffered pain and pruritus erythema at the injection site after the first dose of the BNT162b2 vaccine, accompanied by impaired liver function.162 Subsequently, the patient’s symptoms were significantly improved after corticosteroid therapy.
Piccolo et al. noted that a 41-year-old woman had chilblain-like lesions (CLL) on her fingers and was accompanied by severe pain after receiving the second dose of the BNT162b2 vaccine.163 This symptom is most likely related to the strong activation of innate immunity and the production of potent antibodies.186 Additionally, CLL was observed in another 41-year-old female vaccinee, accompanied by severe pain.187 Although the reasons for CLL in the above cases have not been clarified, the occurrence of CLL after the COVID-19 mRNA vaccine proves the correlation of CLL with the vaccination.186
In conclusion, although COVID-19 vaccination may be associated with diseases such as thrombosis, myocarditis, and allergy, the proportion of adverse events is low, and vaccination is still an effective means to control and block the epidemic.
COVID-19 vaccine mainly functions by inducing neutralizing antibodies and memory cells. However, for patients with innate immune diseases, such as autoimmune rheumatism and a history of allergies or tumors, COVID-19 vaccination may cause adverse events. In addition, elderly and pregnant women are also of concern. Compared to adults, vaccine immunization of the elderly may not achieve the desired protective effect due to their weakened immune system functions.188,189,190 For pregnant women, the COVID-19 vaccine may cause adverse events, such as abortion, premature birth, or fetal malformation.191,192 Here, we summarize the effects of vaccination in different populations (Fig. 9).
Effect of vaccination in different populations. COVID-19 vaccines are still effective for pregnant women, patients with autoimmune diseases, and controlled HIV-infected patients, and the overall efficacy can maintain about 80–90%, while the 30% neutralization reduction occurs in older people. Moreover, the overall neutralizing activity of COVID-19 vaccines in solid organ transplant recipients, cancer patients, and uncontrolled AIDS patients is significantly reduced
Previous studies have shown that complications including lung injury, diabetes, and cardiovascular diseases in pregnant women after SARS-CoV-2 infection are higher than that in non-pregnant women.193 However, adverse events, such as abortion or fetal malformation, may occur after COVID-19 vaccination,191,192 which have raised concerns. Shimabukuro et al.192 evaluated the effects of COVID-19 vaccination on pregnant women and fetuses using the V-safe monitoring and VERS systems. The results indicated that adverse reactions were higher in pregnant women than in non-pregnant women. The most significant adverse event was pain at the injection site. After mRNA vaccination, pregnancy loss occurred in 13.9% of the pregnant women, 86.1% had a normal pregnancy, and 9.4% had a premature delivery. Although pregnancy loss and premature birth could occur, both are low-probability cases, and the benefits of vaccination far outweigh the risks. In addition, the proportion of local or systemic adverse reactions in elderly non-pregnant women was similar to that in pregnant women,191 indicating that physiological changes during pregnancy did not significantly impact the occurrence of adverse events.
Two other studies analyzed the immunogenicity of COVID-19 in pregnant women and fetuses, and COVID-19 vaccines overall are approximately 90% effective for the vaccinated women.194,195 R Collier et al. analyzed the immune condition of pregnant or lactating women and fetuses after COVID-19 vaccination.194 Both pregnant and lactating women could produce binding, neutralizing, and functional non-neutralizing antibodies, accompanied by CD4+ and CD8+ T-cell responses. More importantly, binding and neutralizing antibodies were also detected in infant umbilical cord blood and breast milk. These results show that vaccinated pregnant women experience a personal protective effect and produce antibodies that can be delivered to the fetus through the umbilical cord or breast milk to provide immune protection.
Furthermore, a multicenter study conducted in Israel also showed that after vaccination with the BNT162b2 vaccine, IgG antibodies could be produced in the mother. These antibodies can pass through the fetal barrier, and newborns can detect antibody reactions.195 These two studies showed that after the COVID-19 vaccination, the antibodies in pregnant women could be transferred into the fetus through efficient mother-to-child transmission, effectively protecting the fetus.
Although pregnant women are more likely to experience adverse events after vaccination than non-pregnant women, this proportion is still limited. Within the ideal range, the COVID-19 vaccine can simultaneously protect mothers and infants, reducing the probability of fetal infection with SARS-CoV-2 after birth to a certain extent. Therefore, pregnant women should be voluntarily vaccinated with the COVID-19 vaccine. Meanwhile, government and medical institutions should further improve the health monitoring of pregnant women in the trial to ensure the safety of pregnant women and fetuses.
Several studies have analyzed the related immunization levels in the elderly (> 80 years of age) after the COVID-19 vaccination. About 70% protection suggested that at least two vaccination doses should be given to these people.189,190 Lisa et al.190 compared the production of serum neutralizing antibodies between elderly (>80 years old) and young (<60 years old) vaccine recipients after vaccination with BNT162b2. The IgG antibody titer of the elderly subjects was generally lower than that of the young subjects. Although the antibody levels increased after secondary immunization, 31.3% of the elderly did not produce SARS-CoV-2 neutralizing antibodies, while the antibodies were not detected in only 2.2% of the young subjects after the second dose. Because virus variants, especially variants of concern (VOC), have stronger infectivity or immune escape ability and are prevalent globally. Collier et al.189 evaluated the effect of serum neutralizing antibodies in elderly individuals on VOC strains Alpha, Beta, and Gamma after two doses of the BNT162b2 vaccine. Neutralizing antibodies against the VOC strain were detected in all age groups. Therefore, the COVID-19 vaccination can still protect the elderly. However, compared with young vaccinated individuals, the CD4+ T-cell response of elderly participants was poor and manifested as low levels of IFN-γ and IL-2. Consequently, government and medical institutions should conduct long-term monitoring of the elderly population and timely deliver “booster shot” vaccination or increase the vaccine dosage to maintain immune efficacy.
Although the COVID-19 vaccine is an effective method to control the pandemic, the current global vaccine resources are still relatively scarce, and complete immunization has not been achieved in most countries. Shrotri et al.196 conducted a prospective cohort study to systematically analyze the protective effect of a single dose of AZD1222 or BNT162b2 vaccine in individuals aged ≥ 65. After the first dose of the vaccine, evident protection for the elderly lasted for at least 4 weeks, and SARS-CoV-2 transmission was reduced to a certain extent. Another study showed that a single dose of the COVID-19 vaccine could reduce the risk of hospitalization in elderly patients infected with SARS-CoV-2.197
The collective findings support the view that the elderly should be actively vaccinated against COVID-19. If two doses of vaccine cannot be administered, they should be vaccinated with a single dose. The COVID-19 vaccine can reduce the risk of SARS-CoV-2 transmission to a certain extent, decrease the risk of hospitalization, and promote the safety of the elderly.
To reduce the immune system’s recognition and attack, patients with solid organ (e.g., kidney and heart) transplantation require long-term immunosuppressants, such as tacrolimus, corticosteroids, and mycophenolate organs.198 Although immunosuppressive drugs can maintain transplanted organs, they may also affect the body’s antiviral immunity, making solid organ transplant patients more susceptible to SARS-CoV-2 infection and increased mortality risk.198
Effective immunization of this population is necessary to reduce the infection and death caused by SARS-CoV-2. Several studies have reported that the efficiency of COVID-19 vaccines in solid organ transplant patients after single-dose/two-dose vaccination and enhanced immunization (third dose) was only 20–50%.199,200,201 Boyarsky et al. evaluated the effect of a single dose of BNT162b2 or mRNA-1273 vaccine in organ transplant patients.199 Only 76 (17%) of the 436 subjects elicited neutralizing antibodies, and the titer of these antibodies in elderly patients was lower than that in young individuals. Individuals vaccinated with mRNA-1273 produced higher levels of antibodies. These results showed that a single dose of the COVID-19 vaccine could not effectively prevent SARS-CoV-2 infection in organ transplant patients. Subsequently, this group analyzed two vaccine doses in 658 organ transplant patients.200 15% of the subjects produced neutralizing antibodies after the first dose of vaccine, whereas 54% after the second dose, indicating that complete vaccination should be fully deployed for organ transplant patients and that these individuals should be closely monitored after vaccination to prevent SARS-CoV-2 infection. Another study carried out by Benotmane I et al. showed that after the third dose of the mRNA-1273 vaccine, neutralizing antibodies were detected in the serum of 49% of renal transplant patients.201 However, some patients still did not produce neutralizing antibodies, especially those receiving triple immunosuppressive therapy with tacrolimus, corticosteroids, and mycophenolate mofetil after vaccination. In addition to the mRNA vaccine, the protective effect of an inactivated vaccine—the CoronaVac vaccine on organ transplant patients was also evaluated 31 days after two doses.198 Sixteen of the 85 renal transplant patients had neutralizing antibody reactions.
Furthermore, this result may be related to some participants’ small sample size and impaired renal function. Monitoring neutralizing antibody levels in organ transplant patients should be strengthened, and a booster shot should be administered in time. Mazzola et al.202 assessed antibody levels in other organ transplant patients after two doses of the BNT162b2 vaccine. In liver, kidney, and heart transplant patients, serum conversion rates were 37.5, 16.6, and 34.8%, respectively. The lower neutralization level in kidney transplant patients was consistent with the study by Sadioğlu et al.198
The collective findings support the view that for solid organ transplant patients who take immunosuppressants, timely vaccination is important, and clinicians should closely monitor their appropriate antibody levels. Based on the actual situation of this population, immunosuppressive programs and vaccination countermeasures should be formulated to reduce SARS-CoV-2 infection rates.
Besides organ transplant patients, cancer patients are also a COVID-19 high-susceptible population. Anti-tumor treatments, including radiotherapy and chemotherapy, may lead to systemic hypoimmunity.203 Several studies have indicated that vaccination can protect about 50–60% of cancer patients from the SARS-CoV-2 infection; thus, they should receive COVID-19 vaccines as soon as possible and complete at least two doses of injection.204,205,206
Monin et al.204 evaluated the safety and immunogenicity of a single dose and two doses of the BNT162b2 vaccine in cancer patients. Twenty-one days after the first dose of the vaccine, 21 of the 56 patients with solid tumors and eight of the 44 patients with blood cancer displayed an anti-S protein immune response. These findings showed that a single dose of the COVID-19 vaccine could not effectively prevent cancer patients, especially those with blood cancer, from the infection with SARS-CoV-2. In contrast, 18 patients with solid cancer and three patients with blood cancer were seroconverted after the second dose of the vaccine. In addition, the BNT162b2 vaccine was safe for patients with breast and lung cancer, and no death caused by vaccination was reported during the trial.
Similarly, Palich et al. evaluated the neutralization activity of the BNT162b2 vaccine in patients with cancer.206 The seroconversion rate after vaccination was only 55%. Terpos et al.207 and Maneikis et al.208 studied the effectiveness of the BNT162b2 vaccine in elderly patients with multiple myeloma and hematological malignancies, respectively. After the first dose of the vaccine, low levels of neutralizing antibodies were detected in the serum of the myeloma patients, which may be due to the inhibition of B-cell proliferation and antibody production by myeloma cells. Patients with hematological malignancies who received two doses of the BNT162b2 vaccine could display serious SARS-CoV-2 breakthrough infections since malignant hematological tumors can destroy immune homeostasis, and the immunosuppressive drug used in the treatment can also affect the production of neutralizing antibodies.
The above studies demonstrate that patients with malignant tumors are susceptible to COVID-19 and should receive timely vaccinations. The vaccination schedule should be based on the patient’s antibody titers to appropriately shorten the interval between the two vaccine injections205 and ensure a strong immune response. Moreover, patients with malignant tumors should be closely monitored after receiving the COVID-19 vaccine to prevent serious breakthrough infections.
Organ transplant patients and tumor patients may be affected by immunosuppressive drugs and systemic hypoimmunity.198,207 In addition, HIV-infected and autoimmune disease patients are also susceptible to SARS-CoV-2 infection due to their impaired immune system function and immunosuppressants. Several studies have shown that the overall efficacy of the COVID-19 vaccine in controlled HIV-infected people and people with autoimmune disease was about 80%, while the vaccination could not prevent the breakthrough infection in patients with progressive AIDS.209,210
In one study, the AZD1222 vaccine induced strong neutralization reactions in HIV-negative individuals and AIDS patients with well-controlled infections after receiving antiretroviral therapy (ART).27 Fourteen days after the second dose of the AZD1222 vaccine, HIV-negative individuals and HIV-positive patients treated with ART showed similar neutralizing antibody levels, and antibodies were detected in 87% (13/15) of HIV-infected persons. The results indicate that for HIV patients receiving ART, COVID-19 vaccination can produce an immune response similar to HIV-negative individuals. In contrast, for HIV patients whose condition is not effectively controlled, especially those with progressive AIDS, two doses of the vaccine may not prevent breakthrough infection.209
In addition to individuals infected with HIV, patients with autoimmune diseases (e.g., autoimmune rheumatism) may also get impaired immunity from the COVID-19 vaccine because of their medication with immunosuppressants, such as mycophenolate mofetil and corticosteroids.210 In one study, after two doses of the BNT162b2 vaccine, 86% of patients with autoimmune rheumatism experienced serum transformation, but the levels of S1/S2 neutralizing antibodies were significantly lower than that in healthy individuals. Some patients with enteritis who received immunosuppressive treatment also showed reduced immunogenicity following the BNT162b2 and AZD1222 vaccines.211 These findings highlight that immunization should be completed promptly for individuals receiving the immune drug and that the drug dosage should be adjusted appropriately during vaccine injection to ensure the production of neutralizing antibodies.
ADE is a phenomenon in which the pathogenic effect of some viral infections is strengthened in sub-neutralizing antibodies or non-neutralizing antibodies.212,213,214 In other words, after natural immunization or vaccination, when contacting the relevant virus again, the antibody produced before might enhance the infection ability of the virus and eventually aggravate the disease. Currently, there is no definitive mechanism to explain the causes of this phenomenon.215 The ADE simulated in vitro attributes to the pathogenic mechanism as follows: (1) The entry of virus-mediated by the Fcγ receptor (Fcγ R) increases viral infection as well as replication;216,217 (2) Excessive antibody Fc-mediated effector functions or immunocomplex formation enhances inflammation and immunopathology.214,215
Previous studies have shown that HIV, Ebola, influenza, and flaviviruses may induce ADE.215 And it was reported that respiratory syncytial virus and dengue virus vaccines could also cause ADE, so it is necessary to evaluate the ADE risk of COVID-19 vaccines.218 Although no serious ADE event caused by the COVID-19 vaccine has been released,217 the data obtained from other coronaviruses like SARS-CoV and MERS-CoV vaccines can provide experience.215
Pathogen-specific antibodies that can promote the incidence of pathological ADE should be considered during the development of COVID-19 vaccines. In vitro studies of antibodies against viral infection have identified factors associated with ADE, such as insufficient concentration or low-affinity antibodies.18 However, protective antibodies may also induce ADE. For instance, the antibody against feline infectious peritonitis virus also enhances infection of monocytes,214 and data from SARS-CoV or other respiratory virus studies suggest that SARS-CoV-2 antibodies may exacerbate COVID-19.217 Clinical studies have shown that SARS-CoV-2 antibodies can bind to mast cells, which may be related to the multisystem inflammatory syndrome in children (MIS-C) and multisystem inflammatory syndrome in adults (MIS-A) after COVID-19.219 The binding of SARS-CoV-2 antibodies to Fc receptors on macrophages and mast cells may represent two different mechanisms of ADE in patients. The above findings indicate the possibility of ADE induced by COVID-19 vaccines, to which more attention should be paid to.220
The preclinical results suggest that vaccination with formalin-inactivated SARS-CoV virions, MVA vaccine expressing SARS-CoV S protein, and S-derived peptide-based vaccine may induce lung disorders in the NHP model.214 When macaques were inoculated with inactivated SARS-CoV vaccine, they showed ADE after viral infection, manifesting as extensive macrophage and lymphocyte infiltration in the lungs and edema in the alveolar cavity. Mice and hamsters inoculated with trimeric S protein vaccine were not infected with SARS-CoV, but the serum produced could promote the entry of ACE2-independent pseudovirus.221 Rhesus monkeys inoculated with a high dose of COVID-19 vaccine had elevated body temperature within 1 day, increased respiratory rate, and decreased appetite within 9–16 days.216 Monkeys euthanized on days 3 and 21 displayed multifocal lung injury, alveolar septum thickening due to edema and fibrin, the slight appearance of type II lung cells, and perivascular lymphocyte proliferation.214
These models and data emphasize the importance of developing a safe anti-antibody-independent COVID-19 vaccine. At the same time, it is necessary to pay close attention to ADE caused by vaccination against COVID-19. Some studies have shown that antibodies with low affinity and poor neutralization ability may aggravate this disease, while current clinical markers cannot distinguish between severe infection and enhanced antibody dependence.214,218 Therefore, data and mitigation methods from SARS-CoV and MERS-CoV are referential to analyze the ADE phenomenon caused by COVID-19 vaccination. It is important to develop better COVID-19 vaccines and immunotherapy, overcome the identified mutants, and reduce possible ADE pathology.
Although COVID-19 vaccines can reduce the risk of infection and the mortality of patients, problems with the vaccines at present include declining neutralization activity of variants and vaccination-related adverse events.14,153,222 Adopting mix-and-match vaccines223 and developing new vaccines, such as VLPs and nanoparticle vaccines,224 improving existing vaccine adjuvants,225 and changing the vaccination route226 might enhance the efficacy of vaccines and reduce the occurrence of adverse events to some degree (Fig. 1).
In the absence of available vaccine resources, the second injection of an allogeneic vaccine may effectively advance the immunization process. However, vaccination with non-homologous vaccines may raise concerns about safety and effectiveness. Borobia et al. assessed the immunogenicity after inoculating a heterogeneous COVID-19 vaccine and indicated that the heterogeneous vaccine might provide greater immune protection. An initial dose of AZD1222, followed by the BNT162b2 vaccine, can induce strong immune responses and is safe.227 The research of Hillus et al.228 reached a similar conclusion. Compared with two doses of AZD1222 administered 10–12 weeks apart and BNT162b2 administered 2–3 weeks apart, the AZD1222 and BNT162b2 vaccines administered at an interval of 10–12 weeks were more effective, with better tolerance and immunogenicity. Heterologous vaccination can complement the advantages of different vaccines,229 as vaccination with BNT162b2 can elicit strong B-cell immunity and induce high levels of neutralizing antibodies, whereas the AZD1222 vaccine can induce strong T-cell responses. Therefore, this scheme is suitable for individuals with decreased immune function (e.g., organ transplants and cancer patients). Several studies evaluated the neutralization activity of the Omicron variant by the booster dose of homologous or heterologous inoculation.230,231 Both homologous and heterologous enhancers could increase the neutralization activity of subjects’ serum against the Omicron variant, but the neutralization efficiency of an additional heterologous vaccine was higher, supporting the sequential vaccination with heterologous vaccines.
In addition, several studies have shown that individuals previously infected with SARS-CoV-2 have a stronger immune response after the vaccination.138,232,233,234 Planas et al. tested the serum and antibody levels of 21 medical staff infected with SARS-CoV-2 12 months before vaccinating with a single dose of COVID-19 vaccine (vaccinated 7–81 days before sampling).138 The serum effectively neutralized Alpha, Beta, and Delta variants, and similar results were obtained by Mazzoni et al.232 After a single dose of the vaccine, the cellular and humoral immunity levels of patients who had rehabilitated from COVID-19 were further strengthened,233 and memory B-cell responses were significantly enhanced. These findings explain the significant increase in antibody levels after the first vaccination of rehabilitation patients.24 Havervall et al. showed that a single dose of COVID-19 vaccine could be used as an effective immune enhancer within at least 11 months after being infected with SARS-CoV-2.234 Liu and colleagues evaluated the efficiency of the BNT162b2 booster dose against B.1.1.529 (Omicron) variant and found that the serum neutralizing antibody levels from previous-infected recipients with booster dose is higher than naive-uninfected counterparts.235
The collective findings support the view that vaccination should be actively carried out, regardless of whether the individuals have been infected with SARS-CoV-2 or not. Although previously infected individuals are better protected after a single dose of vaccine, the possibility of breakthrough infection still exists as this immune enhancement may be related to the body’s level of memory B cells.24 However, there may be individual differences in the level of memory B cells. Therefore, regular antibody testing should be performed for rehabilitated persons who have received a single dose of vaccine to ensure lasting immunity. In addition, it is also a feasible method to implement heterologous vaccination in case of a vaccine shortage. The mixed-vaccination results of CoronaVac and ZF2001 vaccines also supported this view, as the former is much safer while the latter has better immunogenicity.236 In addition, Zhu et al. found that the mix-vaccination of CoronaVac and Ad5-nCoV can induce higher neutralizing antibodies and provide more effective protection than homologous vaccination.237
New vaccine platforms, such as mRNA vaccines, provide more powerful immune protection than traditional vaccines. However, these vaccines have lower neutralizing activity against variants, especially the Beta and Delta.14,222 Nanoparticle vaccines may have better neutralizing activity than mRNA vaccines,224,238,239 providing a new direction for vaccine development.
Ko et al.224 designed a nanoparticle vaccine consisting of 24 polymer SARS-CoV-2 RBD nanoparticles and a ferritin skeleton. The vaccine caused cross-neutralizing antibody reactions to bat coronavirus, SARS-CoV, and SARS-CoV-2, including Alpha, Beta, and Gamma variants. The DH1041-DH1045 potent neutralizing antibody induced by the vaccine had neutralizing activity against various mutations, including K417N, E484K, and N501Y. Walls et al. designed a self-assembled protein nanoparticle immunogen composed of 60 SARS-CoV-2 S protein RBDs. The immunogen can target different immune epitopes and still induce high levels of neutralizing antibody expression at low doses.239 Moreover, compared with traditional vaccines, nanoparticles can exist in B-cell follicles for a long time, producing a sustained germinal center reaction to ensure the high-level production of antibodies.238 In addition, according to the self-assembly function of ferritin, S protein RBD,224 hemagglutinin,240, and other important viral proteins can be inserted and act as the physiologically relevant trimeric viral spike form to further improve the vaccine efficacy.238 Therefore, by optimizing the packaging of antigens and producing a stronger, longer-lasting immune response, nanoparticle vaccines are likely to play an important role in future COVID-19 vaccines.
An adjuvant is a vaccine component to enhance the immune response, playing a very important role in improving the efficacy of vaccines and reducing adverse events to ensure safety.225,241 In the past two decades, a series of new adjuvants have been used in licensed vaccines, including Aluminum hydroxide, MF59, AS03, CpG 1018, and CoVaccine HT,241 among which the Aluminum hydroxide can reduce the immune-related pathological reactions while other adjuvants can trigger specific cell receptors and induce an innate immune response in the injection site as well as the draining lymph nodes, further promoting the production of antibodies.225,242 Therefore, appropriate adjuvants are critical for maintaining vaccines’ durability and effectiveness. Here, some brief information on existing adjuvants used in COVID-19 vaccines is provided in Table 4.
Alum is the most widely used adjuvant in global vaccine development, which can induce the antibody response and different CD4+ cell responses (low level).225,241 Relevant mechanisms can be explained as enhancing anti-phagocytosis and activating the proinflammatory NLRP3 pathway.242 In addition, Aluminum adjuvants can reduce immune-related pathological reactions and improve safety, explaining the excellent safety of BBIBP-CorV and CoronaVac (both of the vaccines used Aluminum hydroxide as adjuvants).221,243 However, the immunogenicity of aluminum adjuvant is poor. The chemical modification of alum with short peptide antigens composed of repeated serine phosphate residues can significantly enhance GC cell and antibody responses.244
MF59 is a squalene oil-in-water emulsion adjuvant approved for use in influenza vaccines in more than 38 countries, and it is biodegradable and biocompatible.245 MF59 showed good tolerance and safety, and the inoculation of vaccines that use this adjuvant can motivate the activation of macrophages and the production of chemokines. These chemokines will recruit neutrophils, eosinophils, and monocytes to the lymph nodes, further form a cascade amplification reaction, and activate B cells and T cells.225 In addition, MF59 can stimulate IL-4 and STAT6 signal pathways and induce the antibody response. It is worth noting that the above response does not depend on type 1 interferon or inflammatory pathway.246 Thereby, MF59 has been selected as the adjuvant of COVID-19 vaccines.
AS03 is similar to MF59 but has an additional immune-enhanced component α- tocopherol (vitamin E). Thus, it can induce the expression of proinflammatory cytokines and chemokines independently (not depending on the type I interferon).242 In addition, AS03 can trigger a transient innate immune response, the injection of AS03 induces the transient production of cytokines in the mice model, and vitamin E can further enhance the expression of some chemokines and cytokines like CCL2, CCL3, and IL-6.225 AS03 is evaluated as the adjuvant of several recombinant S protein vaccines in the clinical trial, the add of AS03 further improve Th2-unbiased cell responses and the production of IFN-γ, which may enhance the efficacy of COVID-19 vaccines.247
CoVaccine HT is also an oil-in-water (O/W) emulsion, while CpG is a synthetic DNA sequence containing an unmethylated CpG sequence.242,248 Compared with the aluminum hydroxide adjuvant, AMP-CpG and CoVaccine HT showed better immunogenicity.249 Using AMP-CpG as an adjuvant, persistent antibody and T-cell reactions were still induced in elderly mice at low-dose S protein levels. Reducing the dose of S protein may decrease the occurrence of adverse events and improve vaccine safety. Compared to aluminum hydroxide, CoVaccine HT can promote the production and maturation of neutralizing antibodies to a greater extent, thereby quickly inducing an immune response to SARS-CoV-2.248
The use of aluminum adjuvants may reduce the adverse events of related vaccines and improve vaccine safety. However, the immunogenicity of aluminum adjuvants is poor. Therefore, the common use of different adjuvants may improve immunogenicity while ensuring subjects’ safety.
In addition to sequential immunization (mixed-vaccination), development of new vaccines (such as nanoparticle vaccine), and adjuvant improvement, changing the vaccination route is also a feasible measure to improve the protection and efficacy of existing COVID-19 vaccines.3,250 All WHO-approved vaccines adopt the intramuscular route (i.m route), and most of them can only protect the lower respiratory tract except for Ad26.COV-2.S, which can both protect the upper and lower respiratory tract.48 However, the new VOC Omicron has stronger infectivity of the upper respiratory tract and mainly causes symptoms of the upper respiratory tract, so the existing vaccine is difficult to protect effectively.122,235,251 Mucosal immunity plays an important role in preventing pathogen invasion. The intranasal administration(inhalation route, i.n route) of vaccines may achieve a better protection effect on preventing SARS-CoV-2 infection (especially Omicron variant).3,250,252,253 Compared with the traditional i.m route, the i.n route can effectively induce a local immune response. Vaccine antigen enters the respiratory tract and passes through the mucus layer through inhalation to induce the production of local IgA and provide protection at the pathogen’s entry site.253 In addition, the i.n route can induce the production of higher levels of mucosal antibodies. Although some IgG can be detected on the mucosal surface after the intramuscular injection, the lack of mucosal IgA still makes the respiratory tract vulnerable to infection.3 In addition, the i.n route has better compliance than the i.m route, and the administration is more convenient. However, the i.n route still has some disadvantages: the systemic immune response induced by this administration method is often lower than that of the i.m route because the titer of the virus may decrease when it is made into aerosol; the i.n route may cause antigen or vaccine adjuvant to enter the central nervous system and cause an adverse reaction; and i.n route usually needs auxiliary drug delivery devices (such as pressure device, atomizer), and the cost is higher, which limits the application of this approach.
Among the currently approved inactivated vaccine, viral vector vaccine, protein subunit vaccine, and mRNA vaccine, only viral vector vaccine has the potential to apply intranasal administration because inactivated vaccine, protein subunit vaccine, and mRNA vaccine antigens cannot actively enter cells, so it is difficult to stimulate mucosa effectively, and they remain difficult to commercialize.250 Van Doremalen N and colleagues evaluated the efficacy of AZD1222 in macaques and hamsters via intranasal administration. They found that the viral load in the nasal cavity of the experimental group decreased significantly after enhanced intranasal inoculation. No virus particle or RNA was detected in the lung tissue, indicating that intranasal administration is a prospect route for COVID-19 vaccines.254 Wu S et al. evaluated the safety, tolerability, and immunogenicity of the aerosolized Ad5-nCoV. The inhalation group(2 doses via i.n route on days 0 and 28) reported fewer adverse events compared with the injection group(2 doses of Ad5-nCOV via i.m route on days 0 and 28) and the mixed group(1 dose via i.m route on day 0 and the second dose via i.n route on day 28). The mixed group showed the highest induced-immune level, but the antibodies produced by the inhalation group were less than those of the injection group, suggesting that the inhalation route of Ad5-nCoV is an effective measure to boost immunity.226
The above study shows that the i.n route can protect the upper respiratory tract and inhibit virus infection more effectively than the i.m route, and relevant adverse events are fewer. However, the immune response induced by the i.n route alone is lower than that induced by the i.m route. Thus i.n route is more suitable for strengthening immunity. Through the mix route (i.m route at first and then i.n route), higher levels of antibodies can be induced compared with the repeat i.m route and provide stronger protection. As more and more vaccines are approved for clinical trials, the i.n route will be used more widely.
More than 153 candidate vaccines have entered human clinical trials. New vaccine platforms will undoubtedly be evaluated, such as nanoparticle and VLP vaccines.
After vaccination against COVID-19, T-cell immunity (such as the Th1 cell response), B-cell immunity (such as the germinal center response), and other immune responses may be produced.19,21 Differentiated Th cells can enhance the immune response in the body by promoting the activation of CD8+ T cells and secreting IFN-γ.31 With the aid of Th cells, activated B cells proliferate and divide in lymphatic follicles to form germinal centers, eventually form plasma cells, and memory B cells secret high-affinity antibodies. In addition, COVID-19 vaccines can produce memory B cells and memory T cells.24 The antiviral immune barrier in the host body can be constructed through the combined action of the humoral immune response, cellular immune response, and memory cells.
Although the COVID-19 vaccines have achieved exciting results in both animal studies and clinical trials,3 and seven vaccines have been authorized for emergency use by the WHO, adverse events that include pain at the injection site and fever,114,118 as well as complications such as coagulation dysfunction,154 myocarditis,74 immune diseases,155 nervous system diseases159 and lymphatic system diseases160 caused by vaccination, have raised concerns about vaccine safety. Given the low proportion of overall incidence of adverse events of vaccines and the fact that some complications occur mainly in patients with underlying diseases (e.g., cardiovascular diseases and tumors). Governments and relevant agencies are recommended to accelerate the vaccine immunization process. Simultaneously, special attention should be paid to the health status of the recipients, timely treatment of complications, vaccine development, and ensuring the lives and health of patients. In addition, considering the characteristics of some individuals (e.g., the elderly, pregnant women, organ transplant patients, cancer patients, and patients infected with HIV), relevant agencies should closely monitor adverse events and detect antibody titers after immunization.190 For organ transplant and cancer patients, the COVID-19 vaccine showed approximately 50% overall protective efficacy due to the continuous use of immunosuppressive drugs, which is unsatisfactory.201,206 Those populations are susceptible to SARS-CoV-2 infection, and timely immunization-enhanced measures should be performed to reduce breakthrough infections. For HIV-infected individuals, the viral level in the body should be effectively controlled during vaccination. Otherwise, breakthrough infections may still occur.27,209
New SARS-CoV-2 variants like Omicron often have high infectivity and high immune escape ability in the post epidemic era. The existing vaccine strategies are difficult to effectively prevent infections caused by the Omicron variant, which is not only due to the accumulation of more mutation sites in the S protein, but also because the Omicron variant mainly causes upper respiratory tract infection, while the protective antibodies induced by i.m route are often directed at the lower respiratory tract (lung). In this case, changing or adjusting vaccination strategies is very significant to control the infections and alleviate public health pressure. We believe that the following points deserve attention: (1) Although a booster dose can enhance the response of memory cells and increase the antibody titers to produce a stronger protective effect, the fourth dose injection might not effectively Omicron variant infection.150 (2) The optimization of COVID-19 vaccines, such as changing the administration route (use the inhaled vaccine and induced mucosal immunity to protect the upper respiratory tract further), developing new vaccines (for inactivated vaccines, the combined use of seed strain of VOCs like Beta + Delta may induce antibodies with multi-epitopes, as well as the use of VOC sequence for mRNA or viral vector vaccines,151) and adopting sequential immunization (the use of vaccines developed in different routes like inactivated + viral vector vaccine/mRNA vaccine) will provide better protection than existing vaccination strategies. (3) Although the adoption of inhalable and sequential immunization can improve the efficacy of COVID-19 vaccines, the incidence of adverse reactions of additional Ad5-nCoV was higher than the additional inoculation with homologous inactivated vaccine.226 In addition, the inoculation with viral vector vaccines or mRNA vaccines may lead to the complications mentioned above (such as myocarditis and thrombosis). The vaccine’s safety and effectiveness should be balanced. Although the new vaccine platform (such as the mRNA vaccine) may provide more effective protection, its safety is lower than the inactivated vaccine. Suppose multivalent inactivated vaccines like Beta + Delta inactivated vaccine strategies are adopted. In that case, the development can only be carried out after the emergence of a new variant, and the developing speed is lower than the mRNA vaccine uses new variants’ sequences. (4) The emergence of the Omicron variant may indicate the change of the main infection site of SARS-CoV-2 (other VOC usually cause the lung infection except for Omicron), and the symptoms of Omicron infected people are lighter, the hospitalization rate is lower than Delta, infected patients.255 In this case, there are many asymptomatic Omicron infected people. Convenient and effective COVID-19 antiviral drugs (especially oral-taken drugs) will greatly alleviate the severe epidemic situation and contribute to the early end of the COVID-19 pandemic.256 In addition, Omicron might not be the last VOC, a new recombinant variant Delta 21 J/AY.4-Omicron 21 K/BA.1, also called “Deltamicron”, has appeared in many countries like France and America, and the NTD of Delta combined with the RBD of Omicron may lead to optimization of viral binding to host cell membranes.257 Although the detected sequence of Deltacron was lower than Omicron, and the main symptom is mild upper respiratory tract infection, surveillance should be enhanced for this emerging variant.
Furthermore, previously SARS-CoV-2-infected individuals produced high-level antibody responses after a single dose of the COVID-19 vaccine, which may be associated with the strong memory cell response.24 For those who have not been infected with SARS-CoV-2, nanoparticle vaccines may be a better choice to bestow immunity to infections by mutant strains. Compared with traditional vaccines, nanoparticles can remain in germinal center B cells and ensure the production of high-level antibodies by generating a sustained germinal center reaction.238 In addition to developing new vaccines, adjuvants with better immunogenicity or combined adjuvants may reduce adverse events and improve the vaccine’s protective efficacy.248
With the launch of new vaccines and the approval of oral antiviral drugs, such as molnupiravir, the stalemate between humans and SARS-CoV-2 will be broken.256,258 A study conducted by Swadling et al. of 58 medical staff with high exposure risk but had not been infected with SARS-CoV-2 found a higher anti-replication transcription complex (RTC) T-cell reaction.258 These findings may provide new ideas for vaccine design by targeting RTC and inducing similar T-cell responses. And a nasal-delivery IgY antibody based on SARS-CoV-2 RBD showed multi-protection against Beta, Delta, and Omicron variants in the animal model, which promised to be an additional measure of pre-exposure prophylaxis of SARS-CoV-2 infection.259 These new achievements in the pharmaceutical field will undoubtedly become powerful weapons against COVID-19 and help end the pandemic.
Hu, B., Guo, H., Zhou, P. & Shi, Z. L. Characteristics of SARS-CoV-2 and COVID-19. Nat. Rev. Microbiol. 19, 141–154 (2021).
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Coronavirus vaccine development: from SARS and MERS to COVID-19
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Published: 20 December 2020
Volume 27, article number 104, (2020)
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Yen-Der Li, Wei-Yu Chi, Jun-Han Su, Louise Ferrall, Chien-Fu Hung & T.-C. Wu
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Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a new type of coronavirus that causes the Coronavirus Disease 2019 (COVID-19), which has been the most challenging pandemic in this century. Considering its high mortality and rapid spread, an effective vaccine is urgently needed to control this pandemic. As a result, the academia, industry, and government sectors are working tightly together to develop and test a variety of vaccines at an unprecedented pace. In this review, we outline the essential coronavirus biological characteristics that are important for vaccine design. In addition, we summarize key takeaways from previous vaccination studies of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV), highlighting the pros and cons of each immunization strategy. Finally, based on these prior vaccination experiences, we discuss recent progress and potential challenges of COVID-19 vaccine development.
Introduction
Coronaviruses (CoVs) are a group of related viruses that can cause respiratory tract infection in humans ranging from mild symptoms to lethal outcomes. Until now, there are seven genera of CoVs that are known to infect humans [1]. Four of these genera, including Human Coronavirus 229E (HCoV-229E), Human Coronavirus OC43 (HCoV-OC43), Human Coronavirus NL63 (HCoV-NL63), and Human Coronavirus HKU1 (HCoV-HKU1), only cause relatively mild and self-limiting respiratory symptoms [2]. Alternatively, the other three CoVs, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), are highly pathogenic and can lead to severe respiratory diseases and fatal outcome in infected patients. The first lethal coronavirus SARS-CoV emerged in 2002 in Guangdong Province, China. During the 2002–2004 outbreak, SARS-CoV had infected 8,098 people and resulted in 774 SARS-associated deaths (~ 10% mortality rate) across 29 countries before it disappeared [3]. In 2012, MERS-CoV emerged in Saudi Arabia. It caused two outbreaks in South Korea in 2015 and in Saudi Arabia in 2018, and still has ongoing reports of sporadic cases nowadays. As of January 2020, there are 2,519 confirmed MERS cases and 866 deaths (~ 35% mortality rate) across 27 countries [4]. In December 2019, a new type of CoV that can cause severe respiratory illness emerged in Wuhan, China. The World Health Organization named this novel virus SARS-CoV-2 and the disease COVID-19, or Coronavirus Disease 2019. The clinical manifestation of COVID-19 can vary from asymptomatic and mild flu-like symptoms to acute respiratory distress syndrome and death. Long-term pulmonary, cardiological, and neurological complications have also been reported in COVID-19 cases [5]. Compared with SARS-CoV and MERS-CoV, SARS-CoV-2 is highly contagious with an estimated reproductive number of 2.2 (one existing COVID-19 case can cause an average of 2.2 new infections) [6]. In addition, its ability to spread through asymptomatic patients has posed a great challenge to containment measures [7]. By October 2020, SARS-CoV-2 has infected more than 43 million individuals and resulted in about 1.15 million deaths (~ 3% mortality rate) in 235 countries, areas or territories worldwide [8]. Needless to say, COVID-19 has become the most serious public health crisis of our generation and has a profound impact on the global economy and geopolitics. Although our understanding of pathogenic CoVs has been steadily accumulating for about two decades, no effective vaccine has yet been approved for the prevention of human CoV infection. Considering the rapid spread and high mortality of COVID-19, an effective vaccine is urgently needed to control this pandemic. In this review, we summarize relevant CoV biology, SARS and MERS immunization strategies, and recent efforts of COVID-19 vaccine development. We hope this review can provide essential knowledge for any researcher who is interested in COVID-19 vaccine development.
Coronavirus biology and its implication on vaccine development
Coronaviruses, whose name derives from their characteristic crown-like appearance under the electron microscope, are enveloped RNA viruses with a diameter of approximately 80–160 nm [9, 10]. The genome of CoVs is a ~ 30 kb single-stranded positive-sense RNA molecule, which is the largest genome of all known RNA viruses [9,10,11]. The 5′-terminus of the CoV genome contains two overlapping open reading frames (ORFs): ORF 1a and ORF 1b, spanning two-thirds of the genome length (Fig. 1a) [9,10,11]. ORF 1a and ORF 1ab can be translated into two polyproteins (pp), pp1a and pp1ab, which are further cleaved into 16 non-structural proteins (Nsps) involved in viral genome replication and subgenomic mRNA synthesis [9,10,11]. The 3′-terminus of the CoV genome encodes four major structural proteins in the order of spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins (Fig. 1a) [9,10,11]. S, E, M protein forms the envelope of the CoV, while N protein forms the capsid to pack genomic RNA (Fig. 1b) [9,10,11]. The 3′-terminus of the genome also encodes multiple accessory proteins, which are usually genus-specific and can help CoV evade the immune system or increase virulence [9,10,11]. For instance, SARS-CoV contains accessory protein ORF 3a, 3b, 6, 7a, 7b, 8a, 8b and 9b, MERS-CoV contains ORF 3, 4a, 4b, 5, 8b, and SARS-CoV-2 contains ORF 3a, 6, 7a, 7b, 8, 10 (Fig. 1a) [12,13,14].
Fig. 1
figure 1
The genome and virion structure of coronaviruses (CoVs). a The genome structure of SARS-CoV, MERS-CoV, and SARS-CoV-2 [12,13,14]. The 5′-terminus of the CoV genome contains two overlapping open reading frames (ORFs): ORF 1a and ORF 1b, spanning two-thirds of the genome length. ORF 1a and ORF 1ab can be translated into two polyproteins (pp), pp1a and pp1ab, which are further cleaved into 16 non-structural proteins (Nsps). The 3′-terminus of the CoV genome encodes four major structural proteins in the order of spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins. Genus-specific accessory proteins are also encoded at the 3′-terminus of the CoV genome. b The virion structure of SARS-CoV-2 [16]. The spike (S), envelope (E), membrane (M) proteins form the envelope of the CoV, and the nucleocapsid (N) proteins form the capsid to pack the genomic RNA. The spike protein binds to angiotensin converting enzyme 2 (ACE2) on the cell membrane, which allows the virus to enter the cell. (Created with BioRender.com.)
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Many viral proteins are essential for the life cycle of CoVs. For entering target cells, S protein first binds to cellular receptors through its receptor-binding domain (RBD), and the receptor-virus complex is subsequently translocated to endosomes (Fig. 2) [15]. Both SARS-CoV and SARS-CoV-2 S proteins bind to angiotensin-converting enzyme 2 (ACE2), while the S protein of MERS-CoV uses dipeptidyl peptidase-4 (DPP4) as its cellular receptor (Fig. 1b) [16]. At the endosome, S protein is further cleaved into S1 (RBD-containing) and S2 (non-RBD-containing) subunits, and the S2 subunit mediates fusion between the viral envelope and the host cell membrane [15]. After entering the cell, several Nsps, particularly RNA‐dependent RNA polymerase (Nsp12) and helicase (Nsp13), mediate the replication of the CoV genome and the transcription of CoV mRNA [17]. The CoV mRNA is further translated into different nonstructural and structural proteins. The N proteins bind to CoV genomic RNA to form viral nucleocapsids, and S, E, M proteins form the envelope of CoV [15]. After assembly, viral particles bud through an endoplasmic reticulum (ER)-Golgi pathway and exit the cells by exocytosis (Fig. 2) [15].
Fig. 2
figure 2
The life cycle of SARS-CoV-2 [9, 10, 15]. Upon binding to the membrane receptor ACE2, SARS-CoV-2 virion enters the host cell and releases its plus-strand RNA genome. The plus-strand RNA translates pp1a and pp1ab, which are further cleaved into multiple non-structural proteins (Nsps) including an RNA-dependent RNA polymerase (Nsp12). The RNA-dependent RNA polymerase transcribes a negative-strand genomic RNA, and then uses this negative-strand genomic RNA as template to generate more plus-strand genomic RNA (genomic replication) and many different subgenomic RNAs (subgenomic transcription). The subgenomic RNAs are further translated into major structural proteins (N, S, M, E), which will assemble with plus-strand genomic RNA to form a mature virion in lumen of the ER. Finally, the whole virus leaves the cell through exocytosis. (Reprinted from “Coronavirus Replication Cycle”, by BioRender.com (2020). Retrieved from https://app.biorender.com/biorender-templates)
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The S protein is particularly important for virus-cell receptor binding and virus-cell membrane fusion, suggesting that it can be an effective target for CoV vaccine design [15]. In fact, studies have shown that antibodies generated against the S protein are long-lasting and immunodominant in recovered SARS patients [18, 19]. In addition, several studies have demonstrated that the anti-S antibody can neutralize SARS-CoV and MERS-CoV and provides protective effects in animals and humans [20,21,22]. Moreover, many S protein-based vaccines against SARS-CoV and MERS-CoV have been shown to elicit potent immune responses and protective effects in preclinical models [23,24,25,26,27]. These results corroborate that CoV S protein serves as an ideal vaccine target to induce neutralizing antibodies and protective immunity. Besides S protein, other structural proteins have also been tested as vaccine targets. N protein-based vaccines usually cannot induce neutralizing antibodies, likely due to the fact that N protein is not displayed on the CoV surface [16]. However, N protein has the advantage of being more conserved across CoV species than S protein, making it a potential target for a T-cell inducing, universal CoV vaccine [16]. One recent study has shown that a viral vector vaccine expressing N protein can induce CD4+ T cell-dependent protection against SARS-CoV and MERS-CoV, suggesting the feasibility of N protein-based T-cell inducing CoV vaccines [28]. M protein-based vaccines, on the other hand, can induce a high titer of antibody response in immunized animals [29]. However, no neutralization antibody or protective immunity data of M protein-based vaccines in preclinical models have been demonstrated. Finally, very few CoV E protein-based immunization studies have been reported so far, and none of the studies demonstrated induction of neutralizing antibodies or protective immunity [30].
There are also immunopathological complications associated with the SARS-CoV and MERS-CoV vaccines that require addressing and further optimization. One adverse effect is the induction of antibody-dependent enhancement (ADE) effect, which is usually caused by vaccine-induced suboptimal antibodies that facilitates viral entry into host cells [11, 31]. A study found that SARS-CoV vaccine based on full-length S protein enhances SARS-CoV infection of human cell lines in vitro [32]. Additionally, two studies have also shown that anti-S protein serum results in increased viral infectivity of SARS-CoV [33, 34]. These results raise safety concerns for S protein-based SARS-CoV and MERS-CoV vaccines. One potential strategy to overcome the ADE problem is to design vaccines that only contain major neutralizing epitopes, such as the S1 subunit or the RBD domain of the S protein. This strategy can decrease the induction of non-neutralizing antibodies by CoV vaccines and therefore reduce the ADE effect. Another potential adverse effect is vaccine-induced eosinophilic immunopathology, which is an unwanted Th2-skewed immune response elicited by vaccination [11, 35]. At least two studies have reported that whole inactivated virus vaccine of SARS-CoV induces eosinophilic proinflammatory pulmonary response after mice challenged with SARS-CoV [36, 37]. In addition, one study also reported that immunization with SARS-CoV virus-like particle (VLP) vaccine leads to eosinophilic immunopathology in the lung after viral challenge [37]. In order to prevent this Th2-type immunopathology, a few studies have worked on adjuvant optimization. They found that appropriate adjuvants, such as Toll-like receptor agonist and delta-inulin polysaccharide, can increase serum neutralizing antibody titers and reduce lung eosinophilic immunopathology [38, 39]. Their results provide a promising strategy to deal with Th2-skewed immune response induced by some CoV vaccines.
Previous progress of SARS-CoV and MERS-CoV immunization strategies
Various forms of vaccines targeting SARS-CoV and MERS-CoV have been developed and tested in preclinical models. However, only a few of them entered clinical trials and none of them have been FDA approved. These approaches include protein subunit vaccines, virus-like particle vaccines, DNA vaccines, viral vector vaccines, whole-inactivated vaccines and live-attenuated vaccines. The following sections outline the principles of various forms of SARS-CoV and MERS-CoV vaccine development (Table 1), and the latest results from both preclinical studies and clinical trials (Table 2).
Table 1 Advantages and disadvantages of different vaccine platforms
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Table 2 Clinical trials of SARS, MERS and COVID-19 vaccines
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Protein subunit vaccine
Protein subunit vaccines consist of viral antigenic fragments produced by recombinant protein techniques. They are easy to produce, and relatively safe and well-tolerated compared to whole virus vaccines and viral vector vaccines. The drawback of protein subunit vaccines is their low immunogenicity. Therefore, adjuvants and fusion with immunostimulatory molecules are usually used together with subunit vaccines to overcome this challenge.
The development of SARS-CoV protein subunit vaccines was initially surrounding full-length S protein-based vaccines and then later focused on S protein RBD-based vaccines. None of the SARS-CoV protein subunit vaccines entered clinical trials, but they induced potent antibody responses and protective effects in preclinical models [23, 24, 32, 40,41,42,43,44]. Studies have shown that full-length S protein, extracellular domain of the S protein, and trimeric S proteins (triSpike) are all immunogenic and can elicit protection against SARS-CoV infection [23, 24, 32]. However, Kam et al. and Jamue et al. have found that triSpike vaccine can also cause Fcγ receptor II (FcγRII)-dependent SARS-CoV infection in human B cells in vitro [32, 33]. On the other hand, S protein RBD-based vaccines are able to induce high-titer neutralizing antibodies without causing obvious pathogenic effects [40,41,42,43,44]. This is probably because RBD-based vaccines do not contain additional non-neutralizing epitopes as full-length S protein vaccines do. One study has shown that RBD-based vaccines not only protect most of the SARS-CoV challenged mice with no detectable viral RNA in the lung, but can also induce long-lasting S-specific antibodies that can be maintained for 12 months [42]. Furthermore, RBD-based SARS-CoV vaccines have also been shown to induce RBD-specific IFN-γ producing cellular immune responses in mice [44]. As a result, SARS-CoV RBD has become the main target for SARS vaccines. Finally, SARS-CoV subunit vaccines based on S2 subunit, N and M structural proteins have also been tested [29, 45, 46]. However, no evidence has shown that they can induce neutralizing antibodies or protective effects against viral challenge.
Guided by previous SARS-CoV experiences, most proteins subunit vaccines of MERS-CoV are focused on RBD-based vaccines. RBD-based MERS-CoV vaccines generally show great immunogenicity and elicit potent neutralizing antibodies, cell-mediated immunity, and protective effect against MERS-CoV infection [25, 26]. One study from Tai et al. found that trimeric RBD protein vaccines can induce long-lasting neutralizing antibodies for 6 months [26]. Another study also from Tai et al. demonstrated that recombinant RBD proteins from different MERS-CoV strains can induce antibodies that cross-neutralize with divergent human and camel MERS-CoV strains [25]. These results indicate that MERS-CoV RBD serves as a promising vaccine target with the ability to induce long-lasting and broad-spectrum neutralizing antibodies against infection. Other than RBD-based vaccines, RBD-containing S1 subunit vaccines have also been shown to induce neutralizing antibodies and protection against MERS-CoV [47, 48]. Notably, the N-terminal domain (NTD) of the S protein binds to sialic acid and is important for MERS-CoV infection in certain cell types. Jiaming et al. showed that immunization with NTD-based vaccine also provides protection against MERS-CoV and induces potent humoral and cell-mediated immunity [49]. However, since SARS-CoV-2 NTD does not have the same sialic acid-binding function as MERS-CoV, NTD-based strategy might not be generalizable to SARS-CoV-2 vaccine development.
Apart from antigen design, several other factors also affect the efficacy of protein subunit vaccines [16]. The expression system of protein influences the quality and quantity of protein subunit vaccines. Du et al. demonstrated that SARS-CoV RBD protein expressed by mammalian 293T cells induces stronger neutralizing antibody responses than RBD expressed by insect cells and E. coli, which is probably due to the native conformation and post-translational modification maintained in mammalian cellular system [43]. In addition, adjuvants play an important role in enhancing the immunogenicity of protein subunit vaccines. Zhang et al. have examined multiple adjuvants (Freund’s, aluminum, Monophosphoryl lipid A, Montanide ISA51 and MF59) in conjugation with MERS-CoV RBD and found that MF59 best potentiate the protein to elicit neutralizing antibodies and protective effects [50]. Their data provide a good starting point for optimizing adjuvants for SARS-CoV-2 subunit vaccines. Moreover, the immunization route of the subunit vaccine can also affect its potency, and in combination with different antigen and adjuvants, the optimized vaccination pathway may change. For example, Li et al. demonstrated that for SARS-CoV S and S1 subunit vaccine, intramuscular (I.M.) route induces stronger antibody responses than subcutaneous (S.C.) route, while Lan et al. showed that S.C. route is preferable over I.M. injection for Freund’s and CpG-adjuvanted MERS-CoV RBD vaccine [23, 51]. Therefore, the ideal route might need to be customized for SARS-CoV-2 subunit vaccines.
Virus-like particle vaccine
Virus-like particles (VLPs) are self-assembled viral structural proteins that mimic the conformation of native viruses but lack the viral genome. Compared with protein subunit vaccines, VLP vaccines present epitope in conformation that is more similar to the native virus, leading to better immunization responses. In addition, compared to whole virus vaccines, the production of VLP vaccines does not involve live virus or inactivation steps, which makes them safer vaccine candidates. The highly repetitive antigenic surface of VLP vaccines also help induce stronger antibody response by efficiently cross-linking B-cell surface receptors. Up to now, VLP vaccines have been commercialized for the protection against human papillomavirus (Cervarix™ and Gardasil®) and hepatitis B virus (Engerix® and Recombivax HB®) [52].
Few SARS-CoV and MERS-CoV VLP vaccines have been reported so far. For SARS-CoV, Lokugamage et al. have demonstrated that chimeric VLPs composed of SARS-CoV S protein and mouse hepatitis virus E, M and N proteins can induce neutralizing antibody responses and reduce SARS-CoV virus titer in mice lung after viral challenge [53]. In addition, another study performed by Liu et al. showed that chimeric VLPs consisting of SARS-CoV S protein and influenza virus M1 protein can induce neutralizing antibodies and provide protection against lethal challenge in mice [54]. However, one study used the same chimeric VLPs as Lokugamage et al. and showed that this VLP vaccine can lead to pulmonary immunopathology on challenge with SARS-CoV [37, 53]. Therefore, potential adverse effects of coronavirus VLP vaccines should be monitored. For MERS-CoV VLP vaccines, Wang et al. have shown that VLPs containing MERS-CoV S, E and M proteins can induce specific antibody response and Th1-mediated cellular immunity in rhesus macaques [55]. The same research group developed another chimeric VLP vaccine containing the fusion of the receptor-binding domain (RBD) of MERS-CoV S protein and the canine parvovirus (CPV) VP2 structural protein [56]. They showed that this VLP vaccine induces MERS-CoV-specific antibody response and T-cell immunity in mice [56]. These studies suggested that VLP vaccines hold the potential for clinically effective coronavirus vaccines.
DNA vaccine
DNA vaccines contain genes encoding viral antigenic components that are expressed by plasmid vectors and delivered into cells through electroporation. Compared with other vaccine technologies, DNA vaccines offer a fast and flexible platform for vaccine development and production, making it an attractive technology to combat emerging epidemics like SARS-CoV-2. In addition, antigen production of DNA vaccines happens in the target cells, which helps recapitulate the native conformation and post-translational modification of viral antigens. However, an important drawback of DNA vaccines is their limited immunogenicity due to their inability to spread and amplify in vivo. Therefore, it is important to consider strategies that can enhance the potency of DNA vaccines, such as adding adjuvant or using a prime-boost regimen. Besides, the genomic integration of DNA vaccines into the host chromosome is another biosafety concern, which may lead to mutagenesis and oncogenesis [57]. Even though previous studies have shown that the risk of vaccine plasmid insertion into the host chromosome is pretty low, the FDA and the WHO still recommends integration studies be included as part of the safety program of DNA vaccines [58, 59].
Several DNA vaccine candidates have been reported for SARS-CoV, including the S-, M-, and N protein-based vaccines [60,61,62,63,64]. Although all of them can generate a certain level of antibody and cell-immune responses, only S protein-based DNA vaccine has been shown to induce protective effect against SARS-CoV infection, probably due to the indispensable role of S protein in receptor binding [60]. Yang et al. has demonstrated that immunization with DNA encoding full-length S protein, S protein lacking part of cytoplasmic domain, S protein lacking both cytoplasmic and transmembrane domains can all induce neutralizing antibodies and T-cell immune responses, as well as providing protective effect in mice [60]. This promising result leads to a following phase I clinical trial based on SARS-CoV full-length S protein DNA vaccine, which showed that the vaccine was well-tolerated in patients and can induce neutralizing antibodies and T cell responses in healthy adults [65]. Furthermore, two studies have made use of prime-boost strategy to enhance the potency of S protein-based SARS-CoV DNA vaccine. Zakhartchouk et al. reported that the combination of DNA and whole-inactivated SARS-CoV vaccines can increase the magnitude of antibody response as well as inducing a more desirable Th1-skewed immune response [66]. Woo et al. demonstrated that using DNA vaccine priming plus E. coli expressed recombinant S protein booster can also induce higher neutralization titers than DNA or protein subunit vaccine alone [67].
Similar to SARS-CoV, several studies on MERS-CoV DNA vaccines have demonstrated optimistic results. Muthumani et al. reported that a full-length S protein-based MERS-CoV DNA vaccine can induce potent cellular immunity and antigen-specific neutralizing antibodies in mice, macaques, and camels, and macaques vaccinated with this DNA vaccine were protected against MERS-CoV challenge without demonstrating any clinical or radiographic signs of pneumonia [68]. Building on these encouraging data, a phase I clinical trial based on this MERS-CoV DNA vaccine (GLS-5300, or INO-4700) has been completed [69]. The results showed that GLS-5300 is well tolerated with no vaccine-associated serious adverse events, and immunization with GLS-5300 induces durable immune responses in 85% of participants after two vaccinations [69]. These data support further development of the GLS-5300 vaccine. Notably, a SARS-CoV-2 DNA vaccine candidate, INO-4800, is based on the same design as GLS-5300, and this vaccine is now in phase I/II clinical trial (NCT04447781 and NCT04336410) [70]. In addition, another MERS-CoV vaccine study using full-length S protein DNA priming plus S1 protein subunit booster elicits robust serum-neutralizing activity against several MERS-CoV strains in mice and rhesus macaques [47]. Immunizing rhesus macaques with this DNA prime/protein boost vaccine confers protection against MERS-CoV-induced radiographic pneumonia, supporting this strategy as a promising approach for MERS-CoV vaccine development [47]. Aside from full-length S, S1 subunit is also a good target for MERS-CoV DNA vaccine. One study performed by Al-Amri et al. has compared the immunogenicity of full-length S-based (pS) and S1-based (pS1) MERS-CoV vaccine using the same expression vector [71]. They found that pS1 immunization elicited a balanced Th1/Th2 response and generally higher levels of all IgG isotypes compared to pS vaccination, which may be explained by the fact that the transmembrane domain-lacking S1 subunit is secreted more efficiently to the extracellular space and therefore result in greater uptake by antigen-presenting cells [71]. This study suggested that S1 might be a better target than full-length S for MERS-CoV DNA vaccine [71].
Taken together, DNA vaccines encoding full-length S or S1 protein have demonstrated encouraging results to fight against SARS-CoV and MERS-CoV. The same strategy is likely to be generalizable to SARS-CoV-2 DNA vaccine considering the biological similarity.
Viral vector vaccine
Viral vector vaccines are recombinant viruses that encode antigens of interest in an unrelated modified virus. They deliver antigen into the cells mimicking natural infection, so they induce strong antigen-specific cellular and humoral immune responses per se, thereby obviating the need for additional adjuvants. In addition, viral vectors are able to accept large insertions in their genome, providing a flexible platform for antigen design. Despite these advantages, there are several drawbacks. The manufacturing process for viral vector vaccines is more complicated than other approaches, including the optimization of cellular systems and the exclusion of contaminants, which can greatly affect the efficiency of viral vectors [57]. Moreover, recombinant viruses carry the risk of integrating their genome into the human host, so additional biosafety assessment will be required before entering clinical trials. Finally, if the chosen viral vector can infect the general populations, the pre-existing immunity on the viral vector could dampen the induced immune response, which has been seen in adenovirus- and measle virus-based vaccines [72, 73].
Similar to DNA and protein subunit vaccines, most viral vector coronavirus vaccines target the S antigen. Numerous viral vectors have been used to develop SARS-CoV and MERS-CoV vaccines, which have been described in detail in previous review articles [74, 75]. In the following sections, we will highlight vaccines based on adenovirus, modified vaccinia virus Ankara and Venezuelan equine encephalitis virus, which are the most well studied viral vector platforms for coronavirus vaccines. We will also briefly introduce other recombinant viral platforms that are being actively developed for coronavirus vaccines.
SARS-CoV viral vector vaccine
Adenovirus is a popular viral vector vaccine that has been tested in clinical trials for a wide variety of diseases, and several studies have also examined the efficacy of adenovirus-based SARS-CoV vaccine. The feasibility of SARS adenovirus vector vaccine was first demonstrated in two study by Gao et al. and Liu et al. [76, 77]. They showed that adenoviral vector expressing S1 fragment can induce neutralizing antibodies in monkeys and rats, respectively, but neither studies showed evidences of in vivo protection against SARS-CoV challenge [76, 77]. Later on, See et al. compared the efficacy of SARS-CoV S protein expressing adenovirus vaccine with the whole inactivated SARS-CoV vaccine [78]. They found that both vaccines induce protective effects in mice against SARS-CoV challenge, though the neutralizing antibody response is weaker in adenovirus-based vaccine than whole-inactivated virus vaccine [78]. Besides, Kobinger et al. have also tested a prime-boost regimen of S protein-expressing human adenovirus type 5 and chimpanzee derived adenoviruses in ferrets [79]. Their results showed that this vaccine leads to a substantial reduction in viral load and prevents pneumonia in ferrets after SARS-CoV challenge [79]. All these results have encouraged subsequent development of adenovirus-based MERS and COVID-19 vaccines.
Modified vaccinia virus Ankara (MVA) is another well-established vaccine platform to combat emerging infectious diseases [80]. Bisht et al. has shown that intranasal or intramuscular immunization with highly attenuated MVA containing full-length S gene induces both neutralizing antibody responses and protective immunity in mice, evident by reduced virus titer in mice lung post SARS-CoV challenge [81]. Another study performed by Chen et al. demonstrated that recombinant MVA expressing SARS-CoV S protein elicits neutralizing antibodies in mice, ferrets, and monkeys, but they didn’t show any protection experiment data in this study [82]. However, another two studies performed by Weingartl et al. and Czub et al. showed that MVA vaccine expressing SARS-CoV S protein does not provide protective effect in ferrets, and it even induces inflammatory responses and focal necrosis in the liver [83, 84]. Therefore, potential adverse effects need to be considered for MVA-based SARS-CoV S protein vaccine.
For Venezuelan equine encephalitis (VEE) virus-based SARS-CoV vaccine, Deming et al. has reported that VEE virus replicon particles (VRP) expressing S protein provides complete short- and long-term protection against homologous strain challenge in young and senescent mice [85]. To further improve the efficacy of VEE virus-based vaccine against heterologous SARS-CoV challenge, Sheahan et al. has improved the immunogenicity of VRP S protein vaccine by substituting an attenuated VEE glycoprotein with its wild-type counterpart, and their result showed that the improved VRP S protein vaccine can protect aged mice from heterologous SARS-CoV challenge [86].
Several additional viral vectors have also shown promising results for SARS-CoV vaccines. Two studies from Buchholz et al. and Bukreyev et al. have used an attenuated parainfluenza virus as vector to express SARS-CoV S protein, showing that parainfluenza-based vaccine can induce neutralizing antibody responses and protective effect against SARS-CoV challenge in hamsters and monkeys [30, 87]. Besides, attenuated vesicular stomatitis virus (VSV) have also been tested as SARS-CoV vaccine vectors by Kapadia et al. [88]. Their results showed that immunization with recombinant VSV expressing S protein can induce SARS-neutralizing antibodies and is able to protect mice from SARS-CoV infection [88].
MERS-CoV viral vector vaccine
Several adenovirus-based MERS-CoV vaccines have been developed. Human adenovirus type 5 (Ad5) and type 41 (Ad41) expressing MERS-CoV S or S1 protein have been shown to induce neutralizing antibodies in mice [89, 90]. However, the protection effect of Ad5- and Ad41-based MERS vaccines have not been evaluated [89, 90]. Notably, Ad5-MERS-S vaccine has been used in combination with S protein nanoparticles [91]. Heterologous immunization by priming with Ad5/MERS and boosting with spike protein nanoparticles has demonstrated not only protective effect in hDPP4-transduced mice against MERS-CoV challenge, but also more balanced Th1/Th2 responses than Ad5- or nanoparticles-alone homologous prime-boost vaccines [91]. The Ad5 vector has already been applied to SARS-CoV-2 vaccine development, and promising results have been demonstrated in phase I and II clinical trials [92, 93].
Besides, chimpanzee adenovirus has been employed as viral vector with an aim to overcome the pre-existing immunity problem of human adenoviruses. A MERS-CoV S protein vaccine based on a chimpanzee adenoviral vector (ChAdOx1) was shown to induce high levels of neutralizing antibodies and cell-mediated immune in mice, and to protect hDPP4-transduced mice from lethal MERS-CoV challenge [94, 95]. In addition, ChAdOx1-MERS vaccine has also been demonstrated to reduce viral load in dromedary camels and provide protective immunity in rhesus macaques [96, 97]. Given these promising preclinical results, the ChAdOx1-MERS vaccine has entered a phase I clinical trial, and the trial result showed that ChAdOx1-MERS was safe and well tolerated at all tested doses, and a single dose was capable of inducing both humoral and cellular responses against MERS-CoV [98]. Notably, the same research team has applied ChAdOx1 platform to SARS-CoV-2 vaccine development and their product AZD1222 (or ChAdOx1-nCoV-19) is now a leading player of the COVID-19 vaccine race [99].
The vaccine of modified vaccinia virus Ankara (MVA) expressing full-length MERS-CoV S protein has been reported to induce not only virus-neutralizing antibody responses and MERS-CoV-specific CD8+ T cell response, but also provide protective effect against MERS-CoV in DPP4-transduced mice [100]. Furthermore, dromedary camels immunized with this MVA-based MERS-CoV S protein vaccine generate neutralizing antibodies and show less virus excretion after MERS-CoV infection [101]. Since camel is a major animal reservoir for MERS-CoV, this vaccine provides an opportunity to effectively control camel-to-human transmission [101]. Finally, a phase I clinical trial showed that MVA-MERS-S vaccine has a favorable safety profile, and homologous prime–boost immunization of MVA-MERS-S vaccine induces humoral and cell-mediated immune responses against MERS-CoV, which supports testing MVA-MERS-S vaccine in a larger population [102].
MERS-CoV vaccines dependent on Venezuelan equine encephalitis (VEE) virus have also been studied. Agnihothram et al. have demonstrated that VEE virus replicon particles (VRP) expressing MERS-CoV S protein can induce neutralizing antibodies in young and aged mice [103]. Another study from Zhao et al. found that VRP-based MERS N protein vaccine can induce memory CD4+ immune response and provide protective immunity against MERS-CoV in hDPP4-transduced mice [28]. Since N protein is more conserved than S protein across different coronavirus species, their approach might hold the potential to develop a universal T cell-inducing coronavirus vaccine [28].
Several other vaccine platforms have been applied for the development of MERS-CoV vaccine. Measle virus- and rabies virus-based MERS-CoV S protein vaccines have been shown to induce neutralizing antibodies and provide protective effect against MERS-CoV in hDDP4-transduced mice [104, 105]. Newcastle disease virus and vesicular stomatitis virus vectors have also been employed as S protein-expressing MERS vaccines [106, 107]. However, only in vitro neutralization data have been provided and no in vivo protection data has been demonstrated for these two vaccines [106, 107].
In summary, SARS-CoV and MERS-CoV vaccines based on many viral vectors, including adenovirus, modified vaccinia virus Ankara, Venezuelan equine encephalitis virus, parainfluenza virus, vesicular stomatitis virus, Measle virus, and rabies virus, have been shown to elicit protective immunity against viral challenges. Some of these viral vectors has already become promising candidate platforms for the development of SARS-CoV-2 vaccine.
Whole inactivated vaccine
Whole inactivated vaccines are composed of chemically or radiationally inactivated virions. They contain a full repertoire of immunogenic components of the original virus, and compared with attenuated viruses, they carry no risk of viral reactivation if properly inactivated. Although safer than live attenuated vaccines, the immunogenic epitopes of inactivated viruses may be structurally deformed during the inactivation process, which can undermine the protection they may provide. Moreover, both SARS-CoV and MERS-CoV whole inactivated vaccines have been reported to induce eosinophil-related lung pathology [36, 37]. These disadvantages make whole inactivated vaccines a less attractive strategy for coronavirus vaccine development.
During the early development of SARS-CoV vaccines, inactivated whole virus was once a leading strategy. Studies have shown that UV- and formaldehyde-inactivated SARS-CoV can induce neutralizing antibody response, and a phase I clinical trial using β-propiolactone-inactivated SARS-CoV vaccine demonstrated that it is safe, well-tolerated, and can elicit SARS-CoV-specific neutralizing antibodies [108,109,110]. However, later studies found that a UV-formaldehyde doubly inactivated SARS-CoV vaccine, either unadjuvanted or alum-adjuvanted, provides incomplete protection in mice and induces eosinophilic pulmonary inflammatory response upon SARS-CoV challenge [36]. Similarly, gamma-irradiated MERS-CoV vaccine adjuvanted with alum or MF59 also induces eosinophil-related lung pathology after virus challenge, despite its ability to induce neutralizing antibodies [111]. These results have dampened the enthusiasm of whole-inactivated coronavirus vaccines. Nevertheless, recently two studies have revealed that UV-inactivated SARS-CoV adjuvanted with Toll-like receptor agonists, and formaldehyde-inactivated MERS-CoV adjuvanted with alum and unmethylated CpG, can reduce or even prevent Th2-skewed lung pathology after challenge [38, 112]. These results demonstrated that with an appropriate combination of inactivation method and adjuvants, the whole inactivated virus is still a viable option for coronavirus vaccine development.
Live attenuated vaccine
Live attenuated vaccines are live viruses weakened by deleting or mutating the pathogenic component of the viral genome. Similar to whole inactivated vaccines, they possess nearly the full immunogenic components of the original virus. Furthermore, they preserve the native conformation of viral antigens and present antigens to the immune system as in natural infections. Therefore, live attenuated vaccines are the most immunogenic kind of vaccine and have a long history of success in controlling a variety of infectious diseases [113]. However, live attenuated vaccines also carry a higher risk than other types of vaccines, including the possibility of reversion to a virulent state and the danger of persistent infection in immunocompromised patients. Therefore, biosafety of live attenuated vaccines needs to be carefully evaluated before proceeding to clinical use.
Although a few SARS-CoV and MERS-CoV live attenuated vaccines have demonstrated efficacy in animal models, none of them have proceeded to clinical trials [114,115,116,117]. The envelope (E) protein, besides its structural roles, has a major role in inflammasome activation and is associated with exacerbated inflammation in the lung [118]. As a result, the deletion of E protein can lead to the decreased virulence of coronavirus [119]. Lamirande et al. has reported that SARS-CoV mutants lacking the E gene can induce protective effects in hamsters against SARS-CoV challenge [114]. In addition, nonstructural protein 16 (nsp16) is another viable target for the coronavirus vaccine. Nsp16 encodes ribose 2′-O-methyltransferase that is required for 5′ capping of viral RNA [120]. This methylation helps coronavirus avoid the activation of type I interferon-dependent innate immune response by viral RNA, and therefore nsp16 deletion attenuates virulence [120]. Both SARS-CoV and MERS-CoV nsp16 mutant vaccines have been reported to provide protection against challenge [115, 116]. Moreover, nonstructural protein 14 (nsp14), which encodes exoribonuclease (ExoN) involved in RNA proofreading during replication, is also an useful target for live attenuated coronavirus vaccine [121]. The loss of ExoN will cause a profound decrease in replication fidelity, and lead to attenuation of coronavirus pathogenesis [121]. Graham et al. has shown that ExoN deletion can reduce SARS-CoV virulence in young, aged, immunocompromised mice, and ExoN-deleted SARS-CoV vaccine can induce a protective effect against challenge in these mice [117]. In sum, all the targets mentioned above serve as potential strategies for the development of live attenuated SARS-CoV-2 vaccine.
Recent progress on SARS-CoV-2 vaccine development
Compared with SARS and MERS, which tended to resolve spontaneously after regional outbreak, the worldwide magnitude of the COVID-19 pandemic has made development of vaccine an unprecedented urgency. This urgent need has led to many different approaches in vaccine development considerations. First of all, unconventional vaccine platforms, such as nucleic acid vaccines and viral vector vaccines, are becoming the leading players in the race of COVID-19 vaccine development due to their ability to be developed using sequence information alone [122]. These new platforms are therefore highly adaptable to emerging pathogens, and their safety profiles have already been well examined in recent influenza, Ebola and Zika outbreaks [57]. Secondly, the clinical development process of COVID-19 vaccine has been accelerated by executing trials in parallel rather than following a linear sequence of steps. For example, multiple COVID-19 vaccine candidates directly entered clinical trials before having preclinical data in animal models, and many vaccine trials have adopted an integrated phase I/II or phase II/III approach to save time [123]. Last but not least, in order to meet the massive global need of COVID-19 vaccine, vaccine developing companies, especially the front runners, are ramping up their manufacturing capacity to the scale of ~ 1 billion doses per year [124,125,126]. Governments from the United States and several other countries are also playing an important role in funding the scale-up of potentially effective vaccines [127,128,129].
In this section, we will discuss the latest preclinical and clinical development of COVID-19 vaccines (as of Oct 26, 2020). We will highlight representative COVID-19 vaccines from each major vaccine platform that have published clinical data (Table 2).
Protein subunit vaccine
Up to now, there have been 13 SARS-CoV-2 protein subunit vaccines entering clinical trials [130]. Among these vaccines, a leading company Novavax, with its NVX-CoV2373 vaccine, has entered a phase IIb trial in South Africa (NCT04533399) and a phase III trial in the UK (2020-004123-16). NVX-CoV2373 contains a prefusion stabilized full-length spike protein adjuvanted with their proprietary saponin-based adjuvant [131, 132]. In a preclinical trial, the vaccine induced neutralizing antibodies and prevented viral replication in the respiratory tract in macaques challenged with the virus [131]. The vaccine also induced binding and neutralizing antibodies in all participants in the phase I trial [132]. In their phase I trial, they also observed a dose sparing effect by the adjuvant. They found that both adjuvanted 5 ug and 25 ug dose regimens induced significantly high titers of neutralizing antibody compared to the placebo group and the 25 ug dose without adjuvant group [132]. Another vaccine that has entered the phase II trial is Anhui Zhifei Longcom’s recombinant new coronavirus vaccine (NCT04466085). Instead of using the full-length S protein, Anhui Zhifei Longcom’s vaccine only contains the RBD of the SARS-CoV-2 S protein. However, no further design or data has been provided so far. For the other candidate SARS-CoV-2 protein subunit vaccines, most of them also utilize either full-length S protein or the RBD of S protein as their vaccine antigen. Notably, one recent study has described a generalizable strategy to enhance the immunogenicity of protein subunit coronavirus vaccines [133]. They identified a disulfide-linked dimeric form of MERS-RBD that is significantly more immunogenic and protective than its conventional monomeric counterpart [133]. They applied the same strategy to SARS-CoV-2 and has demonstrated a 10–100-fold enhancement of neutralizing antibody titers [133]. Therefore, this framework of immunogen design could be universally applicable to all protein subunit coronavirus vaccines in the future.
DNA vaccine
There are 4 DNA vaccines for SARS-CoV-2 currently under clinical trials [130]. Among these developers, Inovio is a leading company that has published results on MERS-CoV and SARS-CoV-2 DNA vaccines. Inovio’s SARS-CoV-2 DNA vaccine INO-4800 encodes the full length S protein and is administered intradermally with a hand-held device CELLECTRA to electroporate the skin cell [70, 134]. Having experience in the phase I/IIa trial of their MERS vaccine (INO-4700), they are using the same platform for the SARS-CoV-2 vaccine INO-4800 [69, 70]. They have demonstrated that the vaccine induces neutralizing antibodies and Th1-skewed immune responses in animal models including mice, guinea pigs, and rhesus macaques [70, 135]. The vaccine is now in two phase I/II trial (NCT04447781 and NCT04336410). The interim analysis of the two phase I trials showed it induced humoral and T cell immune responses in 94% participants after two doses while only caused adverse events of grade 1 or below [136].
RNA vaccine
Although there were no RNA vaccine studies for SARS-CoV or MERS-CoV in the past two decades, there have already been 6 novel RNA vaccines reaching clinical trials for SARS-CoV-2 since the outbreak of COVID-19 [130]. RNA vaccines consist of viral antigen-encoding messenger RNAs that can be translated by human cells to produce antigenic proteins and stimulate the immune system. RNA vaccines are usually delivered in complex with additional agents, such as protamine or lipid- and polymer-based nanoparticles, to increase its efficacy [137]. Similar to DNA vaccines, RNA vaccines have the advantages of being highly adaptable to new pathogens and being able to recapitulate the native conformation and modifications of antigenic proteins. Furthermore, compared with DNA vaccines, RNA vaccines have some additional benefits. Unlike DNA, RNA does not interact with host-cell DNA and therefore obviate the risks of genomic integration. Besides, RNA vaccines can be given through multiple routes including traditional intravenous injection, whereas DNA vaccines need to be administered via special devices like electroporation or gene gun. Nevertheless, RNA vaccines do have some drawbacks. Exogenous RNA can activate interferon-mediated antiviral immune response and lead to stalled translation and mRNA degradation, which suppress the efficacy of RNA vaccines [138]. In addition, interferon signaling is associated with inflammation and potential autoimmunity [139]. Even though there have not been severe cases of RNA vaccine-induced autoimmune diseases, it is important to carefully evaluate this potential adverse effect.
Moderna and BioNTech/Pfizer are the two leading developers for a SARS-CoV-2 RNA vaccine. Moderna's mRNA-1273 vaccine encodes a stabilized prefusion spike trimer, in which they substituted the amino acids at 986 and 987 with proline to stabilize the spike protein in its prefusion conformation [140]. The nucleotides of the mRNA were also modified not only to increase its translation and half-life but also to prevent activation of interferon-associated genes upon entering the cell [140]. The preliminary report for their phase I clinical trial showed that: (1) neutralizing antibodies were detected in all 45 patients after two doses of immunization; (2) antibody titers of immunized patients were higher than convalescent serum after two doses of vaccination; (3) Th1-biased immune responses were observed in immunized patients [140]. There were some cases of systemic adverse events after the second dose of vaccination, but no grade 4 adverse events were observed [140]. They concluded that 100 ug can induce a satisfactory immune response and thus will continue to use 100 ug dosage in phase III clinical trial (NCT04470427) [140]. In addition, they also expanded the same phase I trial to include 40 elderly participants with their age older than 55 years old [141]. Their result demonstrated that 100 ug dose of mRNA-1273 induced higher binding- and neutralizing-antibody titers than the 25 ug dose, and the adverse events associated with mRNA-1273 were mild or moderate in these elderly participants [141]. On Nov 16, 2020, Moderna revealed the first interim analysis of their phase III trial (NCT04470427) [142]. Their result showed that among 95 people who developed symptomatic COVID-19 after volunteering in this trial, only 5 of them were from the mRNA-1273 group, and the rest 90 cases were from the placebo group, resulting in a estimated vaccine efficacy of 94.5% [142]. In addition, there were 11 volunteers who developed severe COVID-19 symptoms, and their analysis showed that all 11 cases were in the placebo group and none in the mRNA-1273 group [142]. Their concurrent safety review also did not notice any significant safety concern [142]. Therefore, their promising result suggested that the mRNA-1273 vaccine is safe and effective in preventing symptomatic COVID-19.
BioNTech and Pfizer’s mRNA vaccine has four candidates, BNT162b1, BNT162b2, BNT162a1 and BNT162c2. BNT162b1 and BNT162b2 are both nucleoside modified mRNA (modRNA) vaccine [143]. BNT162b1 encodes a trimerized RBD of spike protein while BNT162b2 encodes a full-length spike protein [143]. On the other hand, BNT162a1 is a uridine mRNA (uRNA)-based vaccine and BNT162c2 is a self-amplifying mRNA (saRNA)-based vaccine [143]. Up to now, BioNTech and Pfizer have published two BNT162b1 phase I/II trial results that were conducted in Germany (NCT04380701) and the US (NCT04368728), respectively [144, 145]. Both studies showed that the two-dose regimen of BNT162b1 elicited RBD-binding and neutralizing antibodies with titers above convalescent human serum [144, 145]. Analysis of cell-mediated immune responses showed Th1-skewed response in most participants, as demonstrated by the detection of IFNγ, IL-2 and IL-12 but not IL-4 in their assay [144, 145]. Although the German trial and the US trial used different dosages of vaccine, the two trials agreed with each other and showed that a regimen of 30–50 ug on day 1 and day 22 is able to elicit favorable immune response without severe adverse effects [144, 145]. Following these two papers, they also published another study comparing the vaccination responses between BNT162b1 and BNT162b2 [146]. BNT162b1 and BNT162b2 were shown to induce similar neutralizing titers in younger and older adults [146]. However, BNT162b2 had less systemic reactogenicity in older adults [146]. Therefore, they decided to move forward with BNT162b2 instead of BNT162b1 into a phase III clinical trial (NCT04368728). On Nov 18, 2020, Pfizer and BioNTech announced the efficacy analysis of their phase III clinical trial (NCT04368728) after meeting all primary efficacy endpoints [147]. Their evaluation showed that BNT162b2 is 95% effective against COVID-19 [147]. This result was based on analyzing 170 confirmed COVID-19 cases, of which 162 cases of COVID-19 were observed in the placebo group while 8 cases in the BNT162b2 group [147]. In addition, among 10 severe COVID-19 cases observed in this trial, 9 of them were in the placebo group and only 1 of them was in the BNT162b2 group [147]. Notably, the observed efficacy in the elderly people was over 94%, which would help protect the most vulnerable population against COVID-19 [147]. No serious safety concern was observed among 43,000 enrolled participants [147]. These data indicated BNT162b2 is another well-tolerated and efficacious COVID-19 vaccine.
Viral vector vaccine
Currently, there are 12 viral vector vaccines in clinical trials, and an additional 36 viral vector vaccines under preclinical development [130]. Many viral vector platforms that have been tested in SARS-CoV and MERS-CoV are being explored in COVID-19 vaccines, including adenovirus (both human and non-human primates), measles virus, modified vaccinia virus Ankara (MVA), parainfluenza virus, rabies virus and vesicular stomatitis virus (VSV) [130]. Surprisingly, Venezuelan equine encephalitis (VEE) virus, which has been extensively studied in SARS and MERS vaccine, hasn’t been tested in any COVID-19 vaccine studies yet. On the other hand, influenza virus vector, which hasn’t been explored for SARS and MERS viral vector vaccines, are now gaining popularity for the development of COVID-19 viral vector vaccine [130]. For COVID-19 viral vector vaccines that have entered clinical trials, 8 out of 12 are based on adenoviruses, and the four leading candidates in this platform are AZD1222 (or ChAdOx1 nCoV-19, developed by Astrazeneca and Oxford University), Gam-COVID-Vac (or Sputnik V, or rAd26S+rAd5-S, developed by Gamaleya Research Institute), Ad5 (developed by CanSino Biological Inc. and Beijing Institute of Biotechnology), and Ad26 (developed by Johnson & Johnson and Beth Israel Deaconess Medical Center) [130].
AZD1222 is a chimpanzee adenovirus-based viral vector vaccine (ChAdOx1) expressing SARS-CoV-2 spike protein [99]. This ChAdOx1 platform has been used to develop MERS-CoV vaccine, which has demonstrated promising preclinical and phase I clinical trial data [94,95,96,97,98]. The AZD1222 vaccine team published their phase I/II trial interim report in July 2020 and showed that AZD1222 can elicit S protein-specific antibody and T-cell response and induce neutralizing antibody in all participants after the prime-boost regimen [99]. No severe adverse effect has been observed [99]. Based on this promising data, AZD1222 launched phase II/III trials in UK (2020-001228-32) and phase III trials in Brazil (ISRCTN89951424), United States (NCT04516746), Russia (NCT04540393) and India (CTRI/2020/08/027170). In Sep 2020, the AZD1222 phase II/III trial in the UK was once put on hold for safety review because a participant has developed unexplained illness, but following later independent review in the UK determined that the trial is still safe and therefore the AZD1222 clinical trial resumed [148, 149]. On Nov 23, 2020, Astrazeneca annouced the interim analysis of their clinical trial in UK (2020-001228-32) and Brazil (ISRCTN89951424) [150]. Their pooled result showed that AZD1222 has an average efficacy of 70%, based on analyzing a total of 131 COVID-19 cases from 11,636 volunteers [150]. Interestingly, one dose regimen showed 90% efficacy when AZD1222 was given as half first dose followed by a full second dose (n = 2,741) [150]. On the other hand, two full dose regimen had only 62% efficacy (n = 8,895) [150]. Due to the response discrepancy between different subgroups, additional trials may be needed to better determine the efficacy and the most suitable regimen of AZD1222. In addition, the Gam-COVID-Vac vaccine team has published their phase I/II trial results [151]. They conducted two different trials, with one using frozen formulation (NCT04436471) and the other using lyophilized formulation (NCT04437875) of the vaccine [151]. In both phase II trials, they tested their patients with heterologous prime-boost immunization of recombinant adenovirus type 26 vector encoding SARS-CoV-2 spike glycoprotein (rAd26-S) plus recombinant adenovirus type 5 vector encoding SARS-CoV-2 spike glycoprotein (rAd5-S) [151]. Their results showed that both frozen and lyophilized formulation of the vaccine induced potent neutralizing antibodies and CD4+ and CD8+ T-cell immune responses, with the immune response of frozen formulation being slightly stronger than the lyophilized formulation [151]. Both vaccines were safe and well-tolerated in all participants [151]. Now this vaccine is also entering phase III trial in Russia (NCT04530396) and Belarus (NCT04564716). On Nov 24, 2020, Gamaleya Research Institute announced the second interim analysis of Gam-COVID-Vac (or Sputnik V) phase III clinical trial (NCT04530396) [152]. Their result showed that Gam-COVID-Vac had a efficacy of 91.4% on Day 28 after the first dose, which was based on analyzing 39 confirmed cases among 18,794 volunteers [152]. They also revealed that on Day 42 after the first dose (Day 21 after the second dose), the vaccine efficacy was even above 95% [152]. There were no unexpected adverse effect documented during the trial [152]. These promising results suggested that Gam-COVID-Vac is safe and effective in preventing COVID-19. Furthermore, the Ad5 vaccine team, whose vaccine is based on human adenovirus 5, has also published their clinical data [92, 93]. In their phase II study, Ad5-vectored COVID-19 vaccine induces significant neutralizing antibodies and T-cell mediated immune response after single immunization [93]. They tested two dosage, 1 × 1011 and 5 × 1010 viral particles, and showed that the 5 × 1010 dose causes less severe adverse reactions without compromising the immunogenicity [93]. Now this vaccine has advance to two phase III global multi-centered clinical trials (NCT04526990 and NCT04540419). Finally, Johnson & Johnson’s Ad26-based COVID-19 vaccine has also entered phase III clinical trial (NCT04505722), but no data from its earlier trial has been reported yet.
Whole inactivated vaccine
Currently, there are 7 whole inactivated COVID-19 vaccine in clinical trials [130]. From the previous experience of SARS-CoV and MERS-CoV vaccine development, whole inactivated virus can induce adverse effect such as eosinophil-related lung immunopathology in preclinical models [36, 37]. Even though no serious adverse effect has been reported for whole-inactivated COVID-19 vaccine, it is important for the research community to keep this in mind and carefully evaluate potential adverse effects. For all ongoing trials of whole inactivated COVID-19 vaccine, three of them have publicly reported their preclinical or clinical data. SinoVac Inc. developed CoronaVac (also known as PiCoVacc), which is a beta-propiolactone inactivated, Vero cell line propagated whole virus vaccine originated from a patient-derived CN-2 SARS-CoV-2 virus strain [153]. In their preclinical study, PiCoVacc induces broad neutralizing antibodies against 10 representative SARS-CoV-2 strains in mice, rats, and non-human primates [153]. Immunizing macaques with three doses of PiCoVacc provides them with protective immunity against SARS-CoV-2 challenge without causing any antibody-dependent enhancement effect [153]. Following their preclinical study, CoronaVac has completed two phase I/II trials (NCT04383574 and NCT04352608, result not yet published) and is now starting phase III clinical trial in Brazil (NCT04456595), Indonesia (669/UN6.KEP/EC/2020) and Turkey (NCT04582344). In addition, Sinopharm Inc. and Wuhan Institute of Biological Products have developed a different COVID-19 inactivated virus vaccine (no specific product name). In this vaccine, WIV04 strain was isolated from a COVID-19 patient in Wuhan, propagated in Vero cells, and followed by two rounds of beta-propiolactone inactivation [154]. They tested three different dosage and three different injection timelines in their phase I and phase II studies, and their phase I/II interim report showed that patients receiving different vaccination regimen all had demonstrated neutralizing antibodies and with only a low rate of adverse reactions [154]. Now they have launched a phase III clinical trial in United Arab Emirates (ChiCTR2000034780) and Kuwait (ChiCTR2000039000). Finally, Sinopharm Inc. also collaborated with Beijing Institute of Biological Products to develop another COVID-19 inactivated virus vaccine BBIBP-CorV [155, 156]. The manufacturing process of BBIBP-CorV is very similar to the other vaccine Sinopharm Inc. produced, except that BBIBP-CorV used a different HB02 strain rather than WIV04 strain [155]. They have tested BBIBP-CorV in preclinical models and showed that two-dose immunization of BBIBP-CorV can protect rhesus macaques from SARS-CoV-2 challenge [155]. Following this, they completed a clinical phase I/II trial with BBIBP-CorV and demonstrated that BBIBP-CorV is safe and well-tolerated in all tested doses in two age groups [156]. Furthermore, their immunogenicity result showed that humoral responses against SARS-CoV-2 were induced in all vaccine recipients 42 days after immunization [156]. Now this vaccine is under phase III clinical trial in United Arab Emirates (ChiCTR2000034780) and Argentina (NCT04560881).
Other vaccine platforms
There are also several other COVID-19 vaccine candidates using different technologies other than the platforms mentioned above. Virus-like particle-based vaccine, which has been demonstrated to induce humoral and cell-mediated immunity in SARS-CoV and MERS-CoV preclinical models, has one candidate COVID-19 vaccine in phase I clinical trial (NCT04450004) and 14 vaccine candidates under preclinical development [130]. However, none of the group has publicly reported their vaccine studies yet. Live attenuated vaccine, which has been shown to provide protective effect in SARS-CoV and MERS-CoV challenged mice, has 3 preclinical ongoing studies [130]. The higher risk of adverse effect has made live attenuated vaccine a less appealing choice for the time-sensitive race of COVID-19 vaccine development. Nevertheless, if successfully developed, live attenuated vaccine can provide the most potent protective effect due to its high similarity to natural infection.
In addition to these traditional platforms, scientists have also developed COVID-19 vaccines using unconventional approaches. Aivita Biomedical, Inc. has developed AV-COVID-19, which is an autologous dendritic cells vaccine loaded with SARS-CoV-2 antigens [157]. AV-COVID-19 is derived from patients’ own peripheral blood monocytes, then differentiated in vitro into dendritic cells, and incubated with SARS-CoV-2 antigens before injecting back into patients’ blood [157]. Now the company has launched a phase I/II clinical trial to evaluate its safety and efficacy profile in adults (NCT04386252). Besides, Symvivo Corporation has developed bacTRL-Spike, a live Bifidobacterium vaccine engineered to deliver synthetic plasmid DNA encoding spike protein from SARS-CoV-2. They have also registered a phase I clinical trial to examine the safety of this vaccine (NCT04334980). Moreover, a group from Nanjing University has found that a plant microRNA, MIR2911, can target SARS-CoV-2 by binding to their mRNA and blocking protein translation [158]. Their data showed that MIR2911 inhibited SARS-CoV-2 replication and accelerated negative conversion of infected patients [158]. Following their study, they are now launching a phase I clinical trial (ChiCTR2000031432) in China to evaluate the safety and tolerance of MIR2911 in patients.
Finally, people have been testing existing licensed vaccines and trying to repurpose them to combat COVID-19. It has been shown that tuberculosis vaccine bacillus Calmette–Guérin (BCG) can train innate immunity and induce nonspecific host defensive reaction against viral pathogens, including respiratory syncytial virus (RSV), influenza A virus and herpes simplex virus type 2 (HSV2) [159,160,161,162]. Additionally, an interesting study compared the national difference in COVID-19 impact and correlated it with national BCG vaccination policy [163]. They found that countries without universal policies of BCG vaccination have been more severely affected compared to countries with universal and long-standing BCG policies [163]. Based on these rationales, there have been at least 13 phase III clinical trials testing whether BCG vaccine can reduce the morbidity and mortality of healthcare workers (NCT04328441, NCT04327206, NCT04350931, NCT04348370, NCT04362124, NCT04369794, NCT04373291, NCT04379336, NCT04384549, NCT04439045, NCT04387409, NCT04417335, NCT04414267).
Additional considerations for SARS-CoV-2 vaccine development
Given the rapid transmission and asymptomatic spread of COVID-19, it is clear that an effective vaccine with global immunization coverage is required to bring people’s lives back to normalcy. However, even when an effective SARS-CoV-2 vaccine becomes available, the duration of vaccine-induced immunity is still largely unknown. Previous SARS studies have shown that SARS-specific IgG and neutralizing antibodies were only maintained for approximately 2 years in patients who recovered from SARS-CoV infection [164, 165]. As a result, permanent immunity is less likely to be the case for COVID-19 vaccines, and a regular vaccination policy might be required in the future. In addition, it is still unclear what is the minimal neutralizing antibody titer that can provide protective effect against SARS-CoV-2 infection. It is believed that the higher neutralizing antibody vaccination induces, the better protective effect it will be. This is consistent with the observation that most COVID-19 reinfection cases only experience mild or no symptom during their first infection, which might not be sufficient to induce strong neutralizing antibodies [166, 167]. Therefore, it is of great importance that further studies characterize the correlation between neutralizing antibody and protective effect to guide COVID-19 vaccine development. Last but not least, various mutations have been detected in the SARS-CoV-2 genome, with D614G mutation being the most prevalent one [168]. D614G is a missense point mutation in S protein that increases the infectivity of SARS-CoV-2 by decreasing S1 shedding and increasing S protein incorporation into virion [169, 170]. Fortunately, D614G mutation does not prevent neutralizing antibodies from binding to SARS-CoV-2 and thus does not provide resistance to vaccination [170]. However, it is possible that such immune-escaping mutations appears in the future and makes COVID-19 vaccine development even more difficult.
Concluding remarks
Since the discovery of human coronaviruses in 1960s, new types of coronaviruses have kept emerging and have gradually become a serious threat to global public health. Even though there have been almost two decades since the first coronavirus outbreak, the scientific and medical community are not well prepared with effective weapons to combat these pathogens. One lesson we learned from this is that the financial and regulatory mechanism of current pharmaceutical market does not provide enough incentive to encourage vaccine development before a deadly outbreak happens. To make up for this, now academic institutions and companies all over the world are developing an explosive numbers of vaccine candidates with highly compressed clinical trial schedules. Fortunately, the biological and clinical lessons we learned from SARS-CoV and MERS-CoV researches, together with the vaccine development experience we gained from other diseases, have already guided us to come up with multiple promising candidate solutions. Besides, multiple therapeutic candidates targeting molecules in SARS-CoV-2 life cycle and human immune response against COVID-19 have also been rapidly explored, with Remdesivir and Dexamethasone being the two leading drugs that showed promising clinical evidences in shortening the time to recovery and decreasing mortality rates [171, 172]. These treatment options can be complementary to SARS-CoV-2 vaccines to achieve overall mitigation of the COVID-19 pandemic. In conclusion, we hope countries all over the world, regardless of political ideologies, can unite and work together to achieve fast and successful COVID-19 vaccine development in the near future.
Availability of data and materials
Not applicable.
Abbreviations
COVID-19:
Coronavirus Disease 2019
CoV:
Coronavirus
SARS-CoV:
Severe Acute Respiratory Syndrome Coronavirus
MERS-CoV:
Middle East Respiratory Syndrome Coronavirus
SARS-CoV-2:
Severe Acute Respiratory Syndrome Coronavirus 2
pp:
Polyproteins
Nsps:
Non-structural proteins
S:
Spike
E:
Envelope
M:
Membrane
N:
Necleocapsid
RBD:
Receptor binding domain
ACE2:
Angiotensin-converting enzyme 2
DPP4:
Dipeptidyl peptidase-4
ER:
Endoplasmic reticulum
ADE:
Antibody-dependent enhancement
NTD:
N-terminal domain
IM:
Intramuscular
SC:
Subcutaneous
VLP:
Virus-like particle
CPV:
Canine parvovirus
VEE:
Venezuelan equine encephalitis
VRP:
Virus replicon particle
Ad#:
Human adenovirus type #
ChAdOx1:
Chimpanzee Adenoviral Vector
ExoN:
Exoribonuclease
modRNA:
Modified RNA
uRNA:
Uridine mRNA
saRNA:
Self-amplifying RNA
RSV:
Respiratory synctial virus
HSV:
Herpes simplex virus
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Yen-Der Li and Wei-Yu Chi have contributed equally to this work
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Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA
Yen-Der Li & Jun-Han Su
Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
Wei-Yu Chi, Louise Ferrall, Chien-Fu Hung & T.-C. Wu
Johns Hopkins School of Medicine, 1550 Orleans St, CRB II – Room 309, Baltimore, MD, 21287, USA
T.-C. Wu
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YDL and WYC contributed to the conception of the manuscript and to the original draft preparation. JHS, LF, and CFH contributed to substantial review and preparation of the manuscript. TCW supervised the review. All authors read and approved the final manuscript.
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Dr T.C. Wu is a co-founder of and has an equity ownership interest in Papivax LLC. Additionally Dr. Wu owns Papivax Biotech Inc. stock options and is a member of Papivax Biotech Inc.’s Scientific Advisory Board. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies.
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Li, YD., Chi, WY., Su, JH. et al. Coronavirus vaccine development: from SARS and MERS to COVID-19. J Biomed Sci 27, 104 (2020). https://doi.org/10.1186/s12929-020-00695-2
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18 | https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.602256/full | COVID-19: Coronavirus Vaccine Development Updates
Jing Zhao&#x;Jing Zhao1†Shan Zhao&#x;Shan Zhao1†Junxian OuJunxian Ou1Jing ZhangJing Zhang2Wendong LanWendong Lan1Wenyi GuanWenyi Guan1Xiaowei WuXiaowei Wu1Yuqian YanYuqian Yan1Wei ZhaoWei Zhao1Jianguo WuJianguo Wu2James ChodoshJames Chodosh3Qiwei Zhang,*Qiwei Zhang1,2*
1Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
2Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, China
3Department of Ophthalmology, Howe Laboratory, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, United States
Coronavirus Disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a newly emerged coronavirus, and has been pandemic since March 2020 and led to many fatalities. Vaccines represent the most efficient means to control and stop the pandemic of COVID-19. However, currently there is no effective COVID-19 vaccine approved to use worldwide except for two human adenovirus vector vaccines, three inactivated vaccines, and one peptide vaccine for early or limited use in China and Russia. Safe and effective vaccines against COVID-19 are in urgent need. Researchers around the world are developing 213 COVID-19 candidate vaccines, among which 44 are in human trials. In this review, we summarize and analyze vaccine progress against SARS-CoV, Middle-East respiratory syndrome Coronavirus (MERS-CoV), and SARS-CoV-2, including inactivated vaccines, live attenuated vaccines, subunit vaccines, virus like particles, nucleic acid vaccines, and viral vector vaccines. As SARS-CoV-2, SARS-CoV, and MERS-CoV share the common genus, Betacoronavirus, this review of the major research progress will provide a reference and new insights into the COVID-19 vaccine design and development.
Coronaviruses are members of the subfamily Coronavirinae composed of four genera -Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus, in the family Coronaviridae, under the order Nidovirales (1). Coronaviruses are positive sense, single-stranded RNA viruses with a spherical shape envelope, a diameter of 100–160 nm and a genome size of 27–32 kb. The 5’ end of the genome occupies approximately 2/3 of the total length and encodes polyprotein (pp1ab), which is cleaved to 16 non-structural proteins involved in the transcription and replication of the genome. The 3’ end encodes structural proteins, including envelope spike glycoproteins (S), envelope (E), membrane glycoprotein (M), and nucleocapsid (N) (1). S1 subunit of the spike glycoprotein mediates recognition by host receptors and S2 subunit promotes fusion of viral envelope with the cell membrane. E and M proteins are responsible for the transmembrane transport assembly, budding, and release of progeny viruses, and the formation of virus envelopes, all of which play an important role in virus production and maturity (2). N protein binds to viral RNA, which is involved in the viral gene replication cycle and immune response to viral infections of host cells (2, 3). Otherwise, there are species-specific accessory genes which are also essential for viral replication (1).
There are seven types of coronaviruses relevant to humans, four of which are human coronaviruses (HCoV-NL63, HCoV-229E, HCoV-OC43, and HKU1), causing limited mild upper respiratory symptoms in immunocompetent populations, while the other three are highly pathogenic coronaviruses - Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and novel Coronavirus (SARS-CoV-2), all causing severe respiratory disease in humans.
The symptoms of SARS usually include fever, chills, and body pain, and infection can develop into pneumonia. According to WHO statistics, from November 1, 2002 to July 1 2003, 8,096 cases and 774 deaths had been confirmed with SARS-CoV infection worldwide, with a fatality rate of 9.6%. MERS is a viral respiratory disease caused by MERS-CoV and was first confirmed in Saudi Arabia in 2012. MERS symptoms usually include fever, cough, and shortness of breath, and infection can also lead to pneumonia. Since 2012, MERS has spread to 27 countries and regions in the Middle East, Asia, and Europe (4), and 80% of cases are from Saudi Arabia. 2,494 cases and 858 deaths with MERS-CoV infection have been reported, with a fatality rate of about 35%. The incubation period is up to 14 days, and the world population is generally susceptible. Dromedary camels are a major host of MERS-CoV and are the main source of infection of humans, with only limited human-to-human transmission.
In December 2019, SARS-CoV-2, a novel coronavirus was identified in Wuhan, China as a new Betacoronavirus (5). This new virus causes Coronavirus Disease 2019 (COVID-19). On February 28th, WHO declared the global emergency risk level as “very high”. On March 12th, the global COVID-19 outbreaks were declared as a pandemic. Many cities around the world mandated lockdowns. As of November 1st, 2020, the pandemic had caused 45,968,799 confirmed cases and 1,192,911 fatalities with the estimated case fatality rate of 2.60% (https://covid19.who.int/). Comparative genomic analysis showed the divergence of SARS-CoV-2 and identified 380 amino acid substitutions between SARS-CoV-2 (Wuhan/HB01 strain) and SARS-CoV (6).
Currently, the pandemic of COVID-19 is still evolving. Effective therapeutic drugs for severe cases and effective vaccines for the healthy people are in urgent need. However, there is no specific prescription drug or effective vaccine licensed to treat or prevent COVID-19 worldwide except for four vaccines for limited use in China and two vaccines for early use in Russia.
As of October 19, 2020, among 212 SARS-CoV-2 candidate vaccines being developed all over the world, 50 have been under clinical evaluation and 162 are in preclinical development (Figure 1). Among them, there are 14 inactivated vaccines, four live attenuated vaccines, 72 protein subunit vaccines, 17 DNA vaccines, 27 RNA-based vaccines, 16 virus-like particle (VLP) vaccines, 26 non-replicating viral vector vaccines, and 18 replicating viral vector vaccines (Figure 1A). For the vaccines in clinical trials, eight are inactivated vaccines, 15 are protein subunit vaccines, six are DNA vaccines, six are RNA-based vaccines, two are VLPs vaccines, nine are non-replicating viral vector vaccines, and four are replicating viral vector vaccines (Figure 1B).
Figure 1 SARS-CoV-2 vaccine candidates. (A) SARS-CoV-2 vaccine candidates in development. (B) SARS-CoV-2 vaccine candidates in clinical trials.
In China, there are 13 vaccine candidates that have entered clinical trials, of which six vaccine candidates are currently in phase III clinical trials. As SARS-CoV-2 is similar to the highly pathogenic SARS-CoV and MERS-CoV, experiences in the development of vaccines against other Betacoronaviruses may facilitate the COVID-19 vaccine development. In this study, we briefly review past and current CoV vaccine research and development against SARS (Table 1), MERS (Table 2), and SARS-CoV-2 (Table 3) (Figure 1), including inactivated vaccines, live attenuated vaccines, subunit vaccines, virus like particles, nucleic acid vaccines, and viral vector vaccines, aiming to provide a reference and new insights, to facilitate the better and faster development of COVID-19 vaccines.
Table 1 SARS-CoV vaccine candidates.
Table 2 MERS-CoV vaccine candidates.
Table 3 SARS-CoV-2 vaccines in clinical phase III trials and early or limited use.
When a new pathogen emerges, for example SARS-CoV, due to the lack of understanding of the pathogenesis and therefore lengthy time to development of efficacious therapeutics, the rapid and simple development of a vaccine against the emerging infectious disease is urgently needed. Therefore, the classic approach using inactivated, cell-culture based viruses is likely to be the fastest and easiest way for CoV vaccine development, as we have the experience of many commercial inactivated vaccines against other viral diseases. Inactivated vaccines may maintain the normal conformation of the S protein (71). Various studies have demonstrated that vaccines based on whole, inactivated SARS-CoV potently elicit considerable levels of neutralizing antibodies in animal models (72).
Evaluations of a SARS-CoV whole virus vaccine double-inactivated with formalin and UV irradiation in ferrets and nonhuman primates showed protection against infection by SARS-CoV-specific T cell and neutralizing antibody responses. The immunogenic profile elicited by double-inactivated SARS-CoV vaccine might be not comparable to that generated by vaccine inactivated by just one approach (73). However, the challenged animals exhibited a Th2-type immunopathologic lung disease, whereas the pathologic changes seen in control groups lacked the eosinophil prominence (Tseng et al., 2012), which indicated that hypersensitivity to SARS-CoV components was induced. This may be called vaccine-associated disease enhancement (VADE) (74), which is similar to that seen with the RSV vaccine. Addition of an adjuvant in inactivated vaccines helped alleviate eosinophilic immune pathology in the lungs. Inactivated SARS-CoV vaccine with δ-inulin adjuvant (38) and ultraviolet inactivated SARS-CoV in toll-like receptor agonist reduced IL-4, IL-13, and eosinophil chemokines, resulting in the reduction of Th2 type eosinophilic pathology (39).
The gamma-ray inactivated MERS-CoV vaccine with adjuvant of alum or MF59 induced high neutralizing antibodies but caused eosinophilic lung pathological changes in vaccinated animals (75, 76). Similarly, inactivated MERS-CoV vaccine appears to carry a hypersensitive-type lung pathology risk from MERS-CoV infection that is similar to that found with inactivated SARS-CoV vaccines from SARS-CoV infection (77). Formalin-inactivated MERS-CoV adjuvanted with alum and CpG induced high titers of anti-S IgG with neutralization reactivity >60%, and a stronger Th1/Th2 response in mice (75, 76). Both SARS-CoV and MERS-CoV vaccines inactivated by either gamma-ray or formalin induced immunopathologic lung disease in vaccinated animals, worthy of attention during the development of the inactivated SARS-CoV-2 vaccine.
Beta-propiolactone inactivated SARS-CoV-2 vaccines have been mainly developed in China. The vaccines developed by Wuhan Institute of Biological Products/Sinopharm, Beijing Institute of Biological Products/Sinopharm, and Sinovac/Instituto Butantan/Bio Pharma have been in clinical III trials. Unlike SARS-CoV and MERS-CoV, SARS-CoV-2 inactivated vaccines showed no evidence of immunopathologic changes in the lungs of vaccinated and SARS-CoV-2 challenged animals. On June 25, 2020, the vaccine candidate of Cansino/Military Academy of Sciences was approved as special drugs for the army by the Central Military Commission’s Health Bureau. On July 22, 2020, inactivated vaccine candidates of Sinopharm and Sinovac were approved for emergency use. On October 12, 2020, Sinopharm opened appointments for COVID-19 vaccination in Beijing and Wuhan. More than 70,000 people have made appointments for vaccination.
On April 12th, 2020, the inactivated vaccine from Wuhan Institute of Biological Products/Sinopharm was approved for clinical trials, which was the world’s first inactivated SARS-CoV-2vaccine that has received clinical trial approval. In phase I/II clinical trials, the vaccine induced high titers of antibodies in different doses, with the positive rate of neutralizing antibody reaching 100% and without adverse reactions (78). Up to September 8, 2020, a phase III clinical trial was ongoing in the UAE, Bahrain, Peru, Morocco, Argentina and other countries and regions, and this vaccine candidate is expected to be listed at the end of 2020 (https://www.echemi.com/cms/118167.html).
The inactivated vaccine from Sinovac also showed safety and effectiveness in rhesus monkeys, producing IgG and reducing virus titers and pathological changes in the lungs, without observable antibody-dependent enhancement of infection (79). On July 3, 2020, the inactivated vaccine from Sinopharm was approved for phase III clinical trial by Brazilian Health Regulatory Agency National Health Inspection Agency. On September 22, 2020, Sinovac started phase III Clinical Trials in Turkey (http://www.sinovac.com/?optionid=754&auto_id=911).
The third SARS-CoV-2 inactivated vaccine from Beijing Institute of Biological Products/Sinopharm started phase III trials in Argentina on September 16, 2020. This inactivated SARS-CoV-2 vaccine is prepared by inoculating African green monkey kidney cells (Vero cell) with the SARS-CoV-2 HB02 strain, culturing, harvesting, inactivating, clarifying, concentrating, purifying, and adding aluminum hydroxide adjuvant. The estimated study completion date is December 1, 2021.
The inactivated SARS-CoV-2 vaccine (Covaxin) developed by Indian Bharat Biotech is the sole inactivated vaccine which has entered phase II trials outside China. The animal experiments showed robust immune responses and protective efficacy, increasing SARS-CoV-2 specific IgG and neutralizing antibodies, reducing replication of the virus in the nasal cavity, throat, and lung tissues of monkeys. No evidence of pneumonia was observed by histopathological examination in vaccinated groups nor were adverse events seen in animals immunized with a two-dose vaccination regimen (http://mtw.so/5JtMTR).
With a long history of successful applications, such as the smallpox and polio vaccines, live attenuated vaccines are similar to natural infections with a wide range of natural viral antigen production over a long period of time and are often more immunogenic than non-replicating vaccines (71, 80).
CoV E protein induces endoplasmic reticulum stress (81) and inflammatory cytokine overexpression in host cells, causing lung tissue damage, edema, and progression to acute respiratory distress syndrome (ARDS). CoV lacking E protein has abnormal morphology and function due to assembly failure and maturation defects, and has been shown to inhibit the host cell’s stress response (2, 82).
SARS-CoV live attenuated vaccine with E gene deletion (SARS-CoV-ΔE) produced neutralizing antibodies and CD4+ with CD8+ T cell responses in mice and ferrets, and reduced inflammatory cell infiltration, edema, and cell destruction (41, 42). When the full-length E gene was deleted or its PDZ-binding motif (PBM) was mutated, revertant viruses either evolved a novel chimeric gene including PBM, or restored the sequence of the PBM in the E protein, respectively (43). Therefore, the modified virus with partial deletion of E gene without affecting PBM may be a live attenuated SARS-CoV vaccine candidate. Additionally, amino acid substitutions in the transmembrane domain (TMD) of E protein to eliminate the ion channel activity could result in virus attenuation, which alleviated pulmonary edema in infected mice. Another SARS-CoV vaccine candidate with simultaneous deletion of 8–12 amino acids in both C-termini of the E and nsp1 genes enhanced IFN responses and decreased viral titers in mice (43, 83).
Non-structural protein 1 (nsp1) (43), nsp16 (44), and nsp14 mutants of SARS-CoV and MERS-CoV have potential as live attenuated vaccines. SARS-CoV-ExoN (-) and MERS-CoV-ExoN (-) are both stable mutants providing immune protection in mice with significantly reduced fidelity and moderate pathogenicity (45, 46). Additionally, the combination of 2’-O-methyltransferase and ExoN mutations provided effective protection in the aged mice (84). Nsp10 is a major replication regulator in SARS-CoV and its deletion generated replication-deficient viruses by interfering and preventing the activation of nsp14 ExoN (85), which indicates a potential epitope for vaccine development.
CoV accessory proteins are implicated in the modulation of interferon signaling and proinflammatory cytokines (86). ORF3, 4a, 4b, and 5 are important for pathogenesis, and the MERS-CoV strains with combined deletion of the accessory genes 3, 4a, 4b, and 5 (rMERS-CoV-ΔORF3-5) significantly weakened virulence and reduced its inhibitory effects toward IFN, becoming a possible vaccine candidate (87). Additionally, MERS-CoV nsp16 mutants induced neutralizing antibodies and reduced viral titer in mice (88). Similarly, papain-like protease (Plpro) of SARS-CoV and MERS-CoV, encoded within nonstructural protein 3 (nsp3) of the replicase polyprotein, processed the viral replicase polyprotein and deubiquitinating (DUB) or deISGylating activity, and blocked upregulation of cytokines CCL5, IFN-β and CXCL10 in stimulated cells. Thus, mutation of Plpro of MERS-CoV inhibited the loss of IFN-β activation (89).
There are four live attenuated COVID-19 candidate vaccines, developed by Mehmet Ali Aydinlar University & Acibadem Labmed Health Services A.S., Meissa Vaccines, Indian Immunologicals LTD & Griffith University, and Codagenix/Serum Institute of India, respectively. However, none of these vaccines have entered clinical trials. Among these vaccines, the vaccine candidate developed by Codagenix/Serum Institute of India is the earliest vaccine made in India and could induce strong immune responses. The vaccine was in the preclinical stage in April and is expect to enter clinical trials in September 2020.
The Bacillus Calmette-Guerin (BCG) vaccine was designed to protect against tuberculosis (TB). It boosts immunity by ‘training’ the immune system to respond to other subsequent infections with greater intensity. In order to find out whether it could reduce the risk of COVID-19 infection among healthcare staff and care home workers who are particularly vulnerable to coronavirus infection, this vaccine candidate is entering a phase III “BRACE” trial with up to 10,078 healthcare workers in hospitals in Australia as participants. In Netherlands, it is in phase IV trial and is enrolling 5,200 elders as participants (https://clinicaltrials.gov/ct2/results?cond=COVID&term=BCG+&cntry=&state=&city=&dist=;https://www.mcri.edu.au/news/could-bcg-vaccine-protect-against-covid-19-uk-recruitment-begins-0).
Subunit vaccines are comprised of purified immunogenic proteins or peptides (90) derived from viruses. In contrast with traditional vaccines, subunit vaccines have less side effects and higher safety at the injection site. However, whether the immunological memory will be formed in the correct manner is not guaranteed. Therefore, adjuvants as well as vaccine delivery systems are needed to enhance immune responses (91).
Most of CoV subunit vaccines focus on the S protein. S protein is the outermost localized protein responsible for receptor binding, especially its highly immunogenic receptor binding domain (RBD) (47), a critical region for receptor interaction (48).
In recent years, Pichia pastoris yeast have served as an expression system for producing a large number of modified proteins in the culture medium without animal-derived growth factors, thus widely applying to the pharmaceutical and vaccine industries. RBD 219N-1 protein, in which an N-linked glycosylated asparagine at the N-1 position of RBD219 has been deleted, expressed by P. pastoris, induced strong RBD-specific neutralizing antibody responses during pseudovirus and live SARS-CoV infections. Manufacture of recombinant RBD219-N1 protein was achieved with higher purity after optimizing the process (7, 8).
Recombinant fusion protein (RBD-Fc) containing 193-amino acid RBD (residues 318–510) and a human IgG1 Fc fragment with higher purification and stability as a vaccine candidate, enhanced antigen-presenting cell recognition by inducing strong neutralizing antibody and cellular immune responses and long-term protective effects in mice against SARS-CoV challenge (9–11).
The MERS-CoV spike protein forms a trimer, and its receptor-binding domain (RBD) serves as a vaccine target. RBD-Fd, a trimeric protein generated by fusing RBD with foldon trimerization motif (50). The outcomes indicated the potential of developing MERS subunit vaccines based on the trimeric RBD of MERS-CoV S protein. In a further study it was found that compared with Freund’s adjuvant, aluminum, monophosphorylate lipid A, and Montanite ISA 51, the combination of S377-588 protein fused with Fc of human IgG (S377-588-Fc) and MF59 adjuvant induced the highest titers of IgG, IgG1, and IgG2a subtypes and neutralizing antibodies after intranasal vaccination (49). Proline-substituted variants of MERS-CoV S2 domain retained S2 in the prefusion conformation, therefore producing a fully stable S trimer vaccine for broader and stronger neutralizing activity. Adjuvanted MERS-CoV S protein nanoparticles injected intramuscularly induced even higher levels of neutralizing antibodies (51).
‘Neutralizing immunogenicity index’ (NII) is a novel concept to evaluate the neutralizing immunogenicity of different epitopes on viral subunit vaccines. NII was used as a tool to identify epitopes with different neutralizing immunogenicity on a MERS-CoV-RBD-based vaccine. By application of this tool, subunit vaccines against MERS-CoV were rationally designed and found to significantly enhance the efficacy of the MERS-CoV RBD vaccine in protecting human-DPP4-transgenic mice from lethal MERS-CoV challenge (92). This methodology may guide the rational design of highly effective subunit vaccines to combat SARS-CoV-2.
B-cell and T-cell epitopes are highly conserved between SARS-CoV-2 and SARS-CoV. The vaccine against a conserved epitope may elicit cross-immune responses to mutant viruses (93). Analysis of T-cell and B-cell epitopes of SARS-CoV revealed that viral mutations mainly targeted epitopes that were highly expressed by MHC-I, while no mutations were found near RBD. In combination with other epitopes, recombinant SARS-CoV-2 S protein is a feasible vaccine candidate.
There are more than 60 subunit vaccines against SARS-CoV-2 under development, including RBD-trimer of S protein, S1, recombinant S proteins, N, M proteins, and others. One of them is in phase III clinical trial, four are in phase II trials, and seven are in phase I trials.
Novavax’s SARS-CoV-2 subunit vaccine candidate NVX-CoV2373 was based on Matrix-M -adjuvanted recombinant protein vaccine with nanoparticle technology using the Sf9 system. It has entered phase I/II clinical trials in May 2020, and has shown outstanding results so far without severe adverse events. It induced high titers of neutralizing antibodies and S protein specific IgG, as well as Th1 biased immune response while two doses of 5 μg of adjuvanted NVX-CoV2373 resulted in effective protection in non-human primate experiments, indicating the potential to protect humans (94) (https://ir.novavax.com/news-releases/news-release-details/novavax-initiates-phase-3-efficacy-trial-covid-19-vaccine-united). On September 24, 2020, Novavax initiated a phase III study of its vaccine candidate, expecting to enroll and immunize up to 10,000 individuals between 18 and 84 (inclusive) years of age in the UK. This is the fastest developed subunit vaccine against SARS-CoV-2.
In China, the SARS-CoV-2 RBD-dimer subunit vaccine by Anhui Zhifei Longcom/Institute of Microbiology, Chinese Academy of Sciences has entered a phase II clinical trial in July (https://clinicaltrials.gov/ct2/show/NCT04466085?term=NCT04466085&draw=2&rank=1). In Russia, on August 26, the Vector Institute registered a phase I/II trial for a subunit vaccine called EpiVacCorona. On October 14, Vladimir Putin announced that EpiVacCorona was granted regulatory approval to use in Russia. This is the second vaccine for limited use in Russia after the Gamelaya Institute’s Sputnik V vaccine. The third subunit vaccine which has entered phase I/II trials was developed by Sanofi/GSK. They launched a phase I/II clinical trial in September and plan to start a phase III trial in December. The fourth RBD subunit vaccine Soberana 1, which has entered phase I/II trials, was developed by Finlay Vaccine Institute in Havana, Cuba. It contains two extra ingredients: proteins from a bacteria and aluminum hydroxide as adjuvants (https://rpcec.sld.cu/ensayos/RPCEC00000332-Sp).
There are seven other SARS-CoV-2 subunit vaccines in phase I trials, developed by Medigen Vaccine Biologics Corp, Vaxine Pty Ltd, Clover Biopharmaceuticals and Gsk, Covaxx, University of Queensland, West China Hospital of China, and Adimmune Corporation. The safety and efficacy of these subunit vaccines should be verified in clinical trials.
During the SARS epidemic, it was found that the titer of neutralizing antibodies against S protein was significantly higher in deceased patients, while the anti-N protein antibody titer was lower during the early stages of infection (16, 17). In contrast, the anti-N antibody rose more rapidly in recovered patients (18, 95). The efficacy of anti-N antibody deserves further exploration.
In MERS-CoV, the B-cell, helper T-cell and cytotoxic T lymphocyte (CTL) epitopes were screened and mapped to the N protein, and are potential epitopes for vaccine candidates to elicit protective neutralizing antibodies and cellular immune responses against MERS-CoV (96). Along with the importance of T-cell-based cellular immunity, and escape of neutralizing antibodies against S protein of MERS-CoV due to its high mutation rate, N protein, rather than S protein, could be a suitable immunogen candidate with the potential to elicit both humoral and cell mediated immune responses (96). Currently the primary focus has been the spike protein. Whether the SARS-CoV-2 N protein is another potential immunological target for vaccines needs to be further verified.
Virus-like particles (VLPs) are similar to intact virions in size and morphology. Without a viral genome, VLPs are unable to replicate or reverse mutate, suggesting better safety, especially for viruses that cause high morbidity and mortality. They may induce strong and broad humoral and cellular immune responses (20, 21, 97).
The S, M, and N proteins of the SARS-CoV are necessary and sufficient for pseudovirus assembly (25). Coexpression of SARS-CoV S protein and E, M and N proteins in mouse hepatitis virus (MHV) resulted in efficient production of MHV VLPs and protected the vaccinated mice from infection. Compared with the control groups, MHV VLPs adjuvated with alum induced high titers of neutralizing antibodies and reduced SARS-CoV titers as well as inflammation in the lung (22). Moreover, the influenza M1 protein is also a common core protein, suggesting the possibility of application to SARS-CoV VLP production. Researchers produced chimeric SARS VLPs (cVLPs) containing the spike protein of SARS and the matrix protein of influenza virus. VLPs with alum as an adjuvant induced significantly higher titers of neutralizing antibodies and protected mice against virus challenge, and led to lower virus titers after intramuscular immunization (98).
The avian influenza M1 was also used as a core protein to generate cVLPs containing modified S protein of MERS-CoV. This recombinant immunogenic cVLP significantly increased neutralizing antibodies and IgG against S protein of MERS-CoV in mice (23). Besides VLPs, a BLP vaccine candidate displaying the MERS-CoV RBD with GEL01 adjuvant also induced humoral, cellular, and local mucosal immune responses in the mouse model, especially in the intestinal tract, indicating its promise as a vaccine candidate (55). This BLP contains three lysin motif (LysM) motifs in an anchor protein combined with MERS-CoV RBD to form RBD-linker-PA3 (RLP3). Gram-positive enhancer matrix (GEM) particles were used as substrates to externally bind to the MERS-CoV RBD through a protein anchor. BLPs are a novel platform and have broad prospects in vaccine development.
Fifteen VLP COVID-19 vaccines are in development. Among them, the vaccine developed by Medicago Inc. is the earliest and started in phase I trials in July 2020. The phase II/III trial is expected to start in November. This is a plant-derived VLP vaccine with GSK or Dynavax adjuvants. It uses the same platform as vaccine candidates for flu, rotavirus, norovirus, West Nile virus, and cancer.
Another VLP vaccine developed by SpyBiotech/Serum Institute of India entered phase I/II trials in September in Australia (https://www.spybiotech.com/news/-). This VLP displayed the RBD of SARS-CoV-2 S protein on the surface of Hepatitis B surface antigen (HBsAg) VLPs, which is safe and immunogenic and has been made in mass production.
The other VLP vaccines are still in preclinical phase. If the immunogenicity is proven, VLPs and BLPs are promising vaccine candidates for SARS-CoV-2 and other life-threatening viruses.
Nucleic acid vaccines are genetic vaccines consisting only of DNA or RNA, which are taken up and translated into protein by host cells and elicit immune responses. Because they contain no viral coat, naked nucleic acids are not generally subject to preexisting immunity that can hamper the clinical efficacy of recombinant virus vaccines. In terms of higher safety and lower cost of production, nucleic acid vaccines have some major advantages over other types. Post-translational modifications under natural conditions are reproduced by the plasmid-encoded protein, retaining immunogenicity (99) and humoral and cellular immune-stimulating capabilities, simultaneously (24). Although there have been concerns about the safety of DNA vaccines in these early stages of development (100), it appears that viral genes integration into host genes through plasmid vectors is extremely rare (101).
SARS-CoV S DNA vaccines produced high levels of IgG against S protein (26) and CD4+ and CD8+ T cell responses (27). Furthermore, serum S protein-specific IgG1 and IgA in the respiratory tracts of mice were significantly elevated through PEI/pci-S complexes formed by polyethyleneimine (PEI) and SARS DNA vaccine, along with increases in IFN-γ, TNF-α, and IL-2 expression.
Raghuwanshi et al. found that plasmid DNA loaded biotinylated chitosan nanoparticles for nasal immunization against N protein induced N protein-specific IgG, mucosal IgA, and IFN-γ expression in mice. When combined with CD40 monoclonal antibody, this vaccine induced higher antibody titers through intramuscular administration than by intranasal vaccination (28). Following intranasal delivery of naked pDNA, no mucosal and systemic immune responses were detected.
There are several DNA vaccines of MERS-CoV under development: pVax1™ (GLS-5300), pVRC8400, and pcDNA3.1-S1 encoding MERS-CoV S1 subunit (56–60). These induced neutralizing antibodies and cellular immune responses in rhesus monkeys, camels, and mice. The IgG and specific cellular response levels of S1 subunit were higher than for S protein. A more balanced Th1/Th2 response avoided the potential safety issues of the S gene vaccines, i.e. the immunopathology and disease enhancement reported in SARS-CoV vaccine candidates (102, 103). The pVax1™ vaccine (GLS-5300) has completed phase I clinical trials. Most participants had three doses of vaccination, and anti-S1 subunit antibodies could still be detected after one year. The humoral and cellular immune responses of the subjects were similar to those recovering from natural infection of MERS-CoV. The vaccine was well tolerated, and no serious vaccine-related adverse events have been reported (57, 61).
Additionally, the MERS-CoV S protein vaccine supplemented with enhanced S1 subunit expression induced neutralizing antibodies and reduced disease severity in non-human primates (NHPs). Compared with pure protein and peptide vaccines, the combination of DNA and protein resulted in a more functional antibody library and stronger Th1 cell immune response (58).
Four DNA vaccine candidates have been studied in phase II clinical trials, including those developed by Inovio Pharmaceuticals (INO-4800), Zydus Cadila Healthcare Limited (ZYCOV-D), Osaka University (DNA plasmid+adjuvant), and Genexine consortium (GX-19), respectively. All these vaccine candidates are based on the spike protein, and have shown immunogenicity and protection in animals. Other DNA vaccines are still in preclinical stages.
INO-4800, a potential COVID-19 DNA vaccine candidate targeting SARS-CoV-2 S protein, induced effective humoral responses in mice and guinea pigs, and protected animals from lower respiratory disease (104). In early April, Inovio Pharmaceuticals started phase I clinical trials. 94% of participants developed the expected immune responses, including neutralizing antibodies and T cell immune responses without serious adverse reactions (http://ir.inovio.com/news-releases/news-releases-details/2020/INOVIO-Announces-Positive-Interim-Phase-1-Data-For-INO-4800-Vaccine-for-COVID-19/default.aspx). Phase IIa trials began in July 2020. However, Inovio announced a partial clinical hold for its phase II/III trial of on September 28, 2020. There were additional questions about INO-4800 reported to the US Food and Drug Administration (FDA), including its CELLECTRA® 2000 delivery device. The phase II/III clinical trial will continue only when these questions have been satisfactorily answered (http://ir.inovio.com/news-releases/news-releases-details/2020/INOVIO-Reports-FDA-Partial-Clinical-Hold-for-Planned-Phase-2–3-Trial-of-COVID-19-Vaccine-Candidate-INO-4800/default.aspx).
In Korea, a DNA vaccine for COVID-19 named GX-19 developed by Genexine Inc. began phase I/IIa clinical trials in June 2020, expected to be completed by 2021 (https://www.bioworld.com/articles/435995-south-koreas-genexine-begins-phase-iiia-trials-for-covid-19-vaccine).
In Japan, a SARS-CoV-2 DNA vaccine developed by Osaka University/Anges/TAKARA BIO/Cytiva/Brickell BioTech is currently in phase I/II clinical studies (https://www.anges.co.jp/pdf_news/public/IGiJ94QWoV9U7EIYJybHY6SNv3BxVXRN.pdf). In India, a SARS-CoV-2 DNA vaccine given by intradermal route was developed by Cadila Healthcare Limited. It entered phase I trial in July 2020 and phase II in August 2020 (http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=45306&EncHid=&userName=vaccine).
mRNA is a minimal and transient information carrier. It does not interact with the host genome, and is safe and can be manufactured rapidly. Any protein can be encoded and expressed by mRNA, which offers maximum flexibility with respect to the development of vaccines for infectious diseases and cancer as well as protein replacement therapies (105). The conventional mRNA vaccines translate the immunogens of interest from the input vaccine transcript.
While direct delivery into the cytosol would certainly enhance antigen expression, a lack of interaction with endosomal RNA receptors may severely weaken immunostimulation by the vaccine (105). Thus, suitable liposomes and complexing agents have been selected to enhance uptake by cells, improve delivery to the translation machinery in the cytoplasm, and prevent degradation of mRNA (105).
With the advantages of high efficiency, safety, low production cost, and the potential for rapid large-scale production, mRNA vaccines have become an attractive alternative to traditional vaccines, with a promising future. In animal models of infectious disease caused by influenza virus, Zika virus, rabies virus, the subcutaneous or intramuscular injection of liposome-encapsulated mRNA (106, 107) or a naked mRNA vaccine through subcutaneous or intranasal injection (108–111) induced effective immunity (106).
Several different mRNA vaccines exhibited high safety and tolerability in different stages of clinical trials. Nonetheless, the risk of an autoimmune response and/or promoting pathological thrombosis (112–115), or severe injection site or systemic reactions (107, 116) still exists in the application of extracellular RNA. Therefore, the safety of mRNA vaccines needs further evaluation. Moreover, the production of mRNA vaccines depends on a transcription system in vitro. When the production scale and speed cannot keep up with the speed of change in the epidemic, large-scale production applications remain challenging.
mRNA vaccines against SARS-CoV-2 developed by Moderna, BioNtech/Pfizer, Curevac, Arcturus, Academy of Military Sciences of China, Chulalongkorn University, and AstraZeneca/Shenzhen Kangtai have entered clinical trials. Among them, Moderna entered phase III trial in July, BioNtech/Pfizer started phase IIb/III trials in July, Curevac started IIa trials in September, Imperial College London started phase I/II trials in June, Arcturus started phase I/II trials in August, and Academy of Military Sciences of China started phase I trials in June. The others are still in development.
The mRNA-1273 vaccine candidate developed by Moderna is the most promising mRNA vaccine to date. This vaccine encodes the prefusion-stabilized spike protein of SARS-CoV-2, and induced S protein specific IgG antibodies in rhesus monkeys after the second vaccination. The vaccination induced type 1 helper T-cell (Th1)-biased CD4 T-cell responses and low or undetectable Th2 or CD8 T-cell responses in nonhuman primates. Compared to the inflammation of airways and adjacent alveolar interstitial found in the control group, animals in the mRNA-1273 group developed only mild inflammation and no viral RNA or antigen was detected in their lungs (117). In early July 2020, Moderna completed enrollment for both cohorts of its phase II study. The vaccine induced anti-SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. Antibody titers were higher after the second vaccination (118). Later in July, Moderna launched a phase III clinical trial (https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-phase-3-cove-study-mrna-vaccine-against-covid).
Another hopeful mRNA vaccine BNT162 was developed by BioTech/Fosun Pharma/Pfizer. Two mRNA candidate vaccines were evaluated in the phase I portion of the trial in the United States: one was BNT162b1, encoding a secreted trimerized SARS-CoV-2 receptor–binding domain, and the other was BNT162b2, encoding a membrane-anchored SARS-CoV-2 full-length spike, which was stabilized in the prefusion conformation. BNT162b2 was associated with a lower incidence and severity of systemic reactions than BNT162b1, particularly in older adults (119). In both younger and older adults, the two vaccine candidates elicited similar dose-dependent SARS-CoV-2–neutralizing geometric mean titers (119). A phase IIb/III trial was launched in July 2020. On November 9, they announced that the vaccine candidate BNT162b2 was found to be more than 90% effective in preventing COVID-19 in participants without evidence of prior SARS-CoV-2 infection in the first interim efficacy analysis from the phase III clinical study (https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-vaccine-candidate-against). The trial is continuing to enroll and is expected to continue through the final analysis when a total of 164 confirmed COVID-19 cases have accrued.
CVnCoV is a mRNA vaccine developed by Curevac. They launched a phase IIa clinical trial on September 29, 2020. Curevac reported preclinical trial data through October 23, 2020. After the second vaccination, titers of neutralizing antibodies and IgG were significantly higher and more lasting. The IgG2a/IgG1 ratios showed a balanced Th1/Th2 profile, and the vaccine appeared to avoid vaccine-induced disease enhancement (https://www.curevac.com/en/2020/10/23/curevac-reports-positive-preclinical-data-for-its-covid-19-vaccine-candidate-cvncov/).
The other mRNA vaccine candidate that entered human phase I/II clinical trials in June was developed by Imperial College London (https://www.imperial.ac.uk/news/198314/imperial-begin-first-human-trials-covid-19). In China, the first COVID-19 mRNA vaccine approved for clinical trials was ARCoV, developed by the People’s Liberation Army (PLA) Academy of Military Sciences, Suzhou Abogen Biosciences, and Walvax Biotechnology Co., Ltd. Their study showed that the COVID-19 mRNA vaccine not only induced high levels of neutralizing antibodies in mice and crab-eating macaques but also induced protective T cell immune responses (120). ARCoV is currently being evaluated in phase 1 clinical trials. Other mRNA vaccine candidates showed immunogenicity by eliciting potent neutralizing antibodies in mice and/or NHPs (121, 122).
Self-amplifying RNA (saRNA) is derived from an alphavirus genome, which encodes the alphaviral replicase and a gene of interest. It amplifies sub-genomic RNA carrying the antigen of interest, resulting in the amplification of transcripts bearing the antigen by several orders of magnitude over the initial dose (123). saRNA is a highly efficient platform for SARS-CoV-2 vaccine development.
Currently, among several saRNA vaccine candidates against SRAS-CoV-2, LUNAR-COV19 developed by Arcturus Therapeutics and Duke-NUS Medical School is the sole one in clinical trials. This vaccine encodes SARS-CoV-2 full length S protein and requires a much smaller dose than the conventional mRNA vaccine, ~ 50 to 100 times less, which would greatly lower the cost per dose. Mice vaccinated with a single dose of LUNAR-COV19 induced stronger T cell responses and significantly higher levels of S protein specific IgG lasting for 50 days after vaccination, as well as robust neutralizing antibodies. Similarly, Th1 biased immune responses were shown in this study, and LUNAR-COV19 also protected mice from SARS-CoV-2 lethal challenge and even measurable infection (124).
Viral vector vaccines can effectively introduce genes encoding viral antigens into host cells. The infected cells produce and release immunogenic antigens within a certain period after vaccination (80). Subunit vaccines and protein-induced immune responses are usually short-lived, and consequently multiple injections are usually required to induce and maintain a systemic immune response. In contrast, nonattenuated viral vectors can invade cells naturally, thus activate the immune system and induce stronger humoral and cellular immune responses. Several viral vectors for CoV vaccines have been developed, such as adenovirus (AdV), modified vaccinia virus Ankara (MVA), measles virus (MV), Venezuelan equine encephalitis virus (VEE), vesicular stomatitis virus (VSV), Newcastle disease virus (NDV), rabies virus (RV), RSV, and others (125, 126). These virus-based vectors provide innovative directions and routes for CoV and other virus vaccine research and development. Through November 3, 2020, 18 replicating viral vector vaccines and 26 non-replicating viral vector vaccines were under development for COVID-19. The former are designed mainly on measles virus, VSV, influenza virus, avian paramyxovirus, and NDV. The latter are based mainly on human adenovirus types 5 or 26, chimpanzee adenovirus, Parainfluenza Virus 5(PIV5), influenza virus, AAV, and MVA.
Human adenovirus type 5 (HAdV-5) vectored vaccines have been extensively developed (33, 34). HAdVs can effectively induce mucosal immune responses, and have been widely studied for their wide host range, strong infectivity, high protein expression, and high safety when imbued with a replication defect. Compared with intramuscular injection, both intranasal and sublingual administration of recombinant adenoviruses encoding SARS-CoV spike protein elicited stronger CD8+ cell response and higher levels of neutralizing antibodies and IgA without VADE (35).
A single injection of the MERS-CoV S protein-coding HAdV-5 or HAdV-41 vectored vaccines elicited mucosal and systemic immunity in mice (33, 34). When boosted with S nanoparticles, the vaccine induced S-specific IgG neutralizing antibodies, as well as Th1 and Th2 cell immune responses to protect adenoviral hDPP4-transducted mice from MERS-CoV challenge (66).
However, it is known that pre-existing immunity to prevalent adenovirus serotypes can inhibit the efficacy of adenovirus-vectored vaccines (127, 128). Therefore, exploring other AdV types as vectors has become a possible solution. The simian adenovirus is an alternative choice for a vector because of minimal pre-existing immunity in humans, except for the Africans (129). The replication-deficient chimpanzee adenoviruses ChAdOx1 and AdC68 (66, 130) expressing MERS-CoV proteins significantly reduced clinical signs in camels (67), induced sustained and high levels of neutralizing antibodies and T cell responses in mice (70), and protected mice against lethal challenge (68). A phase II clinical trial is now underway.
The vaccine candidate AZD1222 is based on ChAdOx1 (a MERS-CoV vaccine mentioned above), and utilizes a replication-deficient chimpanzee adenovirus vector. This entered phase II/III clinical trials in the UK and India in May 2020, and phase III trials in Brazil, South Africa, and the United States. It was developed by Consortium of the Jenner Institute/Astrazeneca/University of Oxford. In their phase I/II, single-blind, randomized controlled trial, spike-specific T-cell responses peaked on day 14, and anti-spike IgG responses rose by day 28, while neutralizing antibodies were shown in all participants after a booster dose. Adverse reactions were significantly reduced by use of prophylactic paracetamol (131).
However, in September, the phase III trial was halted because one volunteer developed transverse myelitis. On October 21, it was reported that that a volunteer in Brazil who once worked in a hospital and had received a dose of placebo in the trial, died of COVID-19 (https://www.nytimes.com/live/2020/10/21/world/covid-19-coronavirus-updates/a-vaccine-trial-volunteer-in-brazil-has-died-but-health-authorities-say-the-vaccine-was-not-to-blame). However the trial was soon restarted. The safety of the chimpanzee adenovirus vectored SARS-CoV-2 vaccine will be closely monitored going forward.
In China, human adenovirus type 5 vectored COVID-19 vaccine (Ad5-nCoV) developed by Cansino Biologics/Beijing Institute of Biotechnology entered phase I trials in early March and phase II trials in April. phase III trials began in August, 2020. The vaccine was approved for China military use on June 25, 2020, which was the first approved COVID-19 vaccine for limited use. Most adverse reactions reported in all dose groups were mild or moderate in severity. No serious adverse event was noted within 28 days post-vaccination. The vaccine showed immunogenicity and tolerance 28 days after the first inoculation. Neutralizing antibodies peaked at day 28 post-vaccination, and specific T-cell response peaked at day 14 (132). In a phase II clinical trial in 508 participants, the Ad5-vectored COVID-19 vaccine given at 5 × 1010 viral particles showed safety and induced significant immune responses in the majority of recipients after a single immunization (133). The vaccine will be studied in a phase III trial in Saudi Arabia and Russia (https://www.arabnews.com/node/1717041/saudi-arabia; https://www.sohu.com/a/414125695_115479). Another HAdV-5 vectored COVID-19 vaccine candidate developed by a Chinese research group also conferred protection from SARS-CoV-2 challenge in rhesus macaques with a single vaccination either intramuscularly or intranasally (134).
On October 8th, China officially joined the COVAX, a global COVID-19 vaccine allocation plan co-led by the World Health Organization (WHO) that aims to help purchase and fairly distribute COVID-19 vaccines (https://www.weforum.org/agenda/2020/09/covax-who-cepi-gavi-covid-19-coronavirus-vaccines-distribution/). CanSino Biologics announced a supply agreement of 35 million doses of COVID-19 vaccine for Mexico from the end of 2020 through the year 2021. Compared with other vaccines developed by Pfizer, AstraZeneca, Covax, the Ad5-nCoV vaccine of CanSino Biologics is the only single-dose regime candidate (http://www.cansinotech.com/html/1///179/180/556.html).
The other approved COVID-19 vaccine is developed by Gamaleya Research Institute of Russia. The first dose contains HAdV-26 vectored vaccine, based on an uncommon adenovirus type. The booster dose is composed of HAdV-5 vectored vaccine, similar to the one being developed by CanSino, China. The phase I trial began in June 2020. Phase 1/2 non-randomized studies of a heterologous prime-boost COVID-19 vaccine based on rAd26-S and rAd5-S showed that the vaccine was safe and well tolerated. Cellular immunity, neutralizing antibodies, and RBD specific IgG were detected in all participants, and no severe adverse reactions were reported after vaccination (135). Named Sputnik-V, this vaccine received early approval for use in Russia in August 2020 without completing a phase III trial (https://www.nature.com/articles/d41586-020-02386-2). On October 14, 2020, Russia granted regulatory approval to a second COVID-19 vaccine, even though the vaccine had yet to begin large scale phase-III trials. This was only two months after approval of their first vaccine. Experts expressed caution due to a lack of safety and efficacy data (https://www.webmd.com/lung/news/20200908/russia-begins-rollout-of-covid-19-vaccine). Due to the incomplete completion of phase III clinical trials, the safety of these vaccine candidates is expected to be evaluated with special scrutiny (https://www.usnews.com/news/world/articles/2020-08-20/un-discussions-with-russia-on-covid-19-vaccine-under-way).
Another HAdV-26 vectored vaccine is developed by Janssen Pharmaceutical Companies of Johnson & Johnson. In the phase I/II clinical trial, the vaccine JNJ-78436735 induced robust humoral and cellular immune responses in middle-age adults and the elderly (136). On September 23, 2020, Johnson & Johnson announced the launch of its large-scale, pivotal, multi-country phase III trial(named ENSEMBLE) for its COVID-19 vaccine candidate. This study enrolled up to 60,000 adults 18 years old and older, including participants over 60 years old, and those both with and without comorbidities associated with an increased risk for progression to severe COVID-19 (https://www.jnj.com/johnson-johnson-initiates-pivotal-global-phase-3-clinical-trial-of-janssens-covid-19-vaccine-candidate).
It is optimized that the type of adenovirus vectors used in the boost dose is different from that in the initial immunization. In theory, the alternate use of human and simian adenovirus vectors in the immunization steps is better than the use of the same type of adenovirus vectors. Additionally, the grouping of participants with high and low levels of pre-existing immunity against the adenovirus vectors should be considered.
Modified vaccinia virus Ankara (MVA) is replication-defective and used for viral antigen expression in mammalian cells. MVA stimulates inflammatory cytokines and chemokines and migration of lymphocytes and monocytes, making it advantageous in vaccine applications. MVA-SARS-CoV produced effective neutralizing antibodies with high immunogenicity in mice, rabbits, and monkeys, and protected against challenge in mice (29–32).
MVA-MERS-S protein vaccines induced neutralizing antibodies and CD8 + T cell responses (62) and prevented tissue damage in AdV-hDPP4 transgenic mice (63). Likewise, intramuscular administration of MVA-MERS-CoV induced neutralizing antibodies in dromedary camels and limited virus replication, resulting in effective immune protection (64).
There are five MVA vectored SARS-CoV-2 vaccines under development. Among them, the spike gene vaccine developed by German Center for Infection Research is registered in a phase I trial. The vaccine is expected to be ready for approval by the end of 2021.
Although the immunity of Measles virus (MV) vector among humans may be an obstacle for its application, the SARS-CoV S protein expressed by the MV vector induced high neutralizing antibodies and Th1 cell immune responses in susceptible mice, along with effective protection from challenge. Similarly, a recombinant Venezuelan equine encephalitis virus (VEE)-SARS-CoV vaccine elicited high IgG titers in mice while retaining wild-type VEE replication ability (36, 37, 137). The use of MV and VEE as viral vectors for CoV vaccines may yet have potential.
A single dose of parainfluenza virus 5 (PIV5)-based vaccine expressing the MERS-CoV S protein induced neutralizing antibodies and robust T cell responses in hDPP4 mice. A single-dose intranasal immunization brought stronger protection than single-dose intramuscular immunization. Mice immunized with PIV5-MERS-S protein developed greater mononuclear cell infiltration and less pathological changes in infected lungs (including edema, hyaline membranes, necrotic cellular debris, etc.), as well as complete protection against a lethal challenge against MERS-CoV and lower viral titers. Compared to inactivated MERS-CoV, histopathological changes in lungs such as hyaline membrane formation and hypersensitivity-type response with perivascular eosinophilic infiltration were milder (138).
In 2019, researchers at the University of Hong Kong and Xiamen University developed a nasal-spray vaccine for the flu based on a genetically weakened influenza virus. Earlier this year, they engineered the same vaccine to produce coronavirus spike protein. On September 9, they received approval to start clinical trials (https://www.hku.hk/press/news_detail_21583.html).
Merck has developed a SARS-CoV-2 vaccine originally developed at Institute Pasteur using a weakened measles virus that carries the coronavirus spike gene. They launched phase I trials in August (https://clinicaltrials.gov/ct2/show/NCT04497298?term=vaccine&cond=covid-19&draw=2&rank=1).
In addition, the intranasal vaccine candidate (MV-012-968) expressing SARS-CoV-2 S protein based on an RSV vector was developed by Meissa. It showed robust immune responses in rats and in healthy adults, and is currently in phase I trials in healthy adults and young children (https://www.biospace.com/article/another-covid-19-vaccine-joins-the-race-this-time-it-s-a-live-weakened-virus/?tdsourcetag=s_pctim_aiomsg).
A SARS-CoV-2 S gene vaccine based on adeno-associated virus was developed by the Massachusetts Eye and Ear, Massachusetts General Hospital and the University of Pennsylvania. Phase I trials are set to begin in late 2020.
ADE is an adverse reaction in which non-neutralizing antibodies produced following virus infection or a vaccination enhance the infectivity of a subsequent virus infection (139). It is a mechanism found to play a role in infection by dengue viruses, HIV, influenza virus, Ebola virus, feline coronavirus, and in SARS-CoV, which facilitates the infection of host target cells by anti-viral humoral immune responses. ADE can be mediated by antibody Fc receptor-associated internalization of the virus, resulting in greater viral replication and cytokine release in the presence of virus-specific antibodies (74). ADE may occur especially when the antibody levels are relatively lower.
It was reported that SARS-CoV used ADE to enhance the infectivity of human promonocytes. Increased TNF-α, IL-4, and IL-6 were detected in human promonocytes isolated from a leukemia patient (HL-CZ cells) infected with SARS-CoV, and treatment with highly diluted anti-sera against SARS-CoV was associated with higher levels of virus infection in cells and increased cytopathic effect (CPE) (140). Moreover, S protein specific-IgG may have promoted proinflammatory cytokine production through FcγRI and/or FcγRIIA, suggesting a potential role of FcγRs for the postulated reprogramming of alternatively activated macrophages. Blockade of FcγRs reduced proinflammatory cytokine production and lung injury (19).
To date, no ADE has been observed in MERS-CoV and SARS-CoV-2. However, due to the taxonomic and structural similarities between SARS-CoV, MERS-CoV, and SARS-COV-2, ADE is an issue that should be considered seriously in designing MERS-CoV and SARS-CoV-2 vaccines, particularly those with a full-length S protein. Neutralizing epitopes could elicit a more robust protective immunity but less or no ADE side-effects. Recent studies have found that MERS-CoV vaccine candidates based on a shorter S1 domain or shorter RBD induce stronger immune responses than those based on the full-length S protein (48, 141). Whether the ADE is common during all coronavirus infections needs further study and verification.
From the SARS epidemic 17 years ago to the MERS-CoV epidemic in 2012, and the COVID-19 pandemic caused by the newly emerged SARS-CoV-2 in December 2019, the threat of future severe acute respiratory diseases due to the CoV family cannot be underestimated. Clinical trials of SARS-CoV vaccines were terminated due to the disappearance of SARS-CoV and the lack of potential patients. The MERS-CoV vaccine completed only phase I clinical trials in humans. The shared experiences in developing SARS-CoV and MERS-CoV vaccines may provide a reference for COVID-19 vaccine development.
Currently, the many different SARS-CoV-2 vaccines are in different stages of development around the world. Different types being tested include recombinant protein subunit vaccines, nucleic acid vaccines, viral vector vaccines, inactivated viruses, and live attenuated vaccines. Among the 212 vaccines being developed, three inactivated vaccines, 4 non-replicating viral vector vaccines, two protein subunit vaccines and two RNA vaccines have entered phase III clinical trials. One human adenovirus vector vaccine and three inactivated vaccines have been approved for limited use in China. In Russia, one adenovirus vector vaccine and one peptide vaccine have been approved for early use. The mRNA vaccine of Moderna, HAdV-5 vector vaccine of CanSino Biologics, inactivated vaccines of Sinopharm, Wuhan Institute of Biological Products, and Sinovac Biotech have all entered phase III clinical trials. The mRNA vaccine of BioNTech, Germany, and the Chimpanzee adenovirus vector vaccine of AstraZeneca and the University of Oxford have entered phase II/III clinical trials (Table 3). Together, these represent the most promising and earliest candidate vaccines against COVID-19.
There remain numerous unknowns for all the current vaccine candidates. For examples, will the vaccine provide effective protection in immune deficient or dysfunctional patients and the elderly, and for how long will it provide immunity? Recently, HKU researchers have confirmed the world’s first case of reinfection by the SARS-CoV-2 (https://www.sciencenews.org/article/coronavirus-covid-19-first-case-reinfection-man-hong-kong), in which reinfection occurred after just a few months from the first infection. SARS-CoV-2 may persist as a source of human infections as is the case for other common-cold associated human coronaviruses, even if patients have acquired some level of immunity via natural infection. If the immunity to SARS-CoV-2 can disappear after natural infection, vaccination should also be considered for those persons with prior infection. Additionally, the combined use of nucleic acid vaccines, subunit vaccines, inactivated vaccines, and viral vector vaccines with nanoparticle technology or adjuvants, and multiple vaccinations of COVID-19 should be considered if immunity wanes over time.
There is consensus that the engagement of the S1 RBD with its receptor destabilizes the trimer (prefusion state), triggering the shedding of the S1 units, which allows a remarkable conformational change in the spike from a large club-shaped structure into a thin and long nail-like structure (postfusion state). β-propiolactone is the chemical inactivating agent successfully used in rabies and other vaccines, and β-propiolactone-treated SARS-CoV-2 viruses exhibit most of their spikes in the postfusion conformation (142). Most COVID-19 vaccine candidates rely on the S protein as their antigen, since this is the primary exposed protein on the surface of the SARS-CoV-2 viral particle, and β-propiolactone is used as the inactivation reagent. However, there is the unfortunate example of the formalin-inactivated respiratory syncytial virus (FI-RSV) vaccine trial of the 1960s, which led to enhancement of disease symptoms in vaccinated children after natural exposure to RSV, with two fatal cases (143). Structural studies revealed that one contributing factor to the vaccine failure was that the prefusion state of the RSV spike was absent and the postfusion state was primarily represented in the FI-RSV vaccine formula (144). Therefore, the inactivated SARS-CoV-2 vaccines may not be the safest, and there is need to confirm the S protein state.
It is well known that RNA viruses have much higher mutation rates than DNA viruses. More and more mutations in the spike protein of SARS-CoV-2 are being continuously reported (145, 146), e.g., the most dominant variant D614G in spike protein (146, 147) and V367F in RBD (145), which may increase viral infectivity. As the spike protein of coronaviruses is a major target for vaccines, neutralizing antibodies, and viral entry inhibitors, spike protein mutations in circulating viral strains may affect the effectiveness of a vaccine. Therefore, it is very important to determine whether the neutralizing capacity of vaccine-induced neutralizing antibodies remain unchanged in clinical trials over time.
While clinical treatment strategies have been optimized to save lives and improve prognosis, a safe and effective vaccine would have far-reaching public health significance for controlling and stopping the COVID-19 pandemic. Clinical trials are indispensable to determine the safety and effectiveness of COVID-19 vaccines, and will also need to evolve to include children, the elderly, pregnant women, and people with underlying medical conditions.
QZ conceptualized the idea for the review. JZhao, SZ, JO, JZhang, WL, WG, XW, and YY performed the literature search, analyzed cited references, and wrote the original article. WZ, JW, JC and QZ critically revised the article. All authors contributed to the article and approved the submitted version.
This work was supported by grants from the National Key Research and Development Program of China (2018YFE0204503) and Natural Science Foundation of Guangdong Province (2018B030312010), as well as the Guangzhou Healthcare Collaborative Innovation Major Project (201803040004 and 201803040007).
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Keywords: Severe Acute Respiratory Syndrome, vaccine, Coronavirus Disease 2019 (COVID-19), Severe Acute Respiratory Syndrome Coronavirus 2, Middle-East Respiratory Syndrome
Citation: Zhao J, Zhao S, Ou J, Zhang J, Lan W, Guan W, Wu X, Yan Y, Zhao W, Wu J, Chodosh J and Zhang Q (2020) COVID-19: Coronavirus Vaccine Development Updates. Front. Immunol. 11:602256. doi: 10.3389/fimmu.2020.602256
Received: 07 September 2020; Accepted: 26 November 2020;Published: 23 December 2020.
Edited by:
Reviewed by:
Copyright © 2020 Zhao, Zhao, Ou, Zhang, Lan, Guan, Wu, Yan, Zhao, Wu, Chodosh and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Qiwei Zhang, [email protected]; orcid.org/0000-0002-2770-111X
†These authors have contributed equally to this work
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19 | https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1440819/full | Individuals carrying the HLA-B*15 allele exhibit favorable responses to COVID-19 vaccines but are more susceptible to Omicron BA.5.2 and XBB.1.16 infection
Lingxin Meng&#x;Lingxin Meng1†Yue Pan&#x;Yue Pan1†Yueping Liu,&#x;Yueping Liu1,2†Rui HeRui He1Yuting SunYuting Sun1Chenhui WangChenhui Wang3Lei FeiLei Fei1Airu ZhuAiru Zhu4Zhongfang WangZhongfang Wang4Yunfei AnYunfei An5Yuzhang Wu*Yuzhang Wu1*Bo Diao*Bo Diao2*Yongwen Chen*Yongwen Chen1*
1Institute of Immunology, PLA, Third Military Medical University, Chongqing, China
2Department of Medical Laboratory Center, General Hospital of Central Theater Command, Wuhan, Hubei, China
3Beijing Institute of Microbiology and Epidemiology, Beijing, China
4State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
5Department of Rheumatology and Immunology, Children’s Hospital of Chongqing Medical University, Chongqing, China
Background: Natural infection or vaccination have provided robust immune defense against SARS-CoV-2 invasion, nevertheless, Omicron variants still successfully cause breakthrough infection, and the underlying mechanisms are poorly understood.
Methods: Sequential blood samples were continuously collected at different time points from 252 volunteers who were received the CanSino Ad5-nCoV (n= 183) vaccine or the Sinovac CoronaVac inactivated vaccine (n= 69). The anti-SARS-CoV-2 prototype and Omicron BA.5.2 as well as XBB.1.16 variant neutralizing antibodies (Nab) in sera were detected by ELISA. Sera were also used to measure pseudo and live virus neutralization assay. The associations between the anti-prototype Nab levels and different HLA-ABC alleles were analyzed using artificial intelligence (AI)-deep learning techniques. The frequency of B cells in PBMCs was investigated by flow cytometry assay (FACs).
Results: Individuals carrying the HLA-B*15 allele manifested the highest concentrations of anti-SARS-CoV-2 prototype Nab after vax administration. Unfortunately, these volunteers are more susceptible to Omicron BA.5.2 breakthrough infection due to their sera have poorer anti-BA.5.2 Nab and lower levels of viral neutralization efficacy. FACs confirmed that a significant decrease in CD19+CD27+RBD+ memory B cells in these HLA-B*15 population compared to other cohorts. Importantly, generating lower concentrations of cross-reactive anti-XBB.1.16 Nab post-BA.5.2 infection caused HLA-B*15 individuals to be further infected by XBB.1.16 variant.
Conclusions: Individuals carrying the HLA-B*15 allele respond better to COVID-19 vax including the CanSino Ad5-nCoV and the Sinovac CoronaVac inactivated vaccines, but are more susceptible to Omicron variant infection, thus, a novel vaccine against this population is necessary for COVID-19 pandemic control in the future.
Since its initial emergence in Wuhan at the end of 2019, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused more than 778 million confirmed cases of coronavirus disease 2019 (COVID-19), and more than 6.3 million fatalities worldwide as of February 2024 (1). SARS-CoV-2 has undergone continuous genetic evolution, and multiple mutation variants including Omicron have been reported (2, 3). Over 248 COVID-19 vaccines have been developed globally, and 9 have emergency been used authorization (4, 5). These vaccines have been reported to successfully induce protective humoral and T-cell-mediated immunity against SARS-CoV-2. For instance, individuals vaccinated with the Ad26.COV2.S or the Pfizer BNT162b2 presented robust neutralizing antibodies (Nab) and strong T-cell responses against the prototype strain, Delta, and Omicron variants (6). Additionally, SARS-CoV-2 spike-specific CD4+ and CD8+ T cells induced by BNT162b2 provide extensive immune coverage against Omicron B.1.1.529 variant (7). However, Omicron variants can still penetrate vaccine induced defenses and cause breakthrough infection, but the mechanisms underlying immune evasion remain unclear.
Human leukocyte antigen (HLA) has been reported to be related to COVID-19 vaccination efficacy, and certain HLA alleles were showed to increase susceptibility to SARS-CoV-2 infection (8, 9). For examples, people carrying the HLA-DQA1*03:03, DRB1*12:01, DRB1*03:01, or the HLA-DRB1*07:01, exhibited high levels of serum Nab after received BNT162b2 vaccine (10, 11). Populations with the HLA-DQB1*06 allele had markedly increased in Nab levels post ChAdOx1, BNT162b2, or mRNA-1273 vaccinations. Conversely, some studies reported that certain HLA supertypes are negatively correlated with vaccine efficacy (12). Unfortunately, no data are available about the associations between certain HLA allele and the levels of anti-SARS-CoV-2 prototype Nab induced by the Ad5-nCoV or CoronaVac inactivated vaccines till now.
Here, 252 volunteers received the Ad5-nCoV (CanSino, n = 183) or the CoronaVac inactivated vaccine (Sinovac, n = 69) were recruited, and sequential blood samples were collected at different time points. We showed that individuals carrying the HLA-B*15 allele have a good Nab response to COVID-19 vaccines, unfortunately, these populations are more susceptible to suffer from Omicron BA.5.2 and XBB.1.16 variant breakthrough infection later.
A total of 252 volunteers were recruited for this study, 183 participants (149 males and 34 females) were inoculated with the Ad5-nCoV vaccine (CanSino, China), and 69 volunteers (38 males and 31 females) were administered by the CoronaVac inactivated vaccine (Sinovac, China). In addition, we acquired 10 normal plasma samples from the First Affiliated Hospital of Guangzhou Medical University before the COVID-19 pandemic. Detail information of individuals vaccinated with both vaccines were showed in Figure 1.
Figure 1. Sampling and experimental setup. A total of 252 volunteers who were administered Ad5-nCoV (CanSino, n = 183) or the CoronaVac inactivated vaccine (Sinovac, n = 69) were recruited, and blood samples were systematically collected on the indicated days. The sera were used to analyze Nab, while PBMCs were selected for HLA-ABC typing, and the associations between Nab levels and HLA-ABC alleles were analyzed via AI-based analysis. Moreover, sera from some Ad5-nCoV-treated volunteers were also used to detect the efficacy of liver and pseudovirus neutralization. Fluorescence-activated cell sorting (FACs) was used to identify SARS-CoV-2-specific memory B cells.
We continuously monitored volunteers who were inoculated with the CanSino Ad5-nCoV vaccine after COVID-19 restrictions were fully lifted in China (December 5, 2022). Some of these volunteers subsequently suffered from Omicron BA.5.2 and XBB.1.16 infection, as confirmed to be positive for SARS-CoV-2 by RT-PCR, and they presented either asymptomatic or mild symptoms (Supplementary Tables 1, 2). Sera and peripheral blood mononuclear cells (PBMCs) were separated by centrifugation. Serum samples were used to detect SARS-CoV-2-specific antibody, and PBMCs were used for HLA-ABC genotyping. The associations between anti-SARS-CoV-2 prototype Nab levels and different HLA-ABC alleles were further analyzed utilizing artificial intelligence (AI)-deep learning techniques. The efficacy of virus neutralization and the frequency of memory B-cell were also investigated (Figure 1).
All volunteers were recruited to measure HLA-ABC genotype polymorphisms using the MiSeqDx™ Next Generation Sequencing (NGS) platform. The predominant alleles of HLA-A supertype in these populations were HLA-A*11 (25.63%), HLA-A*02 (27.74%), and HLA-A*24 (18.7%). For the HLA-B supertype, the leading genotypes were HLA-B*40 (16.39%), HLA-B*15 (13.24%) and HLA-B*46 (9.45%). Among the HLA-C supertype, HLA-C*03 (20.8%), HLA-C*01 (16.81%), HLA-C*07 (11.97%) and HLA-C*14 (11.76%) are the principal alleles (Supplementary Figure 1).
The concentrations of anti-SARS-CoV-2-specific prototype Nab and anti-Spike (S1+S2) antibodies in sera were measured by ELISA. For the CanSino Ad5-nCoV vaccine, both types of antibodies were nearly undetectable before vax booster (over 12 months after the initial 1st dose), this result resembled to previous reports (13, 14). However, the concentrations of both antibodies were significantly triggered by the 2nd dose (vax booster) at 1 month (M1), they were sustained for up to 3 months (M3) and gradually vanished after 6 months (M6) (Figure 2A). Similar results were also observed in volunteers who were received the Sinovac CoronaVac inactivated vaccine (Figure 2B). Therefore, the volunteers were classified into two groups, the high-vax response group (HVG) and low-vax response group (LVG) based on serum concentrations of the anti-prototype Nab (Supplementary Figure 2).
Figure 2. Individuals carrying HLA-B*15 alleles exhibit a favorable response to COVID-19 vaccination. (A) Serum concentrations of anti-prototype Nab and anti-(S1+S2) antibodies in volunteers who received the CanSino Ad5-nCoV vaccine (A) or the Sinovac CoronaVac inactivated vaccine (B) at the indicated time points. The relationships between serum anti-prototype Nab concentrations and HLA-ABC alleles in CanSino Ad5-nCoV-vaccinated volunteers were investigated by XGBoost (C) and Boruta (D). The associations between serum anti-prototype Nab concentrations and HLA-ABC alleles in volunteers administered the Sinovac CoronaVac inactivated vaccine were investigated by XGBoost (E, F). ***p <0.0001.
The heterogeneity of HLA molecules has been reported to affect the efficacy of COVID-19 vaccines (15). We therefore analyzed the associations between certain HLA-ABC allele and anti-SARS-CoV-2 prototype Nab levels utilizing an AI-driven deep learning technique. Interestingly, XGBoost showed individuals carrying the HLA-B*15 allele exhibited the most pronounced increase in anti-prototype Nab levels after vax booster, especially at M3 and M6 compared to Nab in sera of pre-booster (Figure 2C). Boruta analysis also confirmed that HLA-B*15 persons presented an augmenting anti-prototype Nab (Figure 2D). In the context of the Sinovac CoronaVac inactivated vaccine, XGBoost analysis showed that individuals carrying HLA-B*15 alleles manifested the highest levels of anti-SARS-CoV-2 Nab after the 3rd dose of vaccine administration, as compared to that in serum from pre-booster (T0) (Figures 2E, F), confirming individuals carrying HLA-B*15 allele have favorable responses to both the Ad5-nCoV and CoronaVac vaccines.
Volunteers received the Ad5-nCoV vaccine presented better the SARS-CoV-2-specific anti-prototype Nab and the anti-(S1+S2) antibodies than that from persons administered with the CoronaVac vaccine (Supplementary Figure 3), therefore, individuals received the Ad5-nCoV vaccine were continued to monitor their susceptibility to SARS-CoV-2 infection thereafter. COVID-19 restrictions were fully lifted by Chinese government on December 5th, 2022. The timeframe exceeded 9 months after they were received the 2nd dose of Ad5-nCoV vaccine. Unfortunately, all these volunteers were infected by Omicron BA.5.2, as confirmed via SARS-CoV-2-specific RT-PCR. Plasma samples were collected from these individuals after 1 month (M1, n = 96), 3 months (M3, n = 96), and 6 months (M6, n = 22) post infection. ELISA analysis revealed that the anti-prototype Nab and the anti-(S1+S2) antibody levels were increased significantly after BA.5.2 infection, and their concentrations were significantly higher than that triggered by the Ad5-nCoV vaccine (Figure 3A).
Figure 3. HLA-B*15 volunteers exhibited a significant reduction in Nab and viral neutralization efficacy against the SARS-CoV-2 prototype strain after BA.5.2 infection. (A) Serum concentrations of anti-prototype Nab and anti-(S1+S2) antibodies at the indicated time points in volunteers who received the CanSino Ad5-nCoV vaccine following BA.5.2 infection. (B) Heatmap showing the serum concentrations of anti-prototype Nab and anti-(S1+S2) antibodies at different time points in 96 individuals. (C) Serum concentrations of the anti-prototype Nab at M1 post-Omicron BA.5.2 infection were compared between the LVG and HVG groups. (D) The volunteers (n=96) were divided into two groups (HLA-B*15 and others), and the serum concentrations of the anti-prototype Nab at M1 after Omicron BA.5.2 infection were compared. (E) The scores of clinical symptoms were calculated (left) and compared (right) between HLA-B*15 volunteers and others post-BA.5.2 infection. (F) Sera from M1 after the vax booster or post-BA.5.2 infection of the LVG (left) and HVG (right) were used to detect the efficacy of viral neutralization. (G) The volunteers were divided into two groups, HLA-B*15 volunteers and others, and the efficacy of viral neutralization of sera was detected and compared. *p <0.05, ** p <0.01, and ***p <0.001.
A heatmap revealed that individuals who exhibited stronger antibody levels caused by Ad5-nCoV vaccine conversely presented with lower antibody concentrations following BA.5.2 infection (Figure 3B). Indeed, serum from HVG patients had notably lower levels of both types of antibodies at M1 post-BA.5.2 infection than serum from LVG patients (Figure 3C). Individuals with HLA-B*15 allele also manifested significantly lower concentrations of the anti-SARS-CoV-2 prototype Nab at M1 post BA.5.2 infection than that from non-HLA-B*15 patients (Figure 3D). Additionally, the HLA-B*15 patients experienced notably more severe clinical manifestations than that in the non-HLA-B*15 persons (Figure 3E).
The sera from volunteers in the LVG (n = 10) and HVG (n = 10) groups were randomly selected, and the efficacy of viral neutralization was analyzed by a pseudovirus neutralization assay. Results showed that sera from LVG at 1 month of Vax booster (booster-M1) had not any capacity to neutralize SARS-CoV-2 prototype or the close variants, including Alpha, Beta, and Gamma strains, however, serum samples at 1 month of Omicron BA.5.2 infection (BA.5.2-M1) can efficiently neutralize these viruses. Sera from HVG group of booster-M1 have the capacity to neutralize SARS-CoV-2, and samples at BA.5.2-M1 further enhanced the efficacy. Interestingly, sera from the LVG cohort at BA.5.2-M1 exhibited dramatically greater viral neutralization efficacy than those from the HVG cohort (Figure 3F). Individuals in the HVG cohort were further divided into HLA-B*15 and non-HLA-B*15 (others) groups. In the Vax booster-M1 stage, it seems that serum from HLA-B*15 individuals displayed better viral neutralization efficacy than that from LVG individuals or non-HLA-B*15 (others), however, this effect was oppositely observed after BA.5.2 infection (BA.5.2-M1), and the neutralization efficiency of HLA-B*15 sera was reduced dramatically against the SARS-CoV-2 prototype strain and Gamma and Delta variants (Figure 3G), suggesting that sera from HLA-B*15 volunteers diminished viral neutralization efficacy after BA.5.2 infection.
The concentrations of anti-BA.5.2 specific neutralization antibodies (anti-BA.5.2 Nab) in these continuous samples were measured, results showed that Ad5-nCoV vaccine has not the capacity to trigger anti-BA.5.2 Nab (inhibition rate of BA.5.2) production (Figure 4A), indicating Ad5-nCoV vaccine failed to induce a cross-protective humoral response against BA.5.2 variant. However, high levels of anti-BA.5.2 specific Nab were observed at both M1 and M3 following BA.5.2 infection, and their concentrations were sustained for 6 months at least (Figure 4A). Surprisingly, the serum levels of anti-BA.5.2 Nab from HLA-B*15 individuals were significantly lower than that from non-HLA-B*15 (others) cohorts (Figure 4B), confirming that HLA-B*15 individuals had worse humoral responses post BA.5.2 infection.
Figure 4. HLA-B*15-treated volunteers exhibited a significant reduction in Nab and viral neutralization efficacy against Omicron BA.5.2 post infection. (A) Serum concentrations of anti-BA.5.2 Nab at the indicated time points in volunteers who received the CanSino Ad5-nCoV vaccine following BA.5.2 infection. (B) The volunteers were divided into two groups, HLA-B*15 volunteers and others, and the serum concentrations of anti-BA.5.2 Nab at M1 and M3 after Omicron BA.5.2 infection were compared between HLA-B*15 volunteers and others. (C) Sera from M1 after the vax booster or post-BA.5.2 infection of LVG (left) and HVG (right) were used to detect the efficacy of viral neutralization against Omicron variants. (D) The efficacy of viral neutralization against Omicron variants in sera collected at M1 after Omicron BA.5.2 infection was compared between the LVG and HVG groups. (E) Individuals from the HVG group were further divided into HLA-B*15 volunteers and others, and the efficacy of viral neutralization against Omicron variants from sera collected at M1 after Omicron BA.5.2 infection was compared. (F) The efficacy of live viral neutralization from sera collected at M1 after vax booster and post-Omicron BA.5.2 infection. (G) The efficacy of live viral neutralization from sera collected at M1 after vax booster (left) and post-Omicron BA.5.2 infection (right) was compared among the LVG and HLA-B*15 alleles and others. NS: not significantly different, *p <0.05, ** p <0.01, and ***p <0.001.
We then analyzed the efficacy of virus neutralization of these serum samples. Sera from both LVG and HVG groups at BA.5.2-M1, rather than that from booster-M1, efficiently neutralized Omicron BA.5.2, and they also manifested a slight neutralization efficacy against BQ.1.1 and CH.1.1, however, no neutralization efficacy was observed against XBB, XBB.1.16 or XBB.1.1 variants (Figure 4C). Anticipated, sera from LVG and HVG at BA.5.2-M1 stage also manifested high efficacy of virus neutralization (Figure 4D), notably, serum from HLA-B*15 individuals showed a markedly reduced in viral neutralization capacity against Omicron BA.5.2, BQ.1.1 and CH.1.1 variants, compared to that of individuals in both the LVG and HVG groups (Figure 4E).
We also analyzed the efficacy of live virus neutralization of these sera. Expectedly, sera at both the booster-M1 and the BA.5.2-M1 stage have the capacity to neutralize SARS-CoV-2 prototype strain, however, these sera manifested not any neutralization capacity to Omicron XBB.1 or BQ.1.1 variants, and the sera from BA.5.2-M1 manifested greater viral neutralization efficacy than the booster-M1 does (Figure 4F). Interestingly, sera from HLA-B*15 individuals at the booster-M1 exhibited greater neutralizing activity against SARS-CoV-2 prototype than that from the LVG group or other individuals in the HVG group, conversely, sera from HLA-B*15 individuals at the BA.5.2-M1 exhibited a diminished efficacy of virus neutralization (Figure 4G), suggesting HLA-B*15 individuals exhibited a significant decrease in virus neutralization capacity.
Given the critical role of B cells in antibody production, we then examined the status of B cells by FACs. Data from sequential samples (n=10) showed there was no significant difference in the frequency of CD19+CD20+ B cells or CD19+CD27+ memory B cells throughout the whole investigated period (Figure 5A). Individuals were further divided into HLA-B*15 and non-HLA-B*15 cohorts (Figure 5B). Statistical analysis revealed that HLA-B*15 populations had significantly lower percentages of memory B cells than non-HLA-B*15 cohorts (others) from the vax booster stage to the Omicron BA.5.2 infection stage (Figure 5C).
Figure 5. Reduced CD19+CD27+RBD+ memory B cells in the HLA-B*15 population after BA.5.2 infection. (A) FACs analysis of the percentages of CD19+IgG+ B cells, CD19+27+ memory B cells, CD19+27+RBD(WT)+, CD19+27+RBD(BA.5.2)+, and CD19+27+RBD(WT)+(BA.5.2)+ memory B cells at various time points. (B) FACs analysis of CD19+CD20+ B cells and RBD (WT)+ memory B cells between the HLA-B*15 and the non-HLA-B*15 groups. (C) The percentages of CD19+27+ memory B cells in HLA-B*15 individuals and other individuals at different time points were compared. (D) The percentages of CD19+27+RBD(WT)+ and CD19+27+RBD(BA.5.2)+ memory B cells in HLA-B*15 individuals and other individuals at different time points were compared. NS: not significantly different, *p <0.05, ** p <0.01, and ***p <0.001.
We further detected the percentage of RBD(WT)+ and RBD(BA.5.2)+ memory B cells utilizing the recombinant SARS-CoV-2 BA.5.2 RBD Alexa Fluor® 488 protein and the recombinant SARS-CoV-2 spike RBD Alexa Fluor® 647 protein (Figure 5B, Supplementary Figure 4). As expected, the Vax booster enhanced the number of RBD(WT)+CD19+CD27+ memory B cells, while BA.5.2 infection did not further increase cell frequencies (Figure 5A). Compared to vax booster, BA.5.2 infection promoted the percentage of RBD(BA.5.2)+CD19+CD27+ memory B cells (Figure 5A). Importantly, the frequency of RBD(WT)+(BA.5.2)+CD19+CD27+ memory B cells was dramatically increased following BA.5.2 infection (Figure 5A). However, at the booster-M6 and the BA.5.2-M1 as well as the BA.5.2-M3, HLA-B*15 individuals manifested dramatically lower numbers of RBD(WT)+CD19+CD27+ memory B cells in PBMCs than that from non-HLA-B*15 individuals (Figure 5D). Similar results were also observed in the percentage of RBD(BA.5.2)+CD19+CD27+ memory B cells (Figure 5D), confirming the reduction of memory B cells in HLA-B*15 individuals after BA.5.2 infection.
In July 2023, a resurgence of COVID-19 occurred in Chongqing city, and serum samples were collected from 43 volunteers who previously received the Ad5-nCoV vaccine. Based on SARS-CoV-2 antigen detection and symptom assessment, 21 individuals were confirmed to suffer from XBB.1.16 variant infection. ELISA showed that XBB.1.16 infection could not further enhance anti-SARS-CoV-2 Nab levels (Figure 6A), however, XBB.1.16 infection increased the concentration of cross-reactive anti-BA.5.2-Nab (Figure 6B), suggesting that XBB.1.16 infection enhanced the cross-reactive humoral response to BA.5.2 strain.
Figure 6. Individuals carrying the HLA-B*15 allele are more susceptible to Omicron XBB.1.16 infections. Serum concentrations of anti-prototype Nab (A) and anti-BA.5.2 Nab (B) from 21 volunteers who received the CanSino Ad5-nCoV vaccine following infection with Omicron BA.5.2 or XBB.1.16 were detected by ELISA. (C) Serum concentrations of anti-XBB.1.16 in Nab volunteers who received the CanSino Ad5-nCoV vaccine following infection with Omicron BA.5.2 (left) and 22 volunteers who were further infected with XBB.1.16 (right) were detected by ELISA. (D) Serum concentrations of anti-XBB.1.16 Nab in individuals infected with or without XBB.1.16 were compared. (E) Serum concentrations of anti-XBB.1.16 Nab at the indicated time points were compared between HLA-B*15 and other antibodies. (F) Some volunteers, and (G) HLA-B*15 sera were collected at M1 after the vax booster and post-Omicron BA.5.2 and XBB.1.16 infection, and the efficacy of viral neutralization was detected. NS: not significantly different, *p <0.05, ** p <0.01, and ***p <0.001.
Data from continuous samples (n=21) showed that XBB.1.16 infection further enhanced anti-XBB.1.16-specific Nab (Figure 6C), suggesting that Omicron XBB.1.16 infection can enhance humoral immunity. However, as compared to XBB.1.16 uninfected individuals, XBB.1.16 infection did not further enhance the specific anti-XBB.1.16 Nab (Figure 6D). The 21 individuals who suffered from XBB.1.16 infection were classified into HLA-B*15 and non-HLA-B*15 groups, ELISA revealed that at M1 and M3 post-BA.5.2 infection, serum from HLA-B*15 individuals manifested dramatically lower concentrations of cross-reactive anti-XBB.1.16 Nab than did serum from non-HLA-B*15 participants (others) (Figure 6E), indicating that HLA-B*15 individuals are more susceptible to XBB.1.16 infection.
We finally monitored the efficacy of serum neutralizing to various SARS-CoV-2 strains, and sera from some volunteers (Figure 6F) and HLA-B*15 individuals (Figure 6G) at vax booster-M1, BA.5.2-M1, and XBB.1.16-M1 were selected. Results showed that these sera predominantly neutralized the SARS-CoV-2 prototype strain and Omicron BA.5.2, however, they displayed very low neutralizing activity against other Omicron variant strains. Importantly, XBB.1.16 infection did not further enhance the efficacy of viral neutralization.
The COVID-19 pandemic represents one of the most serious public health problems worldwide, and SARS-CoV-2 is still continuous mutation during transmission (16, 17). Omicron variants exhibit more than 60 amino acid mutations in the spike protein, making it significantly distinct from the original prototype strain (18), therefore, high mutability increases the susceptibility of hosts to recurrent Omicron variant infections. Currently, the Ad26.COV2.S, mRNA-1273, the Pfizer BioNTech-Comirnaty vaccine, and the Sinovac-CoronaVac vaccine have been listed as qualified vaccines for emergency use by WHO (5). However, individuals who were received these vaccines do not effectively prevent SARS-CoV-2 variant infections, although COVID-19-related hospitalization, severity, and mortality are reduced markedly (19). In China, the most commonly used vaccines include BBIBP-CorV, CoronaVac, and Ad5-nCoV, and preliminary investigations indicate that Ad5-nCoV vaccine can trigger robust humoral and cellular immunity against SARS-CoV-2 within 28 days, and the Nab levels were declined significantly after 6 months (20). Recipients administered the CoronaVac vaccine also exhibited a notable increase in anti-SARS-CoV-2 prototype Nab levels (21). Similar to these observations, we here illustrated that individuals vaccinated with booster dose of the Ad5-nCoV and the CoronaVac manifested high levels of anti-SARS-CoV-2 prototype Nab (Figures 2A, B), however, the Ad5-nCoV vaccine seems to fail to elicit specific cross-reactive anti-BA.5.2 Nab (Figure 4A) and XBB.1.16-Nab (Figure 6B), indicating that the Ad5-nCoV vaccine may offer limited effectiveness in preventing Omicron variant breakthrough infection.
Early studies have highlighted the associations between certain HLA expression and the rapid dissemination of HIV, HBV, HCV, and SARS-CoV (22). Recently, HLA molecules have also been described as crucial factor in determining the outcome of SARS-CoV-2 infection and vaccination efficacy. For example, the HLA-DRB1*04 may predict disease severity in Iranian COVID-19 patients (23). The specific HLA supertypes, including the HLA-DRB1*15:01, DQB1*06:02, B*27:07, HLA-A*03:01, A*11:01, A*24:02, B*52:01, and C*12:02, are significantly correlated with severe/critical illness following SARS-CoV-2 infection (8, 9). Some Omicron sublineages can downregulate HLA antigens in virus-infected cells through enhancing autophagy and antagonizing CTL-induced cell death (24). Furthermore, certain HLA supertypes, such as the DQA1*03:03, DQB1*06, DRB1*03:01, and DRB1*07:01, augment vaccine-induced anti-SARS-CoV-2 Nab levels (10, 25). Furthermore, it seems that HLA-II molecules, such as the DRB1*03:01, DRB1*07:01, and DRB1*12:01, successfully induce Nab to counteract SARS-CoV-2 in recipients after they were administration of the COVID-19 mRNA vaccine (26). Conversely, some studies revealed a negative association between specific HLA supertypes and vaccine efficacy (27). We here confirmed a significantly positive correlation between HLA-B*15 alleles and seral titers of anti-prototype Nab elicited by the Ad5-nCoV vaccine and the CoronaVac-inactivated vaccine (Figure 2). Previous investigations have demonstrated that individuals carrying HLA-B*15:01 tend to experience asymptomatic SARS-CoV-2 infections (25, 28–30). Remarkably, we here showed that the HLA-B*15 patients experienced notably more severe clinical manifestations than that in the non-HLA-B*15 persons (Figure 3E). Most importantly, HLA-B*15 individuals exhibited markedly lower levels of cross-reactive specific anti-prototype Nab, including anti-BA.5.2 and anti-XBB.1.16 Nab, thus leading to diminished virus neutralization capacity against the Omicron variants. We therefore concluded that HLA-B*15 populations have a better response to SARS-CoV-2 vaccines but are more susceptible to Omicron breakthrough infection.
Recent studies have suggested that “Original antigenic sin” (OAS) or “immune imprinting” are involved in mediating SARS-CoV-2 new variant breakthrough infection, and evidences are also available regarding their impact on the safety and effectiveness of COVID-19 vaccines (31). For instance, individuals previously infected with SARS-CoV-2 (Wuhan strain) did not exhibit a substantial increase in Nab and T-cell responses against Omicron B.1.1.529 upon reinfection (18). Xie X et al. demonstrated that antibodies isolated from COVID-19 patients who experienced breakthrough infections with BA.2 and BA.5 showed significantly diminished neutralizing activity and antibody diversities against other variants, such as BQ.1.1.10 (BQ.1.1 + Y144del), BA.4.6.3, XBB, and CH.1.1, due to the presence of OAS (32). Zhang Z et al. confirmed that BA.2 variant breakthrough infection successfully elicits immune memory B cells derived from the prototype strain or its close variants (including Alpha, Beta, Gamma, and Delta), while the specific antibody response against BA.2 is complicated (33). Here, we showed that the Ad5-nCoV cannot induce cross-reactive anti-BA.5.2 and anti-XBB.1.16 Nab, interestingly, both Nabs were triggered by post-BA.5.2 infection. Additionally, secondary XBB.1.16 infection further enhanced anti-XBB.1.16 Nab, suggesting that immune imprinting is not obviously presented in these volunteers. However, there was a greater reduction in the number of CD19+CD27+ memory B cells in HLA-B*15 individuals than that in other individuals after BA.5.2 infection, this phenomenon might be responsible for the lower level of anti-prototype, anti-BA.5.2 and anti-XBB.1.16 Nab release after BA.5.2 infection.
CD4+ follicular helper T (Tfh) cells play pivotal roles in regulating antibody responses and maintaining long-term memory B cells (34). It seems that the induction of antigen-specific germinal center formation and the production of Nab by SARS-CoV-2 mRNA vaccines are closely associated with the presence of Tfh cells in vivo (35). Specifically, the HLA-DPB1*04-restricted S167-180 epitope has been shown to stimulate Tfh differentiation, leading to a sustained and robust response to COVID-19 mRNA vaccines (36). Here, we revealed a significant decrease in the frequency of memory CD19+ CD27+RBD+ B cells postvaccination and after BA.5.2 infection (Figure 5), potentially resulting in decreased serum antibodies. However, whether Tfh cells also regulate memory B cells in the HLA-B*15 population need further investigation.
An effective vaccine is expected to induce both protective cellular and humoral immunity to all kinds of SARS-CoV-2 variants, and individuals vaccinated with these vaccines also can maintain long-lasting memory B and T-cells in vivo (37, 38). It seems that the HLA restricted CD4+ as well as CD8+ T-cell epitopes are comprehensively distributed in the whole SARS-CoV-2 proteome (39), therefore, the induction of broadly protective cellular responses is a feasible strategy to enhance the effectiveness of COVID-19 vaccines. Recently, Tai W et al., developed a lipid nanoparticle (LNP)-formulated mRNA-based T-cell-inducing antigen, which targeted three SARS-CoV-2 proteome regions that enriched human HLA-I epitopes (HLA-EPs), the sequences of HLA-EPs are highly conserved among SARS-CoV-2 variants, therefore, HLA-EPs induces broad cellular immunity and prevent SARS-CoV-2 infection (40), HLA-EPs would be one of new generations of COVID-19 vaccine, possibly can provide protection for individuals with HLA-B*15.
Some limitations of our study need to be noted. First, we focused only on humoral immune responses and did not explore the potential of T-cell immunity in controlling viral infection. Second, the molecular mechanisms underlying the reduction in memory B cells in HLA-B*15 volunteers remain unclear. Third, the potential alterations in the diversity of B-cell receptors (BCRs) within the same volunteer across different time periods and their correlation with antibody diversity remain unexplored.
Overall, we showed that individuals carrying the HLA-B*15 allele exhibit a more favorable response to vaccines but are more susceptible to breakthrough infections caused by Omicron variants such as BA.5.2 and XBB.1.16. Therefore, novel vaccines and immunological control strategies for this population are necessary for future COVID-19 interventions.
A total of 252 volunteers were recruited for this study. Among them, 183 volunteers received the Ad5-nCoV adenovirus vector vaccine, while 69 volunteers were administered the Sinovac CoronaVac inactivated vaccine. The ages of the volunteers were 18~59 years, and they were not pregnant and had no communicable diseases such as malignancies, diabetes, coronary heart disease, chronic obstructive pulmonary disease, stroke, chronic kidney disease, or chronic infectious diseases such as HIV, HBV, or tuberculosis. Blood samples were collected at various time points, including before the vax booster (Pre) and at 1 month (M1), 3 months (M3) and 6 months (M6) after the vax booster. Additionally, samples from Ad5-nCoV-vaccinated volunteers were collected at 1 month (M1), 3 months (M3) and 6 months (M6) after recovery from BA.5.2 breakthrough infection. Furthermore, blood samples from 21 individuals who recovered from secondary XBB.1.16 breakthrough infection at 1 month (M1) were also collected. Relevant experiments regarding vaccinated individuals were approved by the Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University (2021-78).
Total RNA from PBMCs was extracted and converted into full-length cDNA using high-efficiency reverse transcriptase. The targeted genes were captured using a highly specific capture panel, and the resulting products were supplemented with sequencing primers to generate libraries suitable for sequencing. Following library construction, quantitative analysis was performed using Qubit 3.0, followed by insert size detection using Qsp100. Once the insert size met the expected criteria, paired-end 150 (PE150) sequencing was conducted using the Illumina X10 or NovaSeq 6000 platform. After obtaining the raw sequencing data, data filtering and quality control were performed using fastp (v0.21.0) software. The high-quality sequencing data obtained after filtering were then analyzed for HLA typing using arcasHLA software.
An indirect enzyme-linked immunosorbent assay (ELISA) kit provided by Sino Biological, Inc. (Cat: KIT004) and (Cat: CSB-EL33243HU) was used to measure antibodies was used as described by the manufacturer, and the intensity of the color was measured at 450 nm.
An indirect enzyme-linked immunosorbent assay (ELISA) kit provided by ACROBiosystems (Cat: N107-CN.01, N173-CN.01) was used. This assay kit was used to measure the levels of anti-SARS-CoV-2 neutralizing antibody through a competitive ELISA. The microplate in the kit was precoated with human ACE2 protein. The experiment included 5 simple steps and the absorbance at 450 nm minus the absorbance at 630 nm to remove background prior to statistical analysis. The OD value reflects the amount of protein bound.
The prototype strain and SARS-CoV-2 variants were all self-prepared by Zhongke Guobang (Beijing) Inspection and Testing Co., Ltd. Pseudovirus dilution to 1.3x104/mL using complete DMEM. Vero cells were prepared from the incubator, counted after trypsin digestion, and diluted to a concentration of 2x105 cells/mL using complete DMEM. The plate was then agitated for 2 minutes, and the luminescence was measured using a multifunctional plate reader. Analysis software specific to neutralizing antibody data for COVID-19 was used throughout the calculation process.
Virus was titrated using a focus-forming assay (FFA). Vero E6 cells were seeded in 96-well plates one day before infection. The plasma samples were serially diluted and incubated with an equal volume of virus at 37°C for 1 h. Then, the mixtures were inoculated onto Vero E6 cells at 37°C for 1 h. The cells were then incubated with a rabbit anti-SARS-CoV-2 nucleocapsid protein polyclonal antibody (Cat. No. 40143-T62, Sino Biological, Inc., Beijing), followed by an HRP-labeled goat anti-rabbit secondary antibody (Cat. No. 109-035-088, Jackson ImmunoResearch Laboratories, Inc., West Grove, PA). The foci were visualized by TrueBlue Peroxidase Substrate (KPL, Gaithersburg, MD) and counted with an ELISPOT reader. Viral titers were calculated as the FFU per ml or per gram of tissue.
Peripheral blood mononuclear cells (PBMCs) (approximately 1 x 106 cells/100 µL) were collected at various time points postvaccination and postinfection. The cells were centrifuged at 1000 × g for 5 minutes at 4°C and washed twice with PBS (catalog no. 40143-T62, Gibco). Subsequently, the cells were stained with recombinant SARS-CoV-2 BA.4/BA.5 The RBD Alexa Fluor® 488 protein dye (Catalog No.: AFG11229-020, R&D), recombinant SARS-CoV-2 spike RBD Alexa Fluor® 647 protein (Catalog No.: AFR10500-020, R&D), CD38-Brilliant Violet 421 (Catalog No.: 397119, BioLegend), and CD20-PE/Cyanine7 (Catalog No.: 356617, BioLegend) were diluted (1:100) in FACs buffer (0.1% BSA) at 4°C for 30 minutes. After staining, the cells were washed twice with FACs staining buffer (0.1% BSA). After three washes, the cells were resuspended buffer and filtered through a 35 µm filter. Cell collection was performed using BD FACSaria III, and analysis was conducted using FlowJo 10.8.1.
The data were entered into Excel, and statistical analysis and graphical representations were performed by R-4.3.3. Statistical analysis between two samples was conducted using a t test, while analysis involving three samples or unpaired comparisons was conducted using the Wilcoxon test. Pairwise comparisons among three or more samples were conducted using Tukey’s multiple comparisons test. All the statistical tests were two-sided, and a p value less than 0.05 indicated statistical significance.
The raw sequence data can be obtained from the GSA-Human database (https://ngdc.cncb.ac.cn/gsa-human) with accession number HRA008235. The code that supports the findings of this study is available from the corresponding authors upon request.
The studies involving humans were approved by the Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.
LM: Writing – review & editing, Investigation. YP: Methodology, Writing – original draft. YL: Formal analysis, Writing – review & editing. RH: Resources, Writing – original draft. YS: Data curation, Writing – review & editing. CW: Writing – review & editing, Methodology. LF: Methodology, Writing – review & editing. AZ: Investigation, Writing – original draft. ZW: Writing – original draft, Data curation. YA: Writing – original draft, Validation. YW: Writing – original draft, Conceptualization. BD: Writing – original draft, Formal analysis. YC: Conceptualization, Writing – review & editing.
The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Key Research and Development Program of China (2022YFC2604100), the National Natural Science Foundation of China (NSFC, No. 92369203 and 92269111) and grants from the Emergency Key Program of Guangzhou Laboratory (EKPG21-30-3).
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2024.1440819/full#supplementary-material
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Keywords: COVID-19, Omicron variants, HLA-B*15, vaccination, SARS-CoV-2
Citation: Meng L, Pan Y, Liu Y, He R, Sun Y, Wang C, Fei L, Zhu A, Wang Z, An Y, Wu Y, Diao B and Chen Y (2024) Individuals carrying the HLA-B*15 allele exhibit favorable responses to COVID-19 vaccines but are more susceptible to Omicron BA.5.2 and XBB.1.16 infection. Front. Immunol. 15:1440819. doi: 10.3389/fimmu.2024.1440819
Received: 30 May 2024; Accepted: 19 July 2024;Published: 27 August 2024.
Edited by:
Reviewed by:
Copyright © 2024 Meng, Pan, Liu, He, Sun, Wang, Fei, Zhu, Wang, An, Wu, Diao and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Yongwen Chen, [email protected]; [email protected]; Yuzhang Wu, [email protected]; Bo Diao, [email protected]
†These authors have contributed equally to this work
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20 | https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.585354/full | REVIEW article
Front. Immunol., 14 October 2020
Sec. Vaccines and Molecular Therapeutics
Volume 11 - 2020 | https://doi.org/10.3389/fimmu.2020.585354
A Review of the Progress and Challenges of Developing a Vaccine for COVID-19
\nOmna Sharma Omna Sharma1*Ali A. SultanAli A. Sultan2Hong DingHong Ding3Chris R. Triggle Chris R. Triggle3*
1Weill Cornell Medicine-Qatar, Doha, Qatar
2Department of Microbiology and Immunology, Weill Cornell Medicine-Qatar, Cornell University, Doha, Qatar
3Departments of Medical Education and Pharmacology, Weill Cornell Medicine-Qatar, Education City, Doha, Qatar
A novel coronavirus, which has been designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first detected in December 2019 in Wuhan China and causes the highly infectious disease referred to as COVID-19. COVID-19 has now spread worldwide to become a global pandemic affecting over 24 million people as of August 26th, 2020 and claimed the life of more than 800,000 people worldwide. COVID-19 is asymptomatic for some individuals and for others it can cause symptoms ranging from flu-like to acute respiratory distress syndrome (ARDS), pneumonia and death. Although it is anticipated that an effective vaccine will be available to protect against COVID-19, at present the world is relying on social distancing and hygiene measures and repurposed drugs. There is a worldwide effort to develop an effective vaccine against SARS-CoV-2 and, as of late August 2020, there are 30 vaccines in clinical trials with over 200 in various stages of development. This review will focus on the eight vaccine candidates that entered Phase 1 clinical trials in mid-May, including AstraZeneca/Oxford's AZD1222, Moderna's mRNA-1273 and Sinovac's CoronaVac vaccines, which are currently in advanced stages of vaccine development. In addition to reviewing the different stages of vaccine development, vaccine platforms and vaccine candidates, this review also discusses the biological and immunological basis required of a SARS-CoV-2 vaccine, the importance of a collaborative international effort, the ethical implications of vaccine development, the efficacy needed for an immunogenic vaccine, vaccine coverage, the potential limitations and challenges of vaccine development. Although the demand for a vaccine far surpasses the production capacity, it will be beneficial to have a limited number of vaccines available for the more vulnerable population by the end of 2020 and for the rest of the global population by the end of 2021.
In December 2019, an outbreak of the coronavirus disease 2019 (COVID-19) emerged and was first identified in Wuhan, China and then quickly spread to now become a global pandemic affecting, as of August 26th 2020, more than 24 million people worldwide with the US comprising almost 6 million cases. COVID-19 has been attributed to the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and the illness has caused a spectrum of clinical manifestations ranging from asymptomatic, minor flu-like symptoms to acute respiratory distress syndrome (ARDS), pneumonia and death. It is anticipated that the COVID-19 pandemic can be controlled using social distancing, masks, new antiviral drugs and an effective vaccine. Although developing herd immunity through acquiring natural immunity via infections is possible, the death toll and consequences as such would be devastating (1). This was seen in Sweden where authorities presumed that by infecting up to 60% of the population, herd immunity would be sufficient to protect the more vulnerable population (2). However, this failed and the deaths per million population attributed to COVID-19 in Sweden is at least 5 times that of Germany (2). Hence, developing an effective vaccine is crucial and considered the only practical way to establishing herd immunity.
Researchers around the world are aggressively working around the clock to develop a vaccine against COVID-19. As of late August 2020, there are more than 200 vaccine candidates in various stages of development. While there are 30 vaccines currently in clinical trials, this review will focus on the 8 vaccines that entered Phase 1 clinical trials in mid-May including AstraZeneca/Oxford's AZD1222 and Moderna's mRNA-1273 vaccines. Although the production capacity may not be able to meet the global demand for vaccines in the very near future, it would be beneficial to have a limited number of vaccines available for emergency use and the more vulnerable population as soon as possible with the ultimate aim of distributing vaccines globally to the rest of the population by the end of 2021.
In order to develop a safe and effective vaccine, it is critical that pre-clinical and clinical trials are done with vigilance to avoid severe adverse effects (3). Furthermore, cooperation between international organizations such as the World Health Organization (WHO), Coalition for Epidemic Preparedness Innovations (CEPI), Gavi alliance, Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) and Bill and Melinda Gates Foundation (BMGF) amongst others is essential to ensure adequate funding for vaccines and a collaborative response to the COVID-19 pandemic (3). This review summarizes the biology and immune response demonstrated from previous coronavirus infections and SARS-CoV-2, the various platforms being utilized for COVID-19 vaccine candidates, describes an outline of the process of traditional vaccine development, examines and analyses the progress of 8 different vaccine candidates and outlines the challenges associated with vaccine production in a pandemic. In addition, the question of whether mutations in the spike protein might affect the efficacy of a vaccine is addressed as also are potential problems that may arise by fast-tracking vaccine production. Vaccine development has typically taken up to 15 years, but with fast tracking it is hoped to reduce this to 1.5 years or less thus potentially raising concerns over public acceptance as well as concerns regarding challenges from anti-vaxxers.
Coronaviruses are enveloped, positive-sense single-stranded RNA viruses with a helical nucleocapsid. They belong to the Coronaviridae family in the order Nidovirales, subfamily Orthocoronaviridae and are divided into four genera namely alpha, beta, delta, and gamma coronavirus (4). Severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) is a beta-coronavirus belonging to the same group as severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East Respiratory Syndrome coronavirus (MERS-CoV). Although it is unclear as to how the virus was first transmitted to humans, its origins can be traced to bats, with bats also the original source for other coronavirus infections in humans (5, 6) and also Ebola (7). A study looked at cross-sectional and case-series studies primarily from China and upon analysis, the studies have shown that the mean age of patients diagnosed with COVID-19 was 52 years old with 55.9% of patients being male (8). The most common clinical manifestations included cough, fever, myalgia or fatigue with more than half of patients developing dyspnea (8, 9). Fever was seen more commonly in adults than in children (8). The most prevalent laboratory results included elevated C-reactive protein (CRP), elevated lactate dehydrogenase (LDH), lymphopenia and decreased albumin (8). Higher prothrombin times and D-dimer levels were noted for those admitted to intensive care units (ICU) (9). 36.8% of patients presented with comorbidities - the most common being hypertension, cardiovascular disease and diabetes (8).
The structure of SARS-CoV-2 involves a major trimeric envelope glycoprotein called the S-protein, which is expressed on the surface of the virus and is also the main target for vaccines as it binds to host cells. The S-protein is made of two main subunits namely S1 that controls receptor binding and S2, which governs membrane fusion (10). The S protein also undergoes a significant conformational change from a pre-fusion state to a post-fusion state, achieved by pulling and fusing the cell and viral membranes together (11). The S protein in coronaviruses is quite diverse as supported by the fact that the S proteins for SARS CoV and MERS CoV only share 44% of the genetic sequence (10). The differences in the S protein are primarily attributed mainly to the S1 subunit, which is composed of an N-terminal domain (NTD) and a receptor-binding domain (RBD). The diversity of RBD between SARS-CoV and MERS-CoV is attributed to different host cell entry receptors for the two coronaviruses namely angiotensin converting enzyme 2 (ACE2) for SARS-CoV and also for SARS-CoV-2 while dipeptidyl peptidase 4 (DPP4) is the receptor for MERS-CoV (10, 12). Since SARS-CoV and SARS-CoV-2 share the same entry receptor, monoclonal antibodies against SARS-CoV RBD were tested for cross-reactivity to SARS-CoV-2 RBD and results showed that no binding was detected to SARS CoV-2 RBD despite the similarity in RBD sequences (12). In terms of the severity and clinical consequences of the infection, SARS-CoV was more lethal and aggressive but SARS-CoV-2 is highly contagious and spreads more readily (13). Furthermore, another caveat with SARS-CoV-2 is that in some individuals the symptoms are hidden or the individual is asymptomatic, meaning that potentially an infected person unknowingly infects multiple people (13). Epidemiological studies conducted in China have estimated that the so-called reproduction number (R0) used as a measure of how many others an infected person can potentially infect is 3 (14). The highly infectious nature of SARS-CoV-2 has led to millions of cases worldwide and reinforced the global need for an effective vaccine to stop the spread of disease and reduce the number of deaths.
A strong and potent immune response is essential to clear the SARS-CoV-2 infection from the human body. A study published in the journal Cell showed that infected individuals had a strong T cell response to the virus, which may help them recover from the virus (15, 16). The results showed that all of the patients carried helper T cells that recognized the spike protein on SARS-CoV-2 (15, 16). These patients also had helper T cells against some of the other proteins on SARS-CoV-2. These data indicate that T cells do play a role in eliminating SARS-CoV-2. Helper T cells stimulate B cells to further release antibodies and helper T cells also stimulate cytotoxic T cells. Cytotoxic T cells were demonstrated in 70% of patients (15, 16). Interestingly, 34% of uninfected individuals in the same study were shown to have helper T cells that could respond to a SARS-CoV-2 infection (15, 16). Further analysis of the blood samples collected from 2015 to 2018 revealed that these helper T cells could have been triggered from a previous coronavirus infection since there is some similarity in S proteins between the different coronaviruses (15, 16). It is also worth mentioning that the debate as to the origins of SARS-CoV-2 continues with several reports that the virus may have been circulating much earlier than November-December 2019 with emerging, but to be confirmed, evidence of its presence in sewage samples as early as March 2019 as reported by Spanish researchers from Barcelona (17). Previous exposure to SARS-CoV-2, or a close relative, may explain the low number of cases and deaths reported in countries such as Vietnam. In another study published in Nature the T cell response to the nucleocapsid protein (NP) of SARS-CoV-2 and also the memory T cell response to the NP protein of SARS-CoV were investigated. The results showed that patients who recovered from COVID-19 demonstrated both CD4+ and CD8+ T cells against the NP protein (18). They also illustrated that individuals who have recovered from a SARS-CoV infection still possess T cells specific to SARS-CoV, particularly against the NP protein, and additionally, these T cells have demonstrated the ability to cross react with the SARS-CoV-2 NP protein (18). Analysis of the presence of SARS-CoV-2 T cells in uninfected individuals was also conducted and the results showed that SARS-CoV-2 specific reactive T cells were detected but to a lesser extent for the NP protein and interestingly to a greater extent for other proteins. These findings support the theory that the T cell immune response can be stimulated following exposure to other beta coronaviruses (18). Thus, lasting immunity from a previous coronavirus infection could help protect against SARS-CoV-2 and also raises the possibility that long-lasting T cell immunity will persist in COVID-19 recovered patients (15, 16, 18).
Studies on antibody responses to SARS-CoV-2 infections are ongoing with most studies illustrating that those who recover have antibodies to the virus (19). However, the level of SARS-CoV-2 specific neutralizing antibodies (NAbs) has shown to be varied between different groups of populations, which supports the theory that T cell response also plays an important role in clearing the SARS-CoV-2 infection (19). Elderly patients were shown to be more likely to develop high levels of SARS-CoV-2 specific NAbs compared to younger patients, suggesting a strong innate immune response but whether the high levels of NAbs protect such patients from progression into the critical phases of COVID-19 requires further evaluation (19).
Plasma cells and memory B cells that emerge in response to a primary infection are involved in long-term protection against a reinfection. There is intense interest surrounding the memory B cell response from SARS-CoV-2 and previous coronavirus infections. Results from studies designed to analyze antibodies from COVID-19 infection showed that IgG antibody titers rose in the first 3 weeks following symptom onset (20, 21). Although the IgG titer levels dipped in the second month following symptom onset, the level was still above the threshold and was detectable in the serum, indicating the possibility of protection against a reinfection but more research is needed to better profile the timeline of the IgG response. Examination of the immune response following a SARS-CoV infection indicated that specific IgG response declined within the first 2 years of infection and was detectable in all patients in the first 16 months but was noted to be almost undetectable in about 11.8% of patients in the 24th month (21, 22). Likewise, for the SARS-CoV specific NAb response, NAb levels were detectable up to 2 years after infection but the levels started to decline in the 16th month of follow up (21, 22). Moreover, the study also showed that the rate of decline in NAb levels was faster in men than women but, again, more research needs to be done to determine the accuracy and cellular basis for this observation. Answers to these questions as well as the influence of the age of the patient are needed to better understand the predicted effectiveness of a vaccine.
Several studies and reports have emphasized the NAb responses to different COVID-19 vaccines. Although such knowledge is important, it is also equally crucial to consider T cell responses as these are known to be more durable and provide long lasting immunity. Some reasons as to why the T cell response has not been previously emphasized include that it is more challenging to test for T cell response in trial participants especially in a larger population (23). It is important to ensure that a vaccine is eliciting not only a higher number of NAbs but also a good T cell response to ensure long lasting and effective immunity against SARS-CoV-2 (23).
To date the development of a new vaccine has been a long process that typically takes anywhere from 10 to 15 years (24), as shown by Figure 1. The fastest that a vaccine has been developed and approved for use is for mumps, which took approximately 5 years. Hence, it is clearly a challenge to develop a vaccine against COVID-19 in a span of 12–24 months. The first phase of vaccine development is an exploratory stage involving basic laboratory bench research and computational modeling to identify natural or synthetic antigens that can be used as a vaccine candidate, which might help prevent or treat a disease. The second stage comprises pre-clinical studies, which involve cell-culture or tissue-culture systems and trials on an animal model to assess the safety of the candidate vaccine and its immunogenicity, or ability to provoke an immune response. Once safety, immunogenicity and efficacy are demonstrated on animals, progress is made to human clinical trials which test for safety and immunogenicity in small groups then large groups over 3 phases, as outlined below.
Figure 1. Flowchart showing traditional process of vaccine development from exploratory, pre-clinical studies to Phase 1 studies in a comparatively few control volunteers as depicted by the figure to larger Phase 2 and Phase 3 studies. The symbol is a representation of the number of human subjects in trials.
Phase 1 - Safety: This is the first stage where the vaccine is administered to humans. The vaccine is given to a small number of healthy and immunocompetent individuals to primarily test for safety, appropriate dose and to check for immune response, as a secondary effect.
Phase 2 - Expanded Safety: The vaccine is given to hundreds of people split into different groups by demographics (example: elderly vs. young). These again test primarily for safety, appropriate dosage, and interval between doses and check for immune response, as a secondary effect. This phase serves to confirm the vaccine is safe and immunogenic and also determines the appropriate dose to be used in Phase 3 trials.
Phase 3 - Efficacy: This is a large-scale trial where the vaccine is given to thousands of people to evaluate efficacy. Vaccine efficacy (VE) is defined as the percentage by which the rate of disease incidence is reduced in vaccinated groups as compared to placebo (25). Incidence of disease at the time of Phase 3 trials impacts the sample size. In the case of a low incidence of disease in the population, a large sample size will be needed to adequately determine vaccine efficacy.
Once the human clinical trials are completed, and the safety and the clinical efficacy have been determined, then the vaccine will move to:
• Review and Approval: Normally, regulatory bodies, such as Food and Drug Administration (FDA) of the USA, or European Medicines Agency in EU, must review the results from clinical trials and decide if the vaccine is fit to be approved. As this process can take anywhere from 1 to 2 years, vaccines may be approved for emergency use in a pandemic.
• Manufacturing and Post-Marketing Surveillance: This is done after the vaccine is marketed for public use and monitored for general effectiveness within the population. They also record adverse effects that might be experienced after the vaccine is adopted for widespread use.
Given the upheaval caused by the COVID-19 pandemic and the urgent need for an effective vaccine globally, vaccine development can be accelerated by combining phases, as shown by Figure 2. An example would be combining Phases 1 and 2 to test for safety in hundreds of people directly. Vaccines also do not go through the full approval process and may instead be approved for emergency use for quicker release for use by the most vulnerable groups. Of significance is that 5 vaccines have been selected by the White House for its Operation Warp Speed program to accelerate vaccine development and have them available by the end of 2020 for emergency use and have billions of doses by 2021.
Figure 2. Flowchart showing accelerated process of vaccine development in a pandemic with combined phases, pre-approval, and rapid large-scale manufacturing. The symbol is a representation of the number of human subjects in trials.
There are various platforms being looked at for the development of COVID-19 vaccines. These include RNA, DNA, non-replicating viral vectors and inactivated vaccines. These platforms are illustrated in Figure 3. While RNA and DNA based vaccines have not been developed and licensed for human use in the past, these two platforms do provide an advantage in a pandemic situation. Since both of these platforms do not require bio reactor culture techniques as would be needed, for instance, for an inactivated vaccine, they can be made more rapidly in the laboratory and are based on the genetic sequence of the virus and allows for the development process to be fast-tracked in the event of a pandemic (26). They are also able to generate a robust immune response, which provides an added benefit. In contrast, non-replicating viral vector vaccines can be manufactured on a large scale and have shown to be safe and effective immunologically as seen with an Ebola vaccine candidate (27). On the other hand, vaccines based on inactivated virus technology have been licensed previously but they do not generate as strong of an immune response unless used alongside, as an example, an aluminum adjuvant. Therefore, given the urgent need and demand of a vaccine in this global pandemic, it is not surprising there are several DNA, RNA as well as non-replicating vector vaccines in clinical trials even though there have been no previously licensed vaccines produced based on the DNA or RNA platforms. Table 1 showcases 8 different vaccine candidates along with some characteristics of the different vaccine platforms.
Figure 3. Schematic showing a representation of SARS-CoV-2 along with different components of the virus as potential vaccine targets. SARS-CoV-2 is a single stranded RNA virus, has a lipid bilayer and consists of a spike S protein along with membrane and envelope proteins. DNA and RNA-based vaccines are made from the viral sequence of the virus. Viral vector vaccines utilize another virus, for example an adenovirus, and incorporate genetic material from SARS-CoV-2 into its genome. Inactivated vaccines involve SARS-CoV-2 that has been killed using physical or chemical means.
Table 1. Platforms and candidates of vaccines being used for COVID-19 along with data on their doses, speed2, immune response, advantages and disadvantages.
Inovio Pharmaceuticals is an American company based in Plymouth Meeting Pennsylvania, USA, that specializes in manufacturing DNA-based drugs and vaccines and has a COVID-19 vaccine, INO-4800, currently in Phase 1/2 clinical trials. The clinical trial is split into two parts - A and B. For part A, Inovio initially recruited 40 healthy adults between the ages 19 and 50 in South Korea to test the vaccine for safety and immune response (32). The vaccine is injected intradermal followed by electroporation to ensure uptake into cells. In their studies the participants were split into two groups for either a low (1 mg) or a high dose (2 mg) trial and were administered two doses 4 weeks apart (32). According to their press release, 3 participants (1 from the low dose and 2 from the high dose group) were dropped from the trials since they tested positive for COVID-19 and one participant from the high dose group was dropped for undisclosed reasons that was claimed to be not related to safety or immunogenicity (33).
Based on interim data from a press release, 34 out of 36 (94%) patients enrolled in the trial demonstrated an immune response at week 6 (33). Participants were contacted to check for adverse events periodically and interim data show that at week 8, 10 out of 36 (28%) individuals reported Grade 1 adverse events, which were mild fever and reactions that did not interfere with daily routine (33). They plan to recruit additional participants and expand the age group by incorporating 51–64-year-olds for the Part B component of their Phase 1/2 trials (32). The number of participants in its initial phase 1/2 trials is too few to make quick assumptions about the vaccine despite its supposedly increased immune response and mild adverse events. Since Inovio has not published any data from its clinical trials, the specific details from the safety and immunogenicity of the vaccine are yet to be seen and its slow progress in clinical trials leaves a lot of questions unanswered.
Moderna is another American company based in Cambridge, Massachusetts that is developing an mRNA-based vaccine, mRNA-1273. The mRNA vaccine codes for the spike protein such that when the vaccine is injected into the body, the immune cells processing the mRNA and the manufactured protein will be subsequently marked for destruction (34). Moderna's vaccine is included in the Operation Warp Speed initiative to accelerate vaccine production. It is currently in Phase 3.
Moderna released interim data from its preclinical trials in the journal Nature (35). It is worthwhile to note that this data was released after Moderna had published preliminary data on its Phase 1 trials. They tested their vaccine in mice by immunizing them with either the 0.01, 0.1, or 1 μg dose of the vaccine intramuscularly (35). Results showed that a high pseudo virus NAb response was seen with the 1 μg dose. Additionally, a high pseudo virus NAb response was also seen in mice expressing the mutated form of the spike protein, D614G, which is now beginning to be seen in cases worldwide (35). Furthermore, the 1 μg dose illustrated a robust cytotoxic T cell response along with a balanced Th1/Th2 response (35). This is important because a dominant Th2 response is linked to vaccine-associated enhanced respiratory disease (VAERD). It was also noted that no increased pathology was observed in the mice upon administration of the vaccine at a dose of 1 μg (35). The level of NAb response in a 1 μg dose in mice was stated to be comparable to a 100 μg dose in humans, thus supporting the selection of a 100 μg dose for large scale efficacy trials (35).
Its Phase 1 trials recruited 45 healthy participants of ages 18–55 years old (36). Participants were split equally into 3 groups to account for 3 different doses (25, 100, and 250 μg) (36) Two doses were administered intramuscularly 28 days apart. Two participants (1 in the 25 μg group and 1 in the 250 μg group) who were suspected of exposure to COVID-19, but later tested negative, missed their second dose. Based on a published preliminary report, interim results show that no serious adverse events were reported but one participant experienced transient urticaria, a hives rash, after the first 25 μg dose and was withdrawn from obtaining the second dose (34). There was no fever reported post the first dose but some participants in the 100 (6 out of 15; 40%) and 250 μg (8 out of 14; 57%) groups reported fever after the second dose (36). Local adverse events were primarily Grade 1 and Grade 2, with pain at the injection site being a commonly reported event (36). In addition, participants reported other systemic and local adverse effects including myalgia, headaches, fatigue and chills after both doses. Three patients in the 250 μg group (21%) reported severe systemic adverse effects following the second dose (36).
A specific antibody response was apparent depending on the dose administered and peaked at day 15 after the first dose (36). NAbs were detected in only less than half of the participants following the first vaccination but were detected in all participants following the second vaccination which infers the need for a two-dose vaccine regimen (36). A lower response was noted in the 25 μg group and high responses were noted in the other two dose groups (36). CD4+ T cell responses were detected with the 25 and 100 μg doses with an additional low CD8+ T cell response shown following a second 100 μg dose (36). Moderna is yet to release results from a second group consisting of older participants aged 55 and above and since older individuals have a reduced immune response, it will be important to see the dosage used and if any side-effects result from the possibly higher dose (37).
Moderna's Phase 2a trial involved 600 healthy participants recruited from the ages 18 and above to test for safety and observe adverse reactions and to also check for immunogenicity (38). This was a randomized, double blind trial which split the participants based on age and dose into 8 groups - 4 were taking 50 and 100 μg of the vaccine and the other 4 were taking 50 and 100 μg of saline (placebo) (38). A Phase 3 trial was initiated at the end of July 2020 and is designed to test for efficacy by evaluating the 100 μg dose of the vaccine (35, 36, 39) administered on days 1 and 29. This is a randomized trial incorporating quadruple blinding (39). Moderna aims to recruit 30,000 participants' aged 18 and above in the United States divided into either the vaccine group or placebo group. It has set a broad inclusion criteria, which includes those who have pre-existing conditions provided such conditions are stable and do not require changes in their therapy in the 3 months prior to enrollment (39).
Based on the Phase 1 interim results, the two-dose regimen Moderna has chosen certainly showed an immune response in a greater number of individuals but also reported side effects, although mostly mild to moderate, have also increased following the second dose (36). It will be interesting to see the outcome in the older Phase 1 group and the larger Phase 2 and 3 clinical trials.
BioNTech, a German company, together with Pfizer, an American company, are developing another mRNA-based vaccine, which encodes the SARS-CoV-2 RBD domain. This vaccine candidate, named BNT162, incorporates modified mRNA and also includes a T4 fibritin-derived trimerization domain to enhance immune response (40). Currently in Phase 3 trials, BioNTech/Pfizer is a candidate that is part of Operation Warp Speed. For their phase 1/2 trials in the USA, 45 healthy volunteers were recruited between the ages 18 and 55, split into groups of 12 for different doses (10, 30, and 100 μg) and a group of 9 participants receiving a placebo (40). Two doses for the 10 and 30 μg were administered intramuscularly 20 days apart; the group with 100 μg dosage did not receive a second dose (40).
Based on interim data, participants showed increased IgG levels, which heightened 7 days after the second dose (28-day mark) and remained elevated until 14 days after the second dose (35-day mark) (40). For those that received a 100 μg dose, IgG levels peaked at 21 days after the first dose and did not increase thereafter (40). For NAb titers, elevated levels were observed 21 days after the first dose and 7 days after the second dose (28-day mark) (40). Since the 100 μg group did not receive a second booster dose, no data about immunogenicity is available for that group. Furthermore, results showed that there were no significant differences in immune response between the 30 and 100 μg groups after the first dose (40). These data argue for the 10 and 30 μg doses as better candidates and thus, are more likely to proceed through future trials (40).
For the BNT162 vaccine dose-dependent Grade 1 to Grade 2 systemic or local reactions were noted. Pain at the injection site was a common event and was predominantly mild or moderate with the exception of one severe event in the 100 μg group (40). Commonly occurring systemic events included fatigue, headache, chills, muscle and joint aches. These symptoms increased in severity based on the dose and although particularly severe after the second dose did resolve within a day (40). Some patients reported fever following the first and second doses but these resolved within 1 day (40). No Grade 4 adverse events were reported. However, a few participants complained of Grade 3 pyrexia and sleep disturbance. Laboratory values did not change much for most individuals but a few were noted to have decreased lymphocyte and neutrophil count which then returned to normal 6–8 days post-vaccination (40).
The University of Oxford has formed a partnership with the British pharmaceutical company AstraZeneca to develop a non-replicating chimpanzee viral vector vaccine, formerly known as ChAdOx1 and now designated AZD1222. Currently leading the clinical trials race, AZD1222 is in Phase 3 and is also part of the Operation Warp Speed initiative. Preclinical trials in pig models demonstrated a high antibody response (41). A Phase 1/2 trial was completed and the results were reported in the journal Lancet. They conducted a randomized, single-blinded trial on 1077 healthy participants, aged between 18 and 55 and recruited in the UK (42, 43). These participants received either the AZD1222 vaccine at a dose of 5 × 1010 vaccine particles (n = 543) or a placebo licensed meningococcal vaccine MenACWY (n = 534) (43). A group of 10 participants in the AZD1222 group received a second booster dose of the vaccine 28 days following the first dose (43). The dose for the AZD1222 vaccine was selected based on the Oxford group's prior experience with developing a similar type of ChAdOx1 vaccine for MERS (43).
Participants were also divided based on paracetamol (acetaminophen) prophylaxis as this was used to monitor a reduction in adverse events. Fifty six out of 543 participants in the AZD1222 group and 57 out 534 participants in the placebo MenACWY vaccine group were given paracetamol (43). Results showed that local and systemic adverse events were noted to a lower degree in the paracetamol group as compared to the group with no prophylaxis (43). This finding was also replicated in the placebo groups. In those who received paracetamol, fewer patients reported pain, tenderness, fatigue and headache compared to the non-paracetamol prophylactic group (43). Other less frequently observed events in the group given paracetamol include myalgia, chills and fever (43). These events were reported to be mild to moderate in range and were highest in severity a day after vaccination. However, it is interesting to note that neutropenia was observed in 46% (25 out of 54) of the participants in the AZD1222 group compared to 7% (3 out of 44) of the control MenACWY group (43).
By day 28, specific antibodies peaked in the AZD1222 vaccine group and these levels remained elevated until day 56 (43). Additionally, by day 56, a much higher specific antibody response was noted for the 10 participants who received a booster shot (43). Immune response was not affected by the prophylactic use of paracetamol. A high NAb response was seen in 91% of participants across different assays after the first dose. All participants of the booster dose group had a high NAb response thus supporting the need for a two-dose regimen to increase the NAb response (43). T cell response, observed in all participants, peaked at day 14 and remained elevated through day 56 (43). However, participants in the booster group did not observe an increase in T cell response following the second dose (43).
This Phase 1/2 trial study had some limitations including the very few number (n = 10) of chosen participants for the booster group (43). Since the benefit of a booster dose is apparent on increasing specific and NAb response, it is important that more participants are recruited for the booster group to confirm the finding in large-scale trials and rule out any risk of antibody-dependent enhancement (ADE) of COVID-19.
In addition, a Phase 1/2 trial is ongoing on 2,000 volunteers with or without HIV in South Africa aged 18–65 to check for safety and immune response (44). Participants were split into groups based on varying doses of the vaccine or placebo (44). A phase IIb/III trial involved 12,330 healthy UK volunteers and included those above 5 years of age (45). Participants were split into groups based on age and included cohorts of extreme demographics (5–12 years old and above 70 years old) who are at greater risk from COVID-19 (38). Furthermore, participants were split into groups to either receive the AZD1222 vaccine or a licensed meningococcal MenACWY vaccine as a control (45).
The phase III trial that is now in progress involves over 30,000 volunteers in the United States, Brazil, South Africa and India (43, 46, 47). As per their clinical trial protocol, 2,000 volunteers will be recruited in Brazil where they will receive one shot of 5 × 1010 vaccine particles of the AZD1222 vaccine or 0.5 ml of meningococcal MenACWY vaccine as a placebo (46). Furthermore, volunteers will also be asked to take paracetamol for 1 day after the vaccination (46). Additionally, 30,000 volunteers are being recruited at various sites across the United States where volunteers will either receive 2 doses of 5 × 1010 vaccine particles of the AZD1222 vaccine separated by 4 weeks or a saline placebo (47). Further details and results for these clinical trials are yet to be made available.
CanSino's Ad5-nCoV vaccine is another non-replicating viral vector vaccine utilizing the Ad5 adenovirus to insert the SARS-CoV-2 gene into the human body. In the past CanSino has successfully been involved in the production of an Ebola vaccine. Published data from the its Phase 1 trials in the journal Lancet showcased that no adverse reactions were observed within 28 days post-vaccination for the Ad5-nCoV vaccine (48). CanSino conducted its safety trials on 108 healthy adults in Wuhan between the ages 18 and 60 who were split equally into one of three dose groups (5 × 1010 viral particles or 1 × 1011 viral particles or 1.5 × 1011 viral particles) to test for effects of dose-escalation (48). The most common reported reactions were pain at the site of injection in addition to fever, muscle aches, headaches and fatigue (48). Ten individuals experienced these symptoms at the Grade 3 level with 6 being in the high dose group and accounting for 17% of the high dose group (48). Additionally, some patients reported hyperglycemia, increased levels of total bilirubin and 5 alanine aminotransferase but these were not considered to be clinically significant (48). It was reported that NAb titer levels increased 14 days post-vaccination and peaked 28 days post-vaccination. The T cell response was heightened 14 days post-vaccination (48). Since this vaccine utilizes a human adenovirus, the presence of pre-existing immunity against adenoviruses was considered and results showed that pre-existing immunity to adenovirus showcased diminished NAb levels and T cell response (48).
On July 20th, CanSino published its Phase 2 trial results in the Lancet (49). They conducted a randomized, double-blinded clinical trial on 508 healthy, HIV-negative participants above 18 years of age (49). The participants were given one intramuscular injection of the vaccine, either 1 × 1011 viral particles (n = 253) or 5 × 1010 viral particles (n = 129), or a placebo (n = 126) (49). It was shown that by day 28, specific antibodies peaked to a much higher degree for the 1 × 1011 group at 656.5 geometric mean antibody titers (GMT) and 571.0 GMT for the 5 × 1010 group with high seroconversion rates of 96 and 97%, respectively (49). By day 28, NAbs also peaked for both groups with the 1 × 1011 group achieving a higher response with a GMT of 19.5 and the 5 × 1010 group receiving a GMT of 18.3 (49). However, only 59% of individuals in the 1 × 1011 group and 47% participants in the 5 × 1010 group demonstrated NAb response, thus raising questions about the effectiveness of the immune response in this vaccine (49). Furthermore, it was noted that 52% of the participants had a high level of pre-existing immunity to adenoviruses (49). As such, those with a low level of pre-existing adenoviral immunity reported up to 2 to 3 times higher immune response against SARS-CoV-2. It was also noted that the older group consisting of participants above 55 years of age demonstrated a lower antibody response, particularly the NAbs but both antibody titers were still higher relative to the placebo (49).
Both vaccine groups reported mild to moderate adverse events such as fatigue, fever, headache and pain at the injection site (49). Up to 24% of the 1 × 1011 vaccine group, a percentage significantly higher than the 5 × 1010 vaccine group and placebo, reported a severe Grade 3 adverse event including fever which self-resolved (49). Based on these results, CanSino has indicated that the vaccine dose with 5 × 1010 viral particles will be used in forthcoming Phase 3 trials (49).
On June 25th the China's Central Military Commission approved the use of Ad5-nCoV by the military for a period of 1 year –arguably the equivalent of a Phase III trial (50). Additionally, CanSino will be conducting Phase 3 trials in Saudi Arabia but data about the logistics of the trial have not yet been made available (51).
Both Oxford/Astrazeneca and CanSino utilize adenovirus as a vector for their COVID-19 vaccine. Adenoviruses are common and can cause a variety of illnesses in humans ranging from a cold to conjunctivitis (52). When comparing the NAb response between the two adenoviral vector-based vaccine candidates, it was shown that while Oxford/AstraZeneca's AZD1222 has demonstrated a high NAb level in 91% of individuals following the first dose, and in all individuals following a booster dose, only 59% of individuals in CanSino's vaccine demonstrated a NAb (43, 49, 52). This indicates that a good proportion of participants did not develop an effective immune response due to the presence of pre-existing immunity against human adenoviruses. Oxford/AstraZeneca were able to prevent this outcome by utilizing a genetically modified chimpanzee-derived adenovirus against which humans do not have pre-existing immunity (43, 52). However, CanSino plans to offers its vaccine at a low cost which, combined with its moderate efficacy, may prove advantageous for some countries (52).
Sinopharm is developing two inactivated vaccines in collaboration with Wuhan Institute of Biological Products and Beijing Institute of Biological Products. Both vaccine candidates are currently in Phase 3 trials. Wuhan Institute of Biological Products released interim results for its double blind and randomized Phase 1 and 2 clinical trials in the journal JAMA (53). In the phase 1 trial, 96 participants aged between 18 and 59 were recruited and equally assigned to one of three dose groups (2.5 μg or 5 μg or 10 μg) or an aluminum adjuvant placebo group (53). These participants received three intramuscular shots at days 0, 28 and 56 (53). On day 7, adverse reactions were reported by 20.8% (5 out of 24) in the low dose group, 16.7% (4 out of 24) in the medium dose group, 25% (6 out of 24) in the high dose group and 12.5% (3 out of 24) participants in the aluminum adjuvant placebo group (53). Commonly reported adverse reactions were pain at injection site and fever which were mild and self-resolved (53). 14 days after the third vaccination (day 70), a high NAb response was observed with seroconversion being observed in all participants in the low and high dose groups, 95.8% (23 out of 24) participants in the medium dose group (53). A specific antibody response was also generated to high levels in this phase 1 trial and seroconversion was observed in all participants (53).
In the phase 2 trial, 224 participants aged between 18 and 59 were recruited and equally assigned to one of two dual-dose programs - days 0 and 14 or days 0 and 21 (53). In each schedule, 84 were assigned to the medium dose (5 μg) vaccine group and 28 were assigned to an aluminum adjuvant placebo group (53). It is to be noted that for the immunogenicity component of Phase 2 trials, only the first half of the participants were analyzed within each group. For example, for the day 0 and 14 schedule, 42 were included in the 5 μg dose group and 14 in the placebo group for the immunogenicity component but for safety analysis, all 84 in the 5 μg group and all 28 in the placebo group were considered (53). For the 0- and 14-day schedule, 6% (5 out of 84) in the 5 μg group and 14.3% (4 out of 28) participants in the placebo experienced adverse reactions. For the 0- and 28-day schedule, 19% (16 out of 84) in the 5 μg group and 17.9% (5 out of 28) in the placebo group had adverse reactions (53). As in the phase 1 trial, fever and pain at injection site were commonly reported mild events that resolved on their own (53). A high NAb response was seen in both schedules with a 97.6% (41 out of 42) seroconversion noted for both (53). Additionally, for the specific antibody response, a much higher response was shown with the 0- and 21-day schedule than the 0- and 14-day schedule (53). Seroconversion was also relatively low in the 0- and 14-day schedule with 85.7% (36 out of 42) compared to 100% for the 0- and 21-day schedule (53). This supports the fact that a higher gap between doses is correlated with a higher immune response in this vaccine.
T cell responses were not measured in either trial and hence it is not known if this vaccine can cause VAERD. This potential problem needs to be investigated in large-scale efficacy trials to illustrate both humoral and cellular immune responses. Additionally, the report on phase 2 trials did not analyze all participants for the immunogenicity component of the trial and perhaps, this could create a false sense of security when interpreting the elevated humoral immune response results.
Biological Institute of Biological Products released results pertaining to their pre-clinical trials. A high NAb response was achieved at all doses (2 μg or 4 μg or 8 μg) along with an aluminum adjuvant across different animal species including rats, mice, macaques and cynomolgus monkeys (54). Furthermore, neither high nor low doses of the vaccine were associated with ADE of the disease in the study with macaques (54). It was noted that two doses of the 2 μg dose conferred a highly effective immune response without causing ADE or other immunopathological effects and therefore considered for clinical trials (54). The company also conducted a randomized, double blind, parallel phase 1/2 trial that recruited 1,120 healthy participants aged between 18 and 59 (55). Participants were split into dose and age-dependent groups for either receiving the inactivated vaccine or a placebo (55). Adverse reactions were noted periodically and humoral and cellular immune responses were assessed (55). Based on interim data from a press release, it was noted that a high antibody response was observed with no significant adverse events, but further details are awaited, as no published data has been made available (56). For both of their Phase 3 trials, Sinopharm is looking to conduct them in the United Arab Emirates due to too few active COVID-19 cases in China (57) with plans to recruit up to 15,000 volunteers.
Sinovac is currently developing an inactivated + aluminum adjuvant vaccine, CoronaVac, which is currently in Phase 3 trials. Its Phase 3 trials are being conducted in Brazil and Indonesia due to fewer active cases in China (58, 59). Data published from pre-clinical trials in mice and macaque models showed that sufficient specific IgG response and NAb titer levels were achieved (60). The mice were injected with either 1.5 μg or 3 μg or 6 μg doses of the vaccine along with an alum adjuvant or a saline placebo (60). No ADE was noted in the macaque monkeys that were vaccinated. Furthermore, vaccinated macaques were challenged with SARS-CoV-2 and they were noted to be protected from the virus with decreased viral loads unlike the control group (60). It is important to ensure safety especially in the case of inactivated vaccines and a dose of 6 μg of CoronaVac was found to be protective and had no changes in mental status or appetite and no other side effects were noted in the macaque monkey (60).
A press release for their Phase 1 study mentioned that they recruited 143 healthy participants aged between 18 and 59 for a randomized and double-blinded trial but no results pertaining to the phase 1 study have been made available (61). Phase 2 trials involved 600 participants between the ages 18 and 59 in a randomized, double-blinded trial (62). The participants were split into two dual-dose programs - either the 0- and 14- day or 0- and 28- day schedule (62). Within each schedule, 120 participants were administered the 3 μg dose, 120 participants were administered the 6 μg dose and 60 participants were given a placebo (62). Local adverse events such as pain and swelling were mild to moderate with pain being the most common reported event in both schedules (62). Sixty one participants out of 300 (20.3%) in the 0- and 14-day schedule and 31 out of 300 (10.3%) participants in the 0- and 28-day schedule complained of pain at the injection site post-vaccination (62). These adverse events resolved within 3 days (62). No severe Grade 3 adverse events were reported (62).
NAb responses were high for both 3 and 6 μg doses in both schedules (62). 28 days after the second dose, those in the 0- and 14-day schedule had stable NAb levels but for the 0- and 28-day schedule, NAb levels increased considerably (62). A similar pattern was observed for specific antibodies as well (62). It was also noted that NAb levels diminished with increased age thus suggesting an increased dosage requirement for the elderly (62). T cell immunity was not analyzed in this report and further data is required to provide a complete picture of the immune response generated by the CoronaVac vaccine. Knowing about the T cell response of the vaccine is also necessary to rule out the risk of ADE, as it is known to be associated with the use of inactivated vaccines. Although pre-clinical studies showed no immunopathological findings, it remains to be seen if a similar finding is replicated in human clinical trials.
Sinovac plans to assess the 3 μg dose in the 0-, 14- day and 0-, 28-day schedules in large-scale efficacy trials in Brazil and Indonesia (58, 59, 62). In Brazil, Sinovac is assessing its vaccine over a 0- and 14- day schedule and plans to recruit 8,874 healthcare workers that are above the age of 18 (58). Their large-scale efficacy trials include the elderly above 60 years of age and it will be very interesting to see the outcome achieved in the elderly population (58).
In order to ensure that the threat of COVID-19 is eliminated, it is critical that a coordinated and cooperative approach is taken which includes the collaboration between several international organizations to ensure that a process to ensure that sufficient financing and fair distribution of the vaccine supply is available. GAVI, the Vaccine Alliance is one such organization, which is a global public-private partnership to ensure that individuals from developing countries, particularly children, have access to immunizations (63). It is also part of the recent Global Vaccine Summit, which allocated funding for COVID-19 vaccine development and also to healthcare systems of GAVI-eligible countries and adequate supply for developing countries. In addition, Bill and Melinda Gates Foundation (BMGF) have allocated $250 million toward development of vaccines and for supporting the health care systems of Sub-Saharan Africa and other developing countries (64). Coalition for Epidemic Preparedness Innovations (CEPI) is a foundation that is involved in financing vaccine development and has launched COVID-19 Vaccine Global Access Facility (COVAX) in order allow for equal access of COVID-19 vaccines for countries (65). Lastly, the WHO is very much involved in all aspects of COVID-19 pandemic including ensuring vital equipment and personal protective equipment (PPE) such as masks and medical gowns for health care workers, research for COVID-19 vaccines, providing accurate information pertaining to COVID-19 and coordinating with countries for a response to COVID-19 amongst others (66). The WHO is also documenting data from vaccine candidates in its Draft Landscape of COVID-19 vaccine being updated periodically (28). Additionally, cooperation from individual countries is also equally important in the fight against COVID-19.
Given the urgent need of a vaccine, vaccine development and production are being fast-tracked to hopefully make a safe and effective vaccine available by the end of this year for the more vulnerable group of the population. However, perhaps linked to the upcoming political election in the USA in November of 2020, the White House initiated the Operation Warp Speed program to develop vaccines at an accelerated speed. Moderna's mRNA vaccine and AstraZeneca/University of Oxford's AZD1222 vaccine are part of this program and, given their progress thus far, it is possible that their vaccines will be available by the end of 2020. However, production managers of vaccine candidates have reported feeling pressured to develop a vaccine in a span of months when the traditional process on average takes well-over 10 years (67). The Trump administration has also allocated billions of dollars in funding for these vaccines. However, fast tracking and rushing vaccines could prove to be detrimental as this might result in producing a vaccine that is not optimally effective and may only provide immunity, or incomplete immunity, to some vaccinated individuals (68). Although it is assumed that through the scrutiny of the academic and scientific community a vaccine will not be released for use to the public before all appropriate safety and efficacy tests have been performed, it is important to consider the recent small-scale human trials of the Russian vaccine, Sputnik V, even though in the absence of published data it's use appears to have bypassed safety trials (69). Russia has also begun manufacturing its vaccine with plans to administer it in the Philippines and potentially other countries (70). To date no data pertaining to the safety and immunogenicity of the Russian vaccine has been published although a report from Reuters on August 21st indicated that a Phase 3 study to include more than 40,000 people was to be initiated and, in addition, data on the Sputnik V vaccine was to be published soon (69, 71). To maintain public trust in vaccines it is important that full transparency in all aspects of vaccine development is available.
Another concern is that when clinical trials are being done on comparatively small groups of people, and fast-tracked from one phase to the next there is a risk of masking side-effects that would have been detected if the vaccine was tested in larger populations. Furthermore, it is important to consider whether there was an appropriate demographic consideration in the design of the clinical trials - different races, varying age groups and those with comorbidities - if not, this may lead to unforeseen outcomes upon vaccinating these individuals when the vaccine is released for public use. Hence, given an accelerated timeline, post marketing surveillance becomes of greater importance, as this will provide the necessary vigilance as to the effectiveness of the vaccine along with recording adverse effects once it is released for public use. However, it is also important to note that vaccines developed following the traditional timeline can also be at risk for unforeseen adverse effects. This was noted in Philippines when the French dengue vaccine, Dengvaxia, was administered and caused unexpected complications resulting in over 500 deaths, particularly in previously uninfected school-going children (72).
Several vaccine candidates including Moderna and AstraZeneca/Oxford are planning or entering Phase 3 trials, which require studying effectiveness in approximately 30,000 people. Since several countries are now starting to see a drop in the number of infections, there is a concern as to how will these clinical trials will acquire a sufficient number of people to conduct the studies. Taking advantage of the difference in transmission rates around the world, the Phase 3 trials for some vaccine candidates including AstraZeneca/Oxford's AZD1222 will be conducted in areas with higher COVID-19 infections such as Brazil, USA, India and South Africa thus overcoming, in the case of AZD122, the decrease in disease prevalence in the UK (43, 46, 47). Another way to address this concern includes conducting human challenge trials (HCT). In HCTs volunteers are deliberately infected with the virus in order to monitor their response to the vaccine. Although HCTs have been used relatively safely in the past as they help accelerate vaccine development, the risk-benefit analysis does not align as perfectly in the case of COVID-19. Thus, as of late August 2020 there are still a lot of unknowns about the variable pathogenesis of COVID-19 in the population and there is no proven licensed treatment available and hence there exists a very significant potential risk of the development of severe disease in the volunteers for an HCT (73). Although a risk-benefit analysis can be conducted on an individual basis and assess an individual's health status before inclusion in an HCT, nonetheless, this will likely greatly limit the generation of data being available for the elderly and those with comorbidities.
In addition, given the demand for vaccines, several countries including the United States and Europe have indicated that the vaccines will be initially provided to their own citizens. However, questions are being raised regarding the ethics of fair allocation. Although AstraZeneca has announced collaboration with an Indian institute for supply of adequate doses to low- and middle-income countries, it remains to be seen as to how the allocation of the vaccine when it is approved and becomes available (74). It is also important to prioritize certain groups of people for vaccine allocation including health care workers, the immunocompromised, those with comorbidities, the elderly and those with lower socioeconomic status to ensure distributive justice (75).
With the development of vaccines and clinical trials underway, questions arise as to how much efficacy is needed for the vaccine to be immunogenic. While more research is still needed, preliminary research studies have shown that while an efficacy ≥70% is needed to eliminate the infection, a prophylactic vaccine with an efficacy <70% will still have a major impact and may contribute to eliminating the virus, provided appropriate social distancing measures (76). Vaccines with an efficacy below 70% may also contribute to reducing the duration of infection in those infected with the virus (76).
Given what we know about SARS CoV-2 thus far, the diversity observed between the pandemic sequences of SARS CoV-2 is low (77). However, the widespread presence of the pandemic can cause natural selection to act upon certain mutations (76). There has been a D614G mutation on the spike S protein - a G to A base change from the original Wuhan strain - found primarily in Europe and has been shown to have increased transmissibility and a higher viral load but more research is needed to determine its impact on clinical outcomes (77). Although the D614G mutation is located on the spike S protein, it is not in the RBD but rather in between the individual spike protomers to provide stability through hydrogen bonding (78). This means that while it may have an impact on the infectivity of the virus, it should not drastically affect the effectiveness of vaccines and consequently the NAbs produced against the RBD (78).
Another concern is the phenomenon of ADE of COVID-19 disease and it should be taken into consideration when developing vaccines against SARS-CoV-2. ADE has been observed with other coronaviruses including MERS-CoV and SARS-CoV (78). ADE occurs when antibodies bind to the virus and the resulting antibody-virus complex facilitates viral entry by host macrophages instead of neutralizing the virus (11, 79). Inactivated vaccines particularly pose a risk as they can cause VAERD as has been seen in the past with measles and respiratory syncytial virus (RSV) in humans and with SARS-CoV in animal models (11). VAERD is due to the presence of increased numbers of antibodies that do not neutralize the virus when a high viral load is present (11). This consequently results in immune complex deposition and can lead to severe respiratory disease (11). While ADE is more of a concern for inactivated vaccines, these phenomena should be kept in mind for other COVID-19 vaccine platforms as well (80). Given the urgent global need for a COVID-19 vaccine, being overly pre-cautious should not restrict the release of an otherwise well-tolerated, safe and immunogenic vaccine (80).
Several vaccine candidates are being developed from small-scale companies, such as Moderna, that until COVID-19 are not well-known and have not previously produced an effective vaccine but, nonetheless, have their COVID-19 vaccine in clinical trials. In contrast, vaccines from well-known companies such as GSK and Pfizer are currently in Phase 1 and Phase 1/2 clinical stage, respectively (81). Having vaccine candidates from several developers spread out over various stages in testing and trials is a positive outlook for the future since hopefully this will result in the availability of several effective vaccines that could then meet global needs. At the very least having multiple vaccine candidates at various stages of development and testing boosts confidence that should one vaccine fail in the clinical trials there are other alternative vaccines in development.
The threat of anti-vaxxers is an ever-present danger and already evident as vaccine opponents are refuting statements by experts pertaining to vaccines. Anti-vaxxers and their false theories and influence paved the way for the worst measles outbreak in the United States in 2019 and experts fear similar consequences for COVID-19. Several surveys in May found that between 14 and 23% of Americans are not willing to be vaccinated with 22% claiming they are unsure (82). Another poll showed that only 49% of Americans were willing to take a COVID-19 vaccine when one becomes available (83). These numbers shed light on the growing anti-vaccine sentiment in the community, which can prove to be dangerous and result in high numbers of deaths. The anti-vaccine sentiment is not limited to the US alone. Europe, which witnessed a tripling of measles cases in 2018, Germany and Australia too have a fair share of anti-vaxxer communities. Conceivably even with the worldwide availability of an effective vaccine millions will refuse to accept it. To counter this possibility their has to be a strong and effective scientific and political support demonstrating the safety and efficacy of all approved vaccines.
While experts and scientists are doing their best to convince the population of the benefits of a COVID-19 vaccine, which is apparent by the number of vaccines under clinical trials and the funding being directed toward vaccines to obtain one before 2021, there is a concern about rushing vaccines and producing one with limited effectiveness. Furthermore, if a vaccine is approved for use but subsequently is shown not to be as effective as expected in the population, this could lead to loss of trust in vaccines. In consequence, when an effective vaccine is introduced fewer people may be willing to accept it resulting in a worsening of the pandemic and further reduce the confidence in already approved and effective vaccines for other diseases. Thus, it is important to build trust and effective communication and restore public confidence in the public health system, which includes being transparent and reporting accurate data timely pertaining to vaccines (84).
Although mandating vaccine uptake may be considered as an approach for ensuring herd immunity against COVID-19, certain criteria should be fulfilled before such a policy is put in place (85). One of these include that the Advisory Committee overseeing immunization practices has recommended certain high-risk groups such as the elderly or health-care workers for mandatory vaccines (85). Some other criteria include evidence that COVID-19 is not effectively contained in the region, evidence that information about the vaccine's safety and efficacy is communicated to the public in a transparent manner, presence of adequate supply of the vaccine and evidence that not enough members of high-risk groups are taking the vaccine voluntarily (85). Lastly, should an adverse reaction to a vaccine occur, programs should be in place to ensure that there is compensation provided to these individuals and that a record is kept of adverse events to re-evaluate safety (85). With these criteria, responsible authorities should ensure that an effective and fair policy is in place such that if the need for mandatory vaccine is deemed necessary, public trust in the health care system is not jeopardized.
Over the past 4 months, several companies have been accelerating their vaccine production programs. Vaccine development traditionally takes 10–15 years and to condense this to a period of only 15 months comes with its own drawbacks and challenges.
• Accelerating vaccine development by combining phases involves trials being done on smaller groups. This is a significant concern since when the vaccine is released for public use globally, unknown side-effects may appear in the larger population which were previously not observed within smaller groups. Furthermore, if all demographics (elderly and young) and those with comorbidities are not appropriately considered in the design of the clinical trials, there is a chance that unwarranted side-effects may be observed in those groups when the vaccine is available for public use (86). Post-marketing surveillance would ensure that vaccines are monitored for such side effects in the general population.
• In the past, platforms based on nucleic acids such as DNA and RNA have not resulted in a successful vaccine for human diseases and hence it is yet to be seen how mRNA vaccines will be successfully developed since lipid nanoparticles are temperature-sensitive and this may pose difficulties for scaling up production (29). Furthermore, for DNA vaccines, its reliance on electroporation or an injector delivery device for vaccine administration is a potential issue. Although electroporation is considered to be a safe procedure and is critical to generate an increased immune response, it can complicate vaccine delivery (87).
• Pre-existing immunity to adenoviruses is a concern, particularly for those vaccine candidates utilizing human adenoviruses such as CanSino's Ad5 vaccine, as it may result in a reduced immune response to the vaccine (49, 52). AstraZeneca/Oxford's AZD1222 is another adenoviral vector vaccine candidate but instead of utilizing a human adenovirus in its vaccine, it uses a genetically modified chimpanzee-derived adenovirus (43). This effectively addresses the concern about pre-existing immunity and consequently averts the negative impact on immune response generated to the vaccine (43, 52).
• Rapid large-scale manufacturing of vaccines still remains a challenge with lots of uncertainty to meet the demand of a pandemic.
• There are concerns that political pressure to rush the development and approval processes for a vaccine, which may result in an ineffective vaccine being released for public use. Such a scenario may lead to the public being hesitant from accepting future vaccines (67, 68).
• Although the Global Vaccine Summit has called for an equal allocation of vaccines when a vaccine is released, there is still a concern that some countries will want to secure the vaccine supply for their citizens. A similar concern has been expressed as a result of the recent stockpiling in the USA of the drug, remdesivir, for the treatment of patients with COVID-19 (88).
• Phase 3 trials require over 30,000 volunteers and since these trials are performed during the later stages of development there is a high chance that at that stage there will be fewer cases of COVID-19 and hence, HCTs may be required. Although HCTs have been done in the past, they may pose more risk for COVID-19 given how there is very little known about the pathogenesis and the availability of an effective treatment for COVID-19 (89). As an alternative to HCTs, several vaccine candidates have also utilized the differing transmission rates to their advantage by conducting phase 3 trials in countries with a higher SARS-CoV-2 infection rate to ensure that an adequate number of participants are able to partake in Phase 3 trials.
• Mutations of the virus can result in vaccines having limited effectiveness against it (76, 90).
• There is also risk of vaccine-enhanced disease for inactivated vaccine candidates, notably VAERD that needs to be kept in mind (11, 27). Furthermore, ADE is a known risk for vaccines developed for coronaviruses and a similar concern is being echoed for SARS-CoV-2 and should be kept in mind when developing vaccines against COVID-19 (79). However, given the crucial need for the global availability of a COVID-19 vaccine globally, being concerned and assessing such risks should not prevent the release of otherwise safe and effective vaccines to the public (80).
As of August 2020, many are hopeful that by the end of 2020, or early 2021, an effective vaccine, although not a panacea, will be one of the key pioneers in helping to eliminate the threat from SARS-CoV-2 and controlling the COVID-19 pandemic. Although several vaccines are already under clinical trials with some being in advanced stages, it is also valuable to consider some other vaccines, which can prove to be instrumental in ultimately eliminating the virus. A Chinese-based company, Anhui Zhifei Longcom Biopharmaceutical, is designing a universal protein-subunit based vaccine, now in Phase 2 trials, which involves an artificial protein consisting of a spike receptor-binding domain (RBD) dimer, instead of the usual RBD monomer (91). While its design has been previously explored for other coronaviruses, its immunogenic activity has not been studied. A study published in the journal Cell showed that the RBD dimer design has the ability to generate a higher specific IgG response with a much more elevated NAb titer by up to 10–100-folds than a conventional RBD monomer vaccine, based on studies conducted on mice models (91). Another benefit to the RBD dimer design is that it has the ability to be manufactured on a large-scale which is ideal for a pandemic situation like COVID-19 (90). Although this novel approach is still very much at the early stage of development it will be interesting to closely monitor progress in the development of this vaccine platform.
Although several organizations including WHO have committed to ensuring that developing countries receive an adequate supply of vaccines, it is yet to be seen how politics will influence the outcome and which vaccine will ultimately be successful. Ideally a vaccine has to be made available to close to 8 billion people. Unanswered questions are: 1. Who will pay for the vaccine? Companies who manufacture the vaccines will require recovery of investment and cost of production. 2. How will the vaccine be distributed globally and how quickly? Global cooperation is required; however, most likely the initial distribution will be to the country (or countries) who produced the vaccine. Furthermore, while many are placing their hopes on a vaccine, it is also important to consider alternatives to a vaccine, should a vaccine be less effective than hoped or rapidly become ineffective. Ideally, the availability of effective drugs to protect against infection and reduce morbidity and mortality may also become available but at present there are only limited options (34). Thus, the continued implementation of social distancing and proper hygiene practices including the global availability of appropriate personal protective equipment will be essential. Since it is unclear how promptly global demand for a vaccine will be met, it is likely these other methods will need to be utilized for some time until vaccines are available for everyone. In the absence of a truly effective drug to prevent and/or treat COVID-19 we will likely need to follow the social distancing and hygiene precautions for the foreseeable future and, if necessary, rigorously enforce them so as to control the pandemic.
Even though the more vulnerable group of the population, such as the elderly, immunocompromised, and those with co-morbidities, will be given priority for vaccines, they are not usually included in clinical trials and thus the effectiveness of the vaccine and risk of side effects will be unknown in this population.
There are several vaccine candidates currently in clinical trials with AstraZeneca/Oxford's AZD1222, Moderna's mRNA1273 and Sinovac's CoronaVac vaccines advancing to Phase 3 clinical trials. With many placing their hopes on a vaccine against COVID-19 being available by the end of 2020 or early 2021, it is yet to be seen how the vaccine will be distributed, how national interests will unfold and whether the vaccine will ultimately prove to be safe and effective when administered to the global population at large.
OS reviewed the literature and prepared drafts of the manuscript for final submission. AS assisted in evaluation of the literature and edited drafts of the manuscript. HD assisted in evaluation of literature and finalizing manuscript for submission. CT initiated the review, provided input throughout, and finalized manuscript for submission. All authors contributed to the article and approved the submitted version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Keywords: SARS-CoV-2, COVID-19 pandemic, vaccine development, DNA vaccine, RNA vaccine, non-replication viral vector vaccine, inactivated virus particle vaccine, neutralizing antibodies
Citation: Sharma O, Sultan AA, Ding H and Triggle CR (2020) A Review of the Progress and Challenges of Developing a Vaccine for COVID-19. Front. Immunol. 11:585354. doi: 10.3389/fimmu.2020.585354
Received: 20 July 2020; Accepted: 31 August 2020; Published: 14 October 2020.
Edited by:
Reviewed by:
Copyright © 2020 Sharma, Sultan, Ding and Triggle. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Omna Sharma, [email protected]; Chris R. Triggle, [email protected]
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21 | https://www.tandfonline.com/doi/full/10.4155/tde-2020-0129 | An Overview of Vaccine Development for COVID-19
Seyed H Shahcheraghi
, Jamshid Ayatollahi
, Alaa AA Aljabali
ORCID Icon, Madhur D Shastri
, Shakti D Shukla
ORCID Icon, Dinesh K Chellappan
ORCID Icon, show all
Pages 235-244 | Received 02 Dec 2020, Accepted 15 Feb 2021, Published online: 24 Feb 2021
Abstract
The COVID-19 pandemic continues to endanger world health and the economy. The causative SARS-CoV-2 coronavirus has a unique replication system. The end point of the COVID-19 pandemic is either herd immunity or widespread availability of an effective vaccine. Multiple candidate vaccines – peptide, virus-like particle, viral vectors (replicating and nonreplicating), nucleic acids (DNA or RNA), live attenuated virus, recombinant designed proteins and inactivated virus – are presently under various stages of expansion, and a small number of vaccine candidates have progressed into clinical phases. At the time of writing, three major pharmaceutical companies, namely Pfizer and Moderna, have their vaccines under mass production and administered to the public. This review aims to investigate the most critical vaccines developed for COVID-19 to date.
Keywords:
COVID-19COVID-19 vaccinesSARS-CoV-2
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As demonstrated by COVID-19, new infections caused by RNA viruses which are subject to genetic changes and mutations will continue to create a significant global health danger [Citation1–4]. Despite two past global coronavirus infection epidemics causing SARS and Middle East Respiratory Syndrome, the world remains unprepared to handle the current COVID-19 event effectively, as proven by the fact that COVID-19 has resulted in very many deaths in the world [Citation5,Citation6]. Although COVID-19 is a novel disease, MERS and SARS research has helped investigators understand how the human body reacts to coronaviruses and how the immune system’s response provides defence against the virus [Citation7].
As with the process of drug development, vaccine progress for viral infections is tricky and typically is time-consuming. In the case of COVID-19 disease, the process is much more complicated due to the disease’s uncertain pathogenesis, the lack of availability of a validated animal model and the success of clinical trials on humans [Citation8]. The right dosage and schedule for the vaccine can also be determined using limited human studies. After a single dose, some vaccines induce an adequate immune response, while others need a booster dose after a month or longer. This plan also prolongs the period of studies [Citation9].
Over 56 verified effective candidate vaccines for COVID-19 are being produced in China, North America, Europe and Australasia. It is well recognized that vaccine manufacture is a lengthy and costly process [Citation10,Citation11]. Out of 78 established vigorous plans, 73 are now at preclinical phases [Citation12].
This review discusses the most crucial candidate vaccines for the disease and reviews the latest studies in this field. We searched the official and preprint websites, the databases of Scopus, Medline, Web of Science, PubMed, Open Access Journals, LISTA (EBSCO) and Google Scholar to identify literature with the following terms: ‘COVID-19’ OR ‘2019-nCoV’ OR ‘SARS-CoV-2’ OR ‘Vaccine’.
Vaccines for COVID-19
Live weakened vaccine
In live vaccines, reverse genetic techniques have been effectively applied to inactivate the exonuclease effects of protein 14 (nsp14), a nonstructural peptide, and remove the envelope protein in the disease-causing virus [Citation13]. The Bacille Calmette–Guérin (BCG) vaccine is a live vaccine that has been extensively utilized to prevent tuberculosis and leprosy since 1921 [Citation14]. Scientists have concluded that the BCG vaccine will aid improvements in the immune system, thus decreasing SARS-CoV-2 infection rates. The efficacy of the BCG vaccine in minimizing the incidence of COVID-19 in different children’s hospitals in Western Australia is being tested in a variety of Phase III trials (NCT04327206). The effectiveness of BCG vaccination in increasing health among healthcare staff participating in COVID-19 patient care is being investigated by scientists from Radboud University of Netherlands (NCT04328441). These two studies are estimated to yield results by the end of 2022 [Citation15]. Also, the avian infectious bronchitis virus (IBV) is a contagious chicken coronavirus, and the live IBV vaccine (strain H) has been suggested to be beneficial for SARS because the safety given by strain H is focused on blocking the production of antibodies and other immune responses. Therefore after evaluating its protection in monkeys, the avian IBV vaccine may be investigated as another choice for COVID-19 [Citation16,Citation17].
DNA vaccine
An artificial DNA vaccine directing production of the coronavirus spike (S) protein, the main coronavirus surface antigen presently used in the clinical trial, has been developed to produce a synthetic DNA-based SARS-CoV-2 S protein candidate vaccine based on prior knowledge. The engineered design, INO-4800, leads to vigorous in vitro expression of the S protein. Efficient antibodies that neutralize SARS-CoV-2 infection inhibit S protein binding to the ACE2 receptor, and the circulation of SARS-CoV-2-targeted antibodies to the lungs was assessed following immunization of guinea pigs and mice with INO-4800. This study has verified that INO-4800 is a likely COVID-19 vaccine candidate [Citation18,Citation19].
RNA vaccine
As shown in several preclinical investigations, the S protein is considered a key viral antigen for the progress of COVID-19 vaccines [Citation19].
A new lipid nanoelement–mRNA-based vaccine, mRNA-1273, encodes the SARS-CoV-2 S protein, and started its first Phase I trial in the USA in March 2020. Successful technological progress in the production of vaccines has been demonstrated in the introduction of mRNA-based vaccines; however, the testing and development of vaccines as quickly and efficiently as possible to control COVID-19, which needs global co-operation, continues to present huge problems. A Phase I protection trial is being performed on one of the first vaccines, mRNA-1273. The newly invented encapsulated distribution of RNA and self-amplifying RNA method has helped to produce an mRNA effective vaccine with an improved success rate [Citation20–23]. Scientists have also made accessible the security, immunogenicity and tolerability documents from a study (ClinicalTrials.gov identifier NCT04368728) carried out among individuals aged 18–55 years, who were selected to get two doses (10, 30 or 100 μg) of BNT162b1 during 3 weeks. BNT162b1 is a recombinant mRNA vaccine that encodes the S protein receptor-binding domain (RBD) of the SARS-CoV-2 virus. Nevertheless, for mRNA-based vaccines, some questions still need to be answered [Citation24].
Subunit vaccine
The antigen’s appearance in its most steady and efficient conformation has been one of the difficulties of using the protein subunit vaccine. Virus-like particles (VLPs) are comprised of several protein molecules capable of self-assembling into nanostructures that surround the capsid proteins inside themselves upon recombinant expression [Citation25]. VLPs, which have a lipid membrane arising in the budding form from the cell membrane, may also be chimeric in origin, showing an envelope protein from another virus. In bacterial systems, mammalian cell lines and transgenic plants, a wide variety of advanced platforms express and correctly fold antigenic proteins. Moreover, because VLPs lack a genome of their own, they deliver a degree of stability comparable to that of nonreplicating vectors, thereby verifying the safety of the subunit vaccines and the effectiveness of the live vaccines [Citation8].
Other subunit vaccines are based on MERS-CoV and SARS-CoV recombinant S and S1 proteins and have shown success in several studies [Citation26–29]. Utilizing Tag technology, Clover Biopharmaceuticals is manufacturing a vaccine containing a viral S protein [Citation30]. The SARS-CoV-2 RBD has been shown to have a considerably high binding affinity for the ACE2 receptor [Citation31], signifying that RBD-based vaccines may be suitable for inhibition of COVID-19 infection. Several groups are currently developing RBD-based vaccines via global partnerships [Citation32]. Nanoparticles related to pulmonary surfactant have been applied for generating immunity against influenza and can be utilized as adjuvant to increase the safety of SARS-CoV-2 subunit vaccines [Citation33–35]. The helper T lymphocyte, B cell, adjuvant and cytotoxic T lymphocyte (CTL) epitopes are included in another vaccine construction. The evidence proposes that this vaccine is thermostable and nontoxic, and produces a stable cell immune response. Molecular and biological studies have confirmed the stability of the vaccine structure. This exceptional vaccine is produced by almost 30 extremely epitopes related to proteins that have notable importance in viral entrance, pathogenicity and host receptor identification [Citation36]. Immunobioinformatics has also lately been utilized to classify important cytotoxic epitopes of CTL and B cells in the SARS-CoV-2 S protein. The relationships between these antigenic epitopes and MHC class I molecules related to them have been studied using molecular dynamics models and it has been discovered that the CTL epitopes connect via several contact places with grooves binding peptide of MHC class I, suggesting their ability to produce immune responses. These epitopes’ perfect features may make them suitable to become part of candidate COVID-19 vaccines [Citation37]. The nucleocapsid (N) protein and the probable B cell epitopes of the MERS-CoV E protein have also been proposed as likely immunodefensive goals that stimulate immune responses [Citation38,Citation39].
Three vaccines were built using the designated epitopes in a study by docking method targeted to combat SARS-CoV-2. Three separate adjuvants (HABA, L7/12 protein and β-defensin) and various linkers (GPGPG, EAAAK and KK) were utilized at suitable locations to build these vaccines. The PADRE sequence is also a critical sequence applied in the production of vaccines; it can increase their efficacy, with high therapeutic effects and low toxicity. Furthermore, this sequence enhanced the CTLs response, therefore certifying effective immune responses. This approach can be used for the creation of a likely vaccine against COVID-19 [Citation40,Citation41].
Vector-based vaccines
Viral vectors are commonly utilized together with virus vaccines, in which the genome of one virus is applied to transmit the antigen of another virus, facilitating the advancement of platform system for the creation of viruses. These tools are accessible to create vaccines on a wide scale. The disadvantages of these kinds of vaccines include a wide variety of purification methods, the need for accurate purity verification and virus action [Citation42].
A COVID-19 vaccine using artificial antigen-presenting cells (aAPCs) was advanced by using genetically altered lentivirus, including the SARS-CoV-2 immune regulatory genes and minigenes, to modify the aAPCs as SARS-CoV-2 antigen-presenting. On 15 February 2020 a Phase I clinical trial of 100 applicants began, with an expected study finishing date of 31 December 2024 (NCT04299724). By altering dendritic cells with lentivirus vectors expressing SARS-CoV-2 minigene SMENP and immune regulatory genes, the lentiviral SMENP DC vaccine was designed and advanced. The Phase I trial of the vaccine, including almost 100 patients, began on 24 March 2020, and the assessed study end date will be 31 December 2024 (NCT04276896) [Citation15,Citation34,Citation43,Citation44].
A novel vaccine against COVID-19, ChAdOx1 nCOVID-19, is in the clinical phase; it was primarily advanced to inhibit MERS [Citation12]. The base of the vaccine is an adenovirus vector and the S protein of SARS-CoV-2 [Citation9]. It has been changed so that it cannot be produced in the body of humans. The genetic code for SARS-CoV-2 S protein synthesis has been inserted to enable the adenovirus to generate this protein after vaccination. The result is the creation of an antibody against the S protein [Citation9].
The MERS-CoV S protein-expressing recombinant adenovirus vaccine stimulates bloodstream IgG, lung memory T cells and IgA when administered to BALB/c mice, and creates long-term immunity to the MERS virus, indicating that recombinant adenovirus vaccines can provide defense against the MERS-CoV virus [Citation45]. Adenovirus type 5 (Ad5)-nCoV is the primary new genetically engineered vaccine for COVID-19 advanced by the Beijing Institute of Biotechnology and CanSino Biologics, China. As a vector, the vaccine uses replication-damaged Ad5 to express the SARS-CoV-2 S protein. This vaccine is presently in a successful Phase I clinical trial to examine its efficacy, immunogenicity and reactogenicity in a group of healthy individuals aged 18–60 years (NCT04313127). The study is planned to recruit 108 Wuhan participants who have tested negative for COVID-19 in the diagnostic experiments and is anticipated to be finished by 2022 [Citation15].
Ad26-S forms the basis of another adenoviral vector-based COVID-19 vaccine [Citation46]. As the seroprevalence of Ad26 has been shown to be almost 40% in humans, it is characteristically less immunogenic in comparison with Ad5 [Citation47]; active immunity needs repeated heterologous or homologous vaccination, as has been revealed in Ad26-Ebola and Ad26-HIV vaccine studies in individuals [Citation48,Citation49]. However, an administration of a COVID-19 vaccine designed with an AD26 vector (Ad26.COV2.S) has presented strong safety in a nonhuman (primate) model of SARS-CoV-2 [Citation50,Citation51]. The rabies virus and the Gram-positive enhancer matrix – a bacterial vector – have also been utilized for expressing MERS-CoV S protein. Immune responses to these vaccines were tested for humoral and cellular immune reactions in BALB/c mice, which revealed that the rabies virus-based vaccine induces considerably higher cellular immunity rates and faster antibody responses than the Gram-positive enhancer matrix vector vaccines [Citation52].
shows the current trial phases of different vaccine types.
Figure 1. Clinical phases of COVID-19 vaccine candidates currently under investigation in human clinical trials.
Figure 1. Clinical phases of COVID-19 vaccine candidates currently under investigation in human clinical trials.
Vaccines go through Phase I trials to primarily evaluate their safety, determine the effective doses and investigate potential side effects in a limited number of volunteers. Phase II trials explore the vaccine candidate safety and efficacy in a larger group of volunteers. In Phase III, with very limited vaccine candidates, thousands of volunteers are used to evaluate the vaccine’s efficacy further and assess side effects on different population representatives. This also allows assessment of the various biotechnological methods that have been used to develop clinically viable COVID-19 vaccine candidates in the current pandemic, including DNA-based candidates, viral vectors, subunit vaccines, virus-like particles, inactivated and live-attenuated viruses [Citation53].
Inactivated SARS-CoV-2 vaccine
Investigations have also demonstrated the ability of an inactivated vaccine candidate against COVID-19 (BBIBP-CorV) that stimulates the production of antibodies in rats, mice, rabbits and primates (rhesus macaques and cynomolgus monkeys) to protect against SARS-CoV-2. Two doses of BBIBP-CorV has given a highly effective defense against SARS-CoV-2 infection in rhesus macaques, without observable antibody-dependent infection. Furthermore, BBIBP-CorV shows efficient efficiency and good genetic stability [Citation54].
shows the most important vaccine types being developed against COVID-19.
Figure 2. Summary of strategies for COVID-19 vaccine development compared with classical approaches.
Figure 2. Summary of strategies for COVID-19 vaccine development compared with classical approaches.
The first category of vaccine development includes approaches using the whole organism but inactivated through chemical or physical methods. BBIBP is an example of a vaccine using inactivated viral particles; such an approach has higher stability but requires stabilization of the viral structure, which complicates the vaccine manufacturing process. On the other hand, BCG and IBV were generated through the propagation of live attenuated viruses by cultivating particles under suboptimal growth conditions. INO-4800 represents a new and innovative direction of DNA-based vaccine production through recombinant DNA technology by encoding and expressing the target sequence in a suitable cell line via a viral-based vector. RNA is a relatively new technology for vaccine development; in essence, it utilizes the host body to translate the mRNA fragment of the spike protein to induce an immune response. The two candidates that have been developed so far by this method are mRNA-1273 and BNT162b1. Subunit vaccines contain only the antigenic epitopes (surface fragments) produced through recombinant DNA technologies, such as the RBD-based vaccine and the use of VLPs that elicit the immune response without the risk of developing the infection. The traditional approach for vaccine development is using viral vectors, in which a viral genome such as that of adeno-associated virus is used to deliver the antigen of another virus; some examples of this approach include aAPC vaccine, ChAdOx1, Ad5-nCoV, Ad26-S and LV-SMENP-DC.
COVID-19 vaccines in action
The development of a safe vaccine takes years of research before the product can be deployed to clinical use. Typically after development, testing involves various stages [Citation55]. Phase I, the preclinical phase, involves testing on cells and animals, then testing on a small number of people to confirm immune system stimulation [Citation55]. Phase II testing involves testing in hundreds of people, including children and the elderly, further confirming safety in a different group of people [Citation56]. Finally, the Phase III trial involves testing in thousands of people. In this phase, scientists give vaccines to the volunteers and wait to see how many become infected in the placebo and vaccine group. These trials typically determine whether the vaccine protects against the virus, with or without side effects. Phase III trials are large enough to reveal the efficacy rate and rare side effects. Based on Phase III, regulatory authorities decide to authorize the vaccine initially for the limited approval [Citation57]. Regulators review the complete trial results and plans for manufacturing the vaccine and decide whether to give it full approval.
These testing steps usually take years to complete, and developers must adhere to the necessary protocols to develop safe and effective vaccines. However, in the present pandemic scientists worldwide are in a race to produce safe and effective vaccines in record time, without taking shortcuts on the protocol. Around 70 vaccines developed by universities and companies are in clinical trials, and around 20 of them have reached the final testing stage [Citation58]. At the time of writing, two vaccines, developed by Moderna and Pfizer, have received full approval in different countries for mass immunization [Citation59].
Both the Moderna and Pfizer vaccines are mRNA-based vaccines that tell cells to make the SARS-CoV-2 S protein, to generate an immune response. The Moderna mRNA-1273 vaccine was jointly developed by the Massachusetts-based biotechnology company Moderna, Inc. and the US National Institute of Allergy and Infectious Diseases. This vaccine is a formulation of nanoparticles in which mRNA encoding the full-length spike protein of the coronavirus is encapsulated inside liposomes. The Phase III trial of this vaccine, also known as the COVE trial, consisted of randomized, observer-blinded, placebo-controlled trials conducted at 99 centers across the USA [Citation60]. Volunteers at high risk for SARS-CoV-2 infection were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo with a gap of 28 days. The trial’s primary end point was prevention of COVID-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2 [Citation60].
More than 96% of participants received both the doses, while 2.2% of volunteers were previously infected with SARS-CoV-2, as confirmed by serologic testing. Eleven participants in the mRNA-1273 group and 185 in the placebo group were confirmed as having symptomatic COVID-19 illness. Severe symptoms of COVID-19 were observed in 30 participants, and there was one fatality, all from the placebo group. Serious adverse events were rare in the mRNA-1273 group, and the overall efficiency of the vaccine was observed to be 94.1% [Citation60].
Another vaccine (BNT162b2) for which the US FDA gave emergency use authorization for the prevention of COVID-19 was jointly developed by the major pharmaceutical company Pfizer and its German partner BioNTech. This vaccine was authorized to be used in individuals 16 years of age and older. This vaccine has been approved in Britain, the USA, the EU and Canada [Citation61].
In the multinational, placebo-controlled, observer-blinded, pivotal efficacy Phase III trial of BNT162b2, persons aged 16 years or older were randomly assigned in a 1:1 ratio to receive two doses (30 μg per dose) at 21 days apart [Citation61]. The two groups into which the volunteers were assigned were BNT162b2 and the placebo group. Similar to the Moderna vaccine, BNT162b2 is also formulated as nanoparticles composed of different lipids, encapsulating mRNA that codes for the membrane-anchored SARS-CoV-2 full-length spike protein against which the immune cells initiate the immune response [Citation61]. The primary end points of the trials were the efficacy of the vaccine against laboratory-confirmed COVID-19 and safety. Out of 43,548 volunteers, 21,720 received BNT162b2 and 21,728 received placebos. A total of eight cases of COVID-19 in the BNT162b2 group and 162 cases in the placebo group were observed, confirming overall 95% effectiveness in preventing COVID-19. Similar efficiency of the vaccine was observed in different subgroups defined by sex, race, ethnicity, baseline BMI, age and the presence of coexisting conditions. Among 10 confirmed cases of COVID-19, nine were from the placebo group and one was from the vaccinated group. The incidence of serious adverse events was rare and was identical in both groups [Citation61].
In a head-to-head comparison of both vaccines, each vaccine is effective after both doses. The Pfizer and Moderna vaccines were found to be 95 and 94.1% effective, respectively, after the second dose in adults aged 16 years and older. The two vaccines’ potential side effects are almost identical and include injection site pain, swelling, redness, tiredness, headache, muscle pain, joint pain, chills, fever and nausea/vomiting. However, the vaccines are a bit different when it comes to the question of stability and transportation. The Pfizer vaccine is only stable below −70°C and hence needs to be shipped or transported in temperature-controlled thermal shippers that keep the temperature at this level. The vaccine can be stored in this condition for up to 10 days. For storage of more than 10 days, ultra-low temperature is required.
On the other hand, the Moderna vaccine requires a temperature of -20°C for shipping and can be stored at 2–8°C for 30 days. It is stable for 6 months if stored at -20°C and for up to 12 h at room temperature. The significant difference in the two vaccines’ stability is the result of the different lipids used for their nanoparticle formulations.
Discussion & conclusion
A novel β-coronavirus, SARS-CoV-2, appeared in Wuhan (Hubei Province, China) in December 2019, where it was identified as responsible for the COVID-19 infection [Citation62]. To end the global SARS-CoV-2 pandemic, a vaccine is needed. Any vaccine that is reliable, effective, permanent and accessible to a large population is a good candidate. However, viral particles can mutate, which can make vaccines ineffective; therefore it is important to create a secure and reliable vaccine in advance for future outbreaks of SARS-CoV-2 variants. Most vaccine approaches tend to produce antibodies that neutralize specific proteins such as the S protein. SARS-CoV-2-neutralizing vaccines dependent on RBD S protein will efficiently be created. Apart from antigens, certain supplementary vaccine components can increase the immune response and decrease the amount of antigen necessary for each vaccine dose. The design of a vaccine offering active protective immunity will be the most successful long-term strategy for preventing potential outbreaks of this virus. As of April 2020, 115 vaccine candidates were included in the international COVID-19 vaccine research and design landscape [Citation63]. The most crucial candidate vaccines include viral vector vaccines, nucleic acid-based vaccines, aAPC vaccines, viral proteins and live vaccines [Citation12,Citation20,Citation64,Citation65]. Among all the vaccines in the clinical trial process as options for SARS-CoV-2, the RNA-based vaccines appear to be more effective than other vaccines since large amounts of vaccine are amenable to low-budget development. Though harmless in clinical trials, the immune response caused by an antigen whose production is stimulated by an RNA-based vaccine is lesser than that detected in animal models [Citation66,Citation67]. Like RNA-based vaccines, DNA vaccines are easy to create, inexpensive, and offer better safety and efficacy and lengthy immunogenic persistence. Even so, because they failed to elicit a sufficiently robust immune response to be safe, they have not been licensed for human usage. Instead, vaccines based on extremely immunogenic vectors have been revealed to produce effective immune responses.
Nevertheless, the application of an adenovirus vector to transfer the gene encoding the goal protein, as in the case of Ad5 with the expression of S protein, increases some anxieties associated with immunity against adenovirus types in humans [Citation68]. Finally, lentiviral vectors derived from viral proteins have been associated with some protection issues related to the possible risk of mutagenesis [Citation69]. A thorough study of the immunological associations with SARS-CoV-2 involves the production of an active vaccine; however, most approaches would not serve the required urgency because of the disease epidemic’s severity.
Consequently, a numerical forecast helps direct scientists to produce a vaccine and help monitor the disease. Creating a vaccine is a lengthy and costly process with high rejection rates, and the manufacture of a safe commercial vaccine usually takes many candidates and years [Citation36]. Finally, testing and making COVID-19 vaccines is expected to increase the ‘inevitability of realization’ of indicating vaccine effectiveness and monitoring COVID-19 infection, death and the pandemic itself [Citation70].
Future perspective
The progress of a vaccine signifies the perfect therapeutic option for the COVID-19 epidemic, but despite the development of three vaccines, it can still be a long route to normality.
The best candidate vaccines include vector-based vaccines, nucleic acid vaccines, live vaccines, viral proteins and aAPC vaccines. Currently, RNA-based and vector-based vaccines appear to be more favorable than other types. However, we still need to watch this space for future developments. There is a need to develop safe and effective therapeutics for respiratory inflammation-linked viral infection; this strategy could avoid future events similar to the current pandemic caused by COVID-19.
Executive summary
New innovative technologies have been developed for vaccines for the first time in response to the COVID-19 pandemic.
Emergency use authorization has been granted to four leading vaccine candidates to be used globally.
Currently, under development, there are over 200 COVID-19 vaccine candidates in various stages of trials.
Vaccines traditionally take a long time to develop; the development of multiply efficient and highly effective vaccines against COVID-19 is a remarkable scientific achievement.
Dozens of vaccine candidates fit into eight categories, with four currently being given to individuals globally.
Hopes are rising that we will soon see the end of the pandemic with the roll-out of COVID-19 vaccines.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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22 | https://www.who.int/news/item/19-12-2023-covid-19-vaccinations-shift-to-regular-immunization-as-covax-draws-to-a-close | COVID-19 vaccinations shift to regular immunization as COVAX draws to a close
19 December 2023 Statement
Geneva/New York/Oslo
Reading time: 6 min (1634 words)
COVAX will close 31 December 2023 having delivered nearly 2 billion doses of vaccines to 146 economies, and averted an estimated 2.7 million deaths in AMC lower-income participating economies.
COVAX’s end-to-end efforts helped lower-income economies achieve two-dose coverage of 57%, compared to the global average of 67%.
Low- and lower middle-income economies will continue to receive COVID-19 vaccines and delivery support from Gavi, the Vaccine Alliance in 2024 and 2025, with 83 million doses so far requested for 2024 from 58 economies.
COVAX, the multilateral mechanism for equitable global access to COVID-19 vaccines launched in 2020, will draw to a close on 31 December. Jointly led by the Coalition for Epidemic Preparedness Innovations (CEPI), Gavi, the Vaccine Alliance (Gavi), UNICEF and the World Health Organization (WHO), COVAX has so far supplied nearly 2 billion COVID-19 vaccine doses and safe injection devices to 146 economies. Its efforts are estimated to have helped avert the deaths of at least 2.7 million people in the COVAX Advance Market Commitment (AMC) low- and lower middle-income participating economies (lower-income economies) that received free doses through the mechanism, alongside nearly US$ 2 billion in critical support to turn vaccines into vaccinations.
These 92 lower-income economies that were eligible to participate in the programme with support from the financing mechanism known as the Gavi COVAX Advance Market Commitment (COVAX AMC) will continue to have the option to receive COVID-19 vaccine doses and delivery support through Gavi’s regular programmes. So far, 58 lower-income economies have requested a total of 83 million doses in 2024, with plans to focus on the continued protection of priority groups, including health care workers, community workers and older adults.
Unprecedented emergency response
Drawing on the lessons of the H1N1 pandemic, when the majority of countries missed out on vaccines, COVAX partners advocated from the earliest stages of the COVID-19 emergency that “no one is safe until everyone is safe” – urging the world to place vaccine equity at the heart of the global response, and calling for every country to have at least enough doses to protect those most at risk. By the end of 2020, 190 economies of all income levels had signed agreements to participate in COVAX, making it one of the most significant multilateral partnerships of the 21st century. By November 2020, it had raised US$ 2 billion towards vaccine procurement; and in January 2021, 39 days after the first vaccine administration in a high-income country, the first COVAX-supplied doses were administered in a lower-income country.
COVAX was designed as an end-to-end coordination mechanism encompassing R&D and manufacturing, policy guidance, vaccine portfolio development, regulatory systems, supply allocation and country readiness assessments, transport logistics, vaccine storage and administration, and monitoring country coverage and absorption rates. However, as an emergency solution launched in the midst of the pandemic, COVAX faced many challenges. Without having any cash reserves up front, it was initially limited in its ability to sign early contracts with manufacturers, and while it was able to ship doses to 100 economies in the first six weeks of global roll-out, export bans and other factors meant that large-volume deliveries were only received in the third quarter of 2021.
While COVAX was unable to completely overcome the tragic vaccine inequity that characterized the global response, it made a significant contribution to alleviating the suffering caused by COVID-19 in the Global South. Today, the initiative has supplied 74% of all COVID-19 vaccine doses supplied to low-income countries (LICs) during the pandemic; and in total, 52 of the 92 AMC-eligible economies relied on COVAX for more than half of their COVID-19 vaccine supply. Thanks to the tireless efforts of national governments, health and frontline workers, civil society organisations and others, those doses, delivered free of charge and combined with nearly US$2 billion in delivery support, helped to lift primary series coverage among the 92 AMC-eligible economies to 57%, compared to a global average of 67%. Two-dose coverage of health care workers, those most critical to saving lives and keeping health systems running, stands at 84% in lower-income economies.
COVAX also deployed 2.5 million doses to protect the most vulnerable in humanitarian and conflict settings through a first-of-its kind mechanism called the Humanitarian Buffer, co-designed with international humanitarian organisations, and set up as a last resort to reach those who are not easily reached through government programmes. Attempting to deliver novel products through non-governmental channels proved to be incredibly difficult, but the effort provided deep insight into the systemic barriers that are exacerbated by a global emergency situation. Governments, humanitarian institutions, global health organisations and others are now working to apply these lessons towards ongoing programmes, and advocating for how we can better protect the most vulnerable populations in a future pandemic.
Investing in lessons learnt for a future response
COVAX’s successes and challenges in the bid to overcome inequity have underscored the clear need for the world to be better prepared the next time a viral threat with pandemic potential emerges. The plethora of learnings from COVAX’s unique effort must be considered in the development of future global pandemic preparedness and response architecture. These include strengthening existing capacity by designing, investing in and implementing an end-to-end solution to equitable access ahead of time, one that centres on the needs of the most vulnerable; recognising that vaccine nationalism will persist in future pandemics and putting in place mechanisms to mitigate it – including by diversifying vaccine manufacturing so all regions have access to supply; and accepting the need to take financial risks to avoid potentially deadly delays to the development, procurement and delivery of medical countermeasures.
With collaboration from manufacturers, all of COVAX’s advance purchase supply agreements will have been completed or terminated by the end of 2023, with the exception of one, where a modest volume of supply will continue into the first half of 2024 in support of the new COVID-19 routine immunization programme.
Thanks in large part due to the savings gained through the successful renegotiation of supply contracts, some COVAX AMC funds remain in the contingency mechanism known as the Pandemic Vaccine Pool, and these can now be reinvested into translating the lessons from COVAX Facility into concrete actions. This includes the establishing of an African Vaccine Manufacturing Accelerator (AVMA), a result of our learnings from the pandemic where Africa was left vulnerable to supply restrictions. Investment in AVMA will make up to US$ 1 billion available to support vaccine manufacturing on the African continent. In addition, a First Response Fund will be established to ensure financing for a vaccine response is immediately available in the event of a future pandemic. It also includes funding “The Big Catch-up” effort designed to fill the gaps in immunization resulting from the pandemic which are now causing outbreaks of vaccine-preventable diseases around the world and threatening the achievement of Immunization Agenda 2030 goals.
“Millions of people are alive today who would not have been here without COVAX. Those averted deaths mean mothers can continue to nurture their children, and grandparents can enjoy watching future generations flourish,” said Jane Halton, Chair of the Board of CEPI. “Despite being built and funded from scratch amid the deadliest pandemic the world has seen in more than a century, COVAX’s life-saving accomplishments were considerable. It should take its place in history and be proud of what it was able to accomplish but also serve as a reminder to us all that we can and must do better next time.”
“COVID-19 has been the greatest health challenge of our time, and it was met with innovation and partnership on an equally unprecedented scale,” said José Manuel Barroso, Chair of the Board of Gavi, the Vaccine Alliance. “COVAX’s impact has been historic, as are the insights it has generated on how, concretely, the world can do better next time. As we transition COVID-19 into Gavi’s routine programming, we do so with deep gratitude for the passion, dedication and sacrifice of so many around the globe who fought tirelessly for three years to try and create a more equitable world – and with an unwavering commitment to improve by transforming learnings into tangible action.”
“The joint efforts of all partners to ensure an equitable response to the pandemic helped protect the futures of millions of children in vulnerable communities,” said UNICEF Executive Director Catherine Russell. “This huge and historic undertaking is something we can be collectively proud of and build on. UNICEF will continue to deliver vaccines to the world's youngest to stop the spread of all preventable diseases and build strong health systems for the future.”
"We knew that market forces alone would not deliver equitable access to vaccines and other tools," said Dr Tedros Adhanom Ghebreyesus, WHO Director-General. "The creation of ACT-A and COVAX gave millions of people around the world access to vaccines, tests, treatments and other tools who would otherwise have missed out. COVAX has taught us valuable lessons that will help us to be better prepared for future epidemics and pandemics."
Notes to editors
Key Learnings – For a detailed overview on COVAX key learnings and recommendations for future pandemic preparedness and response, read this white paper: https://www.gavi.org/news-resources/knowledge-products/covax-key-learnings-future-pandemic-preparedness-and-response
“ The Delivery” – For access to a unique interactive deep dive into the stories and data that defined the COVID-19 delivery effort, available to all media organisations under Creative Commons license, please reach out to the media contacts below.
About COVAX
COVAX, the vaccines pillar of the Access to COVID-19 Tools (ACT) Accelerator, was co-convened by the Coalition for Epidemic Preparedness Innovations ( CEPI), Gavi, the Vaccine Alliance ( Gavi), UNICEF and the World Health Organization ( WHO) – working in partnership with countries, donors, developed and developing country vaccine manufacturers, the World Bank, and others. Its efforts focused on ensuring all countries could access COVID-19 vaccines, regardless of income level.
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23 | https://www.medpagetoday.com/infectiousdisease/covid19vaccine/108537 | Here's How Effective the Latest COVID-19 Shots Are for Adults
— Effectiveness of the 2023-2024 vaccine lands at 54% for symptomatic cases
by Katherine Kahn, Staff Writer, MedPage Today February 1, 2024
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The updated 2023-2024 COVID-19 vaccine was approximately 54% effective against symptomatic SARS-CoV-2 infection in adults, and was also effective against the JN.1 variant, which became predominant in January, CDC researchers said.
Overall, vaccine effectiveness against symptomatic COVID was 57% for people ages 18 to 49 years and 46% for people ages 50 and older, reported Ruth Link-Gelles, PhD, of the CDC's National Center for Immunization and Respiratory Diseases, and colleagues in the Morbidity and Mortality Weekly Report.
The updated vaccine is a monovalent XBB.1.5-derived vaccine, and there have been few estimates regarding its effectiveness, the authors noted. This study is the first to look at the vaccine's effectiveness against symptomatic COVID caused by the JN.1 variant, a derivative of BA.2.86.
The data came from the CDC's Increasing Community Access to Testing program that provided no-cost SARS-CoV-2 nucleic acid amplification tests (NAAT) to uninsured people at participating CVS and Walgreens pharmacies from Sept. 21, 2023 to Jan. 14, 2024.
Vaccine effectiveness was 58% among those who received testing 7 to 59 days after receiving the updated vaccine, and 49% among those who received testing 60 to 119 days after receipt.
In a subanalysis, the researchers also looked at spike gene amplification results from reverse transcription-polymerase chain reaction (RT-PCR) COVID tests to differentiate XBB lineages from JN.1 and other Omicron BA.2.86 lineages.
For those who had received the updated vaccine 60 to 119 days earlier, vaccine effectiveness was 49% for tests indicating infection with JN.1 lineages, and 60% for tests indicating infection with non-JN.1 lineages.
"Whereas the goal of the U.S. COVID-19 vaccination program is to prevent severe disease, vaccine effectiveness against symptomatic infection can provide useful insights into protection early after introduction of updated vaccines and during the emergence of new lineages," Link-Gelles and colleagues wrote.
The study only looked at data through 119 days since vaccination -- a relatively brief period of time, the authors pointed out. "Waning of effectiveness is expected with additional elapsed time since vaccination, especially against less severe disease," they noted.
In September 2023, the CDC's Advisory Committee on Immunization Practices (ACIP) recommended that everyone 6 months of age and older get the 2023-2024 updated COVID vaccine.
This analysis looked at 9,222 NAAT COVID test results over the study period among people with COVID-like symptoms. Most people tested were women (61%), about 40% were white, 30% were Hispanic or Latino, and 16% were Black or African American.
Of available NAAT tests, 36% were positive for SARS-CoV-2. The researchers calculated vaccine effectiveness by comparing odds of receipt versus nonreceipt of the updated COVID vaccine among those who tested positive (case patients) and those who tested negative (control patients). Of the 1,125 individuals who had received an updated COVID vaccine at least 7 days before testing, 14% were SARS-CoV-2-negative and 9% were positive.
Notably, only 12% of all people tested reported that they had received an updated vaccine dose, and over 26% had never received any COVID vaccine. Sixty percent reported a previous SARS-CoV-2 infection more than 3 months before the current test.
Link-Gelles and team pointed out that vaccination status, previous infection history, and underlying medical conditions were self-reported and subject to bias. Since there is a high prevalence of infection-induced SARS-CoV-2 immunity among adults in the U.S., previous infection was probably underreported and likely provided some protection against repeat infection.
Katherine Kahn is a staff writer at MedPage Today, covering the infectious diseases beat. She has been a medical writer for over 15 years.
Disclosures
Link-Gelles and co-authors reported no potential conflicts of interest.
Primary Source
Morbidity and Mortality Weekly Report
Source Reference: Link-Gelles R, et al "Early estimates of updated 2023-2024 (monovalent XBB.1.5) COVID-19 vaccine effectiveness against symptomatic SARS-CoV-2 infection attributable to co-circulating Omicron variants among immunocompetent adults -- Increasing Community Access to Testing program, United States, September 2023-January 2024" MMWR 2024; DOI: 10.15585/mmwr.mm7304a2. |
24 | https://www.health.com/news/lingering-cough-after-covid |
What To Do About a Lingering Cough After COVID
A cough can last for quite a while after any viral infection, and it doesn't necessarily mean you're still contagious.
By Korin Miller
Updated on November 28, 2023
Medically reviewed by Karis Cho, MD
Fact checked by Vivianna Shields
Man with lingering cough from COVID covering mouth with inside of elbow
cottonbro / Pexels
Having a cough is one of the main symptoms of COVID-19—but what if that cough lingers long after you've started feeling better or are no longer testing positive for the virus?
A lingering cough after COVID-19 affects nearly 5% of people infected by the virus. While coughing is a common symptom of COVID-19, it can potentially linger for longer than four weeks—and up to six months—after testing negative.1 The Omicron variant targets upper airways more than the lower airways as compared to other variants.2
According to infectious disease doctors, a lingering cough after COVID-19 is possible, but it's not usually a cause for concern—nor is it strictly related to the SARS-CoV-2 virus. "Many viral infections leave people with a chronic cough," Amesh Adalja, MD, a senior scholar at the Johns Hopkins Center for Health Security, told Health. "It is not an uncommon condition."
But why do some people have a lingering cough after having COVID-19—and what (if anything) can be done to help it clear up more quickly? Here's what you need to know.
What Causes a Lingering Cough After COVID-19?
A lingering cough after COVID-19 results from the way the virus affects your body. An upper respiratory infection (URI) like COVID can lead to inflammation.3
"COVID-19 can inflame the mucus membranes of the airways, starting back in the throat and getting down into the bronchial tubes," William Schaffner, MD, an infectious disease specialist and professor at the Vanderbilt University School of Medicine, told Health. "That inflammation may take quite a while to heal in some patients."
A respiratory infection can also change the way vagal sensory nerves communicate with your brain, making you more sensitive to the cough reflex.3 Vagal sensory nerves are part of your parasympathetic nervous system, which helps your body relax. They help control involuntary functions like digestion, breathing, blood pressure, heart rate, and immune system responses.
Though it can be annoying, having a lingering cough isn't necessarily a bad thing. "The whole purpose of a cough is for the body to clear the airway of stuff that shouldn't be down there," said Dr. Schaffner. "When you have inflammation in your airways, you have dying cells and extra mucus in there. Coughing is your body's way of trying to keep the airways clear."
Does the Type of Cough Matter?
There are two primary types of coughs.
Wet (productive) cough: Produces mucus or phlegm
Dry (unproductive) cough: Does not produce mucus or phlegm
It's difficult to diagnose COVID based on the sound of the cough.4 About 60-70% of people COVID-19 experience a dry cough toward the beginning of the infection. However, many people have a wet cough. Your cough might also change.1
Get tested if you think you might have COVID-19—or if you may have been exposed—and reach out to your healthcare provider with any concerns.
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Are You Still Contagious With a Lingering Cough?
A lingering cough after COVID-19 does not always mean you are still contagious. According to the Centers for Disease Control and Prevention (CDC), people with mild to moderate COVID-19 have been shown to remain infectious up to 10 days from symptom onset; for people with more severe COVID infection or those who are moderately or severely immunocompromised, that period extends to 20 days or potentially longer.5
Symptom onset is an essential part of determining when to begin isolation. However, if you're near the end of your isolation period and symptoms are still present but improving—especially if you have been fever-free for 24 hours—you're likely in the clear from spreading the virus.6
This even extends to people who are possibly still testing positive after the full 10-day isolation and masking period. According to the CDC, some people who have recovered from COVID-19 may still test positive for the virus through more sensitive PCR testing for up to three months. Prolonged positive antibody testing doesn't necessarily indicate transmission risk unless you are immunocompromised. If that is the case, you should consult with a healthcare provider.7
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Is a Cough a Sign of Long COVID?
Long COVID, or post-COVID conditions (PCC), can include a wide range of new, returning, or ongoing health symptoms that people experience after being infected with SARS-CoV-2. These symptoms last for at least three months from the onset of a COVID-19 infection.8 Symptoms can affect any bodily system, including respiratory, digestive, cardiovascular, and neurological. However, there's no official medical test for long COVID, making it a difficult condition to diagnose.8
Cough is one of the most common long-lasting symptoms of COVID.8 One study of about 8,600 adults with long COVID found that about 33% of people experienced chronic cough at least six months after symptom onset.9
Though cough is identified as a potential respiratory symptom of long COVID, experts are hesitant to definitively associate a lingering cough with the condition. "Categorizing something as part of long COVID means it has to interfere with activities of daily living," said Dr. Adalja. "Chronic cough does not usually interfere with people's activities in a way that some other symptoms associated with long COVID do."
Having a lingering cough alone, independent of other symptoms, may also indicate that it's not long COVID. "We wouldn't consider a lingering cough long COVID in and of itself," said Dr. Schaffner. "Usually, these airway irritations don't take that long to clear up."
Possible complications of a persistent cough after COVID-19 include:2
Interstitial lung disease: This is a group of conditions that cause lung scarring and shortness of breath. Interstitial lung disease might also cause persistent coughing.10
Autoimmune conditions: Reduction in immune cells can trigger an autoimmune response, causing your immune system to attack healthy cells, tissues, or organs.
Asthma: Any viral respiratory infection, including COVID, could trigger asthma. Symptoms can include cough, dyspnea (shortness of breath), chest tightness, and/or wheezing, even in those without prior asthma or those with a remote history of asthma.11
Why Is It So Difficult for Long COVID Patients to Get Diagnosed and Treated?
How to Treat a Lingering Cough After COVID-19
There is no specific treatment for a lingering cough after COVID. As with any cough, staying hydrated helps your body clear mucus and promotes healing. Other basic remedies include:12
Using a humidifier
Taking a hot and steamy shower
Consuming honey or cough drops as needed
Exercise can also be helpful in the healing process. Exercise brings more blood flow to your lungs, helping healthier areas of your lungs compensate for damaged areas. Talk to your healthcare provider about which types of exercise might be beneficial.2
The goal is to reduce the cough reflex. Other possible treatments include medications, like inhaled corticosteroids, which reduce the cough reflex, airway inflammation, or mucus secretion.3
When to Seek Medical Attention
A persistent cough might be a sign of another infection. The infection might be viral (e.g., influenza) or bacterial (e.g., pneumonia).13
You may want to seek advice from a healthcare provider if:
The cough hasn't gone away or started to get better a month after having COVID-19
The cough changes or gets worse
You develop symptoms like a fever, increased shortness of breath, or chest pain/chest tightness
A Quick Review
Coughing is your body's way of clearing infection, but a chronic cough can be due to inflammation. A lingering cough after COVID-19 is possible, but it's not usually a cause for concern. It might also not even be related to COVID.
Seek medical attention if your cough persists for more than a month, if it changes or gets worse, or if you develop new symptoms. Treatment can reduce your risk of possible complications and chronic conditions.
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