id
stringlengths 2
2
| url
stringlengths 50
123
| content
stringlengths 2.82k
142k
|
|---|---|---|
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)
Cite this article
2686 Accesses
30 Altmetric
Metrics details
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
Previous article
View issue table of contents
Next article
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.
Download CSVDisplay Table
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).
Previous article
View issue table of contents
Next article
References
World Health Organization. WHO Coronavirus(COVID 19) Dashboard. 2023 Oct 21. https://covid19.who.int/.
Google Scholar
Gangavarapu K, Latif AA, Mullen JL, Alkuzweny M, Hufbauer E, Tsueng G, Haag E, Zeller M, Aceves CM, Zaiets K, et al. Outbreak.Info genomic reports: scalable and dynamic surveillance of SARS-CoV-2 variants and mutations. 2023.
viewView
Google Scholar
Telenti A, Hodcroft EB, Robertson DL. The evolution and biology of SARS-CoV-2 variants. Cold Spring Harb Perspect Med. 2022;12(5):a041390. doi:10.1101/cshperspect.a041390.
View
PubMed Web of Science ®Google Scholar
Jenni P, Shanron S, Patricia J, Judy O. Kuby immunology. 8thed. W. H. Freeman; 25 May 2018.
Google Scholar
Ibarrondo FJ, Fulcher JA, Goodman-Meza D, Elliott J, Hofmann C, Hausner MA, Ferbas KG, Tobin NH, Aldrovandi GM, Yang OO. Rapid decay of anti–SARS-CoV-2 antibodies in persons with mild COVID-19. N Engl J Med. 2020;383(11):1085–8. doi:10.1056/NEJMc2025179.
View
PubMed Web of Science ®Google Scholar
Elliott P, Bodinier B, Eales O, Wang H. Rapid increase in Omicron infections in England during December 2021: REACT-1 study. Science. 2022 Mar 25;375(6587):1406–1411. doi:10.1126/science.abn8347.
viewView
Web of Science ®Google Scholar
McMenamin ME, Nealon J, Lin Y, Wong JY, Cheung JK, Lau EHY, Wu P, Leung GM, Cowling BJ. Vaccine effectiveness of one, two, and three doses of BNT162b2 and CoronaVac against COVID-19 in Hong Kong: a population-based observational study. Lancet Infect Dis. 2022;22(10):1435–43. doi:10.1016/S1473-3099(22)00345-0.
viewView
PubMed Web of Science ®Google Scholar
Lustig Y, Gonen T, Meltzer L, Gilboa M, Indenbaum V, Cohen C, Amit S, Jaber H, Doolman R, Asraf K, et al. Superior immunogenicity and effectiveness of the third compared to the second BNT162b2 vaccine dose. Nat Immunol. 2022;23(6):940–6. doi:10.1038/s41590-022-01212-3.
viewView
PubMed Web of Science ®Google Scholar
Lusvarghi S, Pollett SD, Neerukonda SN, Wang W, Wang R, Vassell R, Epsi NJ, Fries AC, Agan BK, Lindholm DA, et al. SARS-CoV-2 BA.1 variant is neutralized by vaccine booster–elicited serum but evades most convalescent serum and therapeutic antibodies. Sci Transl Med. 2022;14(645):eabn8543. doi:10.1126/scitranslmed.abn8543.
viewView
PubMed Web of Science ®Google Scholar
Fleming-Dutra KE, Britton A, Shang N, Derado G, Link-Gelles R, Accorsi EK, Smith ZR, Miller J, Verani JR, Schrag SJ. Association of prior BNT162b2 COVID-19 vaccination with symptomatic SARS-CoV-2 infection in children and adolescents during Omicron predominance. JAMA. 2022;327(22):2210. doi:10.1001/jama.2022.7493.
viewView
PubMed Web of Science ®Google Scholar
Humoral and cellular immune memory to four COVID-19 vaccines. 33.
Google Scholar
Jung MK, Jeong SD, Noh JY, Kim D-U, Jung S, Song JY, Jeong HW, Park S-H, Shin E-C. BNT162b2-induced memory T cells respond to the Omicron variant with preserved polyfunctionality. Nat microbiol. 2022;7(6):909–17. doi:10.1038/s41564-022-01123-x.
viewView
PubMed Web of Science ®Google Scholar
Munro APS, Feng S, Janani L, Cornelius V, Aley PK, Babbage G, Baxter D, Bula M, Cathie K, Chatterjee K, et al. Safety, immunogenicity, and reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial. Lancet Infect Dis. 2022;22(8):1131–41. doi:10.1016/S1473-3099(22)00271-7.
viewView
PubMed Web of Science ®Google Scholar
Maringer Y, Nelde A, Schroeder SM, Schuhmacher J, Hörber S, Peter A, Karbach J, Jäger E, Walz JS. Durable spike-specific T-cell responses after different COVID-19 vaccination regimens are not further enhanced by booster vaccination. Sci Immunol. 2022;7(78):eadd3899. doi:10.1126/sciimmunol.add3899.
viewView
PubMed Web of Science ®Google Scholar
Wesemann - 2022 - Omicron’s message on vaccines boosting begets bre.Pdf.
viewView
Google Scholar
Muecksch F, Wang Z, Cho A, Gaebler C, Ben Tanfous T, DaSilva J, Bednarski E, Ramos V, Zong S, Johnson B, et al. Increased memory B cell potency and breadth after a SARS-CoV-2 mRNA boost. Nature. 2022;607(7917):128–34. doi:10.1038/s41586-022-04778-y.
viewView
PubMed Web of Science ®Google Scholar
Goel RR, Painter MM, Lundgreen KA, Apostolidis SA, Baxter AE, Giles JR, Mathew D, Pattekar A, Reynaldi A, Khoury DS, et al. Efficient recall of Omicron-reactive B cell memory after a third dose of SARS-CoV-2 mRNA vaccine. Cell. 2022;185(11):1875–87.e8. doi:10.1016/j.cell.2022.04.009.
viewView
PubMed Web of Science ®Google Scholar
Zhao X, Zhang R, Qiao S, Wang X, Zhang W, Ruan W, Dai L, Han P, Gao GF. Omicron SARS-CoV-2 neutralization from inactivated and ZF2001 vaccines. N Engl J Med. 2022;387(3):277–80. doi:10.1056/NEJMc2206900.
View
PubMed Web of Science ®Google Scholar
Shaw RH, Liu X, Stuart ASV, Greenland M, Aley PK, Andrews NJ, Cameron JC, Charlton S, Clutterbuck EA, Collins AM, et al. Effect of priming interval on reactogenicity, peak immunological response, and waning after homologous and heterologous COVID-19 vaccine schedules: exploratory analyses of Com-COV, a randomised control trial. Lancet Respir Med. 2022;10(11):1049–60. doi:10.1016/S2213-2600(22)00163-1.
viewView
PubMed Web of Science ®Google Scholar
Wu Y, Kang L, Guo Z, Liu J, Liu M, Liang W. Incubation period of COVID-19 caused by unique SARS-CoV-2 strains: a systematic review and meta-analysis. JAMA Netw Open. 2022;5(8):e2228008. doi:10.1001/jamanetworkopen.2022.28008.
viewView
PubMed Web of Science ®Google Scholar
Interim recommendations for heterologous COVID-19 vaccine schedules: interim guidance, 16 December 2021. 2021.
Google Scholar
Pérez-Then E, Lucas C, Monteiro VS, Miric M, Brache V, Cochon L, Vogels CB, De la Cruz E, Jorge A, De los Santos M, et al. Immunogenicity of heterologous BNT162b2 booster in fully vaccinated individuals with CoronaVac against SARS-CoV-2 variants Delta and Omicron: the Dominican Republic Experience. 2021. http://medrxiv.org/lookup/doi/10.1101/2021.12.27.21268459.
View
Google Scholar
Muik A, Wallisch A-K, Sänger B, Swanson KA, Mühl J, Chen W, Cai H, Maurus D, Sarkar R, Türeci Ö, et al. Neutralization of SARS-CoV-2 lineage B.1.1.7 pseudovirus by BNT162b2 vaccine–elicited human sera. Sci. 2021;371(6534):1152–3. doi:10.1126/science.abg6105.
viewView
PubMed Web of Science ®Google Scholar
Zuo F, Abolhassani H, Du L, Piralla A, Bertoglio F, de Campos-Mata L, Wan H, Schubert M, Cassaniti I, Wang Y, et al. Heterologous immunization with inactivated vaccine followed by mRNA booster elicits strong humoral and cellular immune responses against the SARS-CoV-2 Omicron variant. 2022. http://medrxiv.org/lookup/doi/10.1101/2022.01.04.22268755.
View
Google Scholar
Lu C, Zhang Y, Liu X, Hou F, Cai R, Yu Z, Liu F, Yang G, Ding J, Xu J, et al. Heterologous boost with mRNA vaccines against SARS-CoV-2 Delta/Omicron variants following an inactivated whole-virus vaccine. 30.
Google Scholar
Li J-X, Wu S-P, Guo X-L, Tang R, Huang B-Y, Chen X-Q, Chen Y, Hou L-H, Liu J-X, Zhong J, et al. Safety and immunogenicity of heterologous boost immunisation with an orally administered aerosolised Ad5-nCoV after two-dose priming with an inactivated SARS-CoV-2 vaccine in Chinese adults: a randomised, open-label, single-centre trial. Lancet Respir Med. 2022;10(8):739–48. doi:10.1016/S2213-2600(22)00087-X.
viewView
PubMed Web of Science ®Google Scholar
Li J, Hou L, Guo X, Jin P, Wu S, Zhu J, Pan H, Wang X, Song Z, Wan J, et al. Heterologous AD5-nCOV plus CoronaVac versus homologous CoronaVac vaccination: a randomized phase 4 trial. Nat Med. 2022;28(2):401–9. doi:10.1038/s41591-021-01677-z.
viewView
PubMed Web of Science ®Google Scholar
Tang J, Zeng C, Cox TM, Li C, Son YM, Cheon IS, Wu Y, Behl S, Taylor JJ, Chakaraborty R, et al. Respiratory mucosal immunity against SARS-CoV-2 after mRNA vaccination. Sci Immunol. 2022;7(76):eadd4853. doi:10.1126/sciimmunol.add4853.
viewView
PubMed Web of Science ®Google Scholar
Mao T, Israelow B, Peña-Hernández MA, Suberi A, Zhou L, Luyten S, Reschke M, Dong H, Homer RJ, Saltzman WM, et al. Unadjuvanted intranasal spike vaccine elicits protective mucosal immunity against sarbecoviruses. Science. 2022;378(6622):eabo2523. doi:10.1126/science.abo2523.
viewView
PubMed Web of Science ®Google Scholar
Yao L, Zhu K-L, Jiang X-L, Wang X-J, Zhan B-D, Gao H-X, Geng X-Y, Duan L-J, Dai E-H, Ma M-J. Omicron subvariants escape antibodies elicited by vaccination and BA.2.2 infection. Lancet Infect Dis. 2022;22(8):1116–17. doi:10.1016/S1473-3099(22)00410-8.
viewView
PubMed Web of Science ®Google Scholar
Quandt J, Muik A, Salisch N, Lui BG, Lutz S, Krüger K, Wallisch A-K, Adams-Quack P, Bacher M, Finlayson A, et al. Omicron BA.1 breakthrough infection drives cross-variant neutralization and memory B cell formation against conserved epitopes. Sci Immunol. 2022;7(75):eabq2427. doi:10.1126/sciimmunol.abq2427.
viewView
PubMed Web of Science ®Google Scholar
Kaku CI, Bergeron AJ, Ahlm C, Normark J, Sakharkar M, Forsell MNE, Walker LM. Recall of preexisting cross-reactive B cell memory after Omicron BA.1 breakthrough infection. Sci Immunol. 2022;7(73):eabq3511. doi:10.1126/sciimmunol.abq3511.
viewView
PubMed Web of Science ®Google Scholar
Koutsakos M, Lee WS, Reynaldi A, Tan H-X, Gare G, Kinsella P, Liew KC, Taiaroa G, Williamson DA, Kent HE, et al. The magnitude and timing of recalled immunity after breakthrough infection is shaped by SARS-CoV-2 variants. Immunity. 2022;55(7):1316–26.e4. doi:10.1016/j.immuni.2022.05.018.
viewView
PubMed Web of Science ®Google Scholar
Minervina AA, Pogorelyy MV, Kirk AM, Crawford JC, Allen EK, Chou C-H, Mettelman RC, Allison KJ, Lin C-Y, Brice DC, et al. SARS-CoV-2 antigen exposure history shapes phenotypes and specificity of memory CD8+ T cells. Nat Immunol. 2022;23(5):781–90. doi:10.1038/s41590-022-01184-4. |
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
Show more
Add to Mendeley
Share
Cite
https://doi.org/10.1016/j.vaccine.2024.126171
Get rights and content
Under a Creative Commons license
open access
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.
Previous article in issue
Next article in issue
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).
Download: Download high-res image (610KB)
Download: Download full-size image
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.
Download: Download high-res image (581KB)
Download: Download full-size image
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:
Download: Download spreadsheet (3MB)
mmc1.
Data availability
All relevant data are within the paper and its Supporting Information files. No additional data are available.
References
[1]
NHS England. NHS encourages pregnant women to get COVID-19 vaccine [Internet]. [cited 2023 Jan 28]. Available from: https://www.england.nhs.uk/2021/10/nhs-encourages-pregnant-women-to-get-covid-19-vaccine/
.
Google Scholar
[2]
M.L. Badell, C.M. Dude, S.A. Rasmussen, D.J. Jamieson
Covid-19 vaccination in pregnancy
BMJ, 10 (378) (2022), Article e069741
Crossref
View in ScopusGoogle Scholar[3]
J. Allotey, E. Stallings, M. Bonet, M. Yap, S. Chatterjee, T. Kew, et al.
Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis
BMJ, 1 (370) (2020), Article m3320
Crossref
View in ScopusGoogle Scholar[4]
H. Engjom, T. van den Akker, A. Aabakke, O. Ayras, K. Bloemenkamp, S. Donati, et al.
Severe COVID-19 in pregnancy is almost exclusively limited to unvaccinated women - time for policies to change
Lancet Reg Health Eur, 13 (2022), Article 100313
View PDFView articleView in ScopusGoogle Scholar[5]
A.G. Edlow, V.M. Castro, L.L. Shook, A.J. Kaimal, R.H. Perlis
Neurodevelopmental outcomes at 1 year in infants of mothers who tested positive for SARS-CoV-2 during pregnancy
JAMA Netw Open, 5 (6) (2022), Article e2215787
Crossref
Google Scholar[6]
N. Fallach, Y. Segal, J. Agassy, G. Perez, A. Peretz, G. Chodick, et al.
Pregnancy outcomes after SARS-CoV-2 infection by trimester: a large, population-based cohort study
PLoS One, 17 (7) (2022), Article e0270893
Crossref
View in ScopusGoogle Scholar[7]
A. Conde-Agudelo, R. Romero
SARS-CoV-2 infection during pregnancy and risk of preeclampsia: a systematic review and meta-analysis
Am J Obstet Gynecol, 226 (1) (2022), pp. 68-89.e3
View PDFView articleView in ScopusGoogle Scholar
[8]
C.A.D. Santos, A.P. Paula, G.G.F. Filho, M.M. Alves, A.F. Nery, M.G.A. Pontes, et al.
Developmental impairment in children exposed during pregnancy to maternal SARS-COV2: a Brazilian cohort study
Int J Infect Dis IJID Off Publ Int Soc Infect Dis (2023)
S1201-9712(23)00802-0
Google Scholar
[9]
I. Gurol-Urganci, J.E. Jardine, F. Carroll, T. Draycott, G. Dunn, A. Fremeaux, et al.
Maternal and perinatal outcomes of pregnant women with SARS-CoV-2 infection at the time of birth in England: national cohort study
Am J Obstet Gynecol, 225 (5) (2021 Nov), pp. 522.e1-522.e11
View PDFView articleGoogle Scholar
[10]
Edlow AG, Castro VM, Shook LL, Haneuse S, Kaimal AJ, Perlis RH. Sex-specific neurodevelopmental outcomes in offspring of mothers with SARS-CoV-2 in pregnancy: an electronic health records cohort. medRxiv. 2022 Nov 18;2022.11.18.22282448.
Google Scholar
[11]
A. Ciapponi, M. Berrueta, P.K. Parker, A. Bardach, A. Mazzoni, S.A. Anderson, et al.
Safety of COVID-19 vaccines during pregnancy: a systematic review and meta-analysis
Vaccine, 41 (25) (2023), pp. 3688-3700
View PDFView articleView in ScopusGoogle Scholar[12]
American College of Obstetricians and Gynecologists. Statement of strong medical consensus for vaccination of pregnant individuals against COVID-19 [Internet]. [cited 2024 Mar 20]. Available from: https://www.acog.org/news/news-releases/2021/08/statement-of-strong-medical-consensus-for-vaccination-of-pregnant-individuals-against-covid-19
.
Google Scholar
[13]
I. Skjesol, J.Q. Tritter
The Norwegian way: COVID-19 vaccination policy and practice
COVID-19 Pandemic Vaccin Strateg Glob Health Policies, 11 (2) (2022), Article 100635
View PDFView articleView in ScopusGoogle Scholar[14]
Norwegian Institute of Public Health. Statistics Bank [Internet]. Available from: https://www.fhi.no/en/hn/statistics/statistics-from-niph/statistikkbanker/
.
Google Scholar
[15]
Statistics Norway. Population, by sex, age, contents, year and region [Internet]. Available from: https://www.ssb.no/en/statbank/table/07459/tableViewLayout1/
.
Google Scholar
[16]
CDC Centers for Disease Control and Preevntion. COVID-19 Vaccines While Pregnant or Breastfeeding [Internet]. Available from: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/pregnancy.htm
l.
Google Scholar
[17]
Statement of Strong Medical Consensus for Vaccination of Pregnant Individuals against COVID-19 [Internet]. 2021 [cited 2023 Dec 8]. Available from: https://www.acog.org/news/news-releases/2021/08/statement-of-strong-medical-consensus-for-vaccination-of-pregnant-individuals-against-covid-19
.
Google Scholar
[18]
Norwegian Institute of Public Health. Advice and information for women who are pregnant or breastfeeding [Internet]. Available from: https://www.fhi.no/en/op/novel-coronavirus-facts-advice/facts-and-general-advice/advice-and-information-for-pregnant-women/
.
Google Scholar
[19]
Norwegian Institute of Public Health. Pregnancy and breastfeeding [Internet] [cited 2023 Feb 19]. Available from: https://www.fhi.no/en/op/novel-coronavirus-facts-advice/facts-and-general-advice/advice-and-information-for-pregnant-women/
.
Google Scholar
[20]
A.K. Örtqvist, E. Dahlqwist, M.C. Magnus, R. Ljung, J. Jonsson, B. Aronsson, et al.
COVID-19 vaccination in pregnant women in Sweden and Norway
Vaccine, 40 (33) (2022), pp. 4686-4692
View PDFView articleView in ScopusGoogle Scholar[21]
I.M. Citu, C. Citu, F. Gorun, A. Motoc, O.M. Gorun, B. Burlea, et al.
Determinants of COVID-19 vaccination hesitancy among Romanian pregnant women
Vaccines, 10 (2) (2022), Article 275
Crossref
View in ScopusGoogle Scholar[22]
Z.U. Mustafa, S. Bashir, A. Shahid, I. Raees, M. Salman, H.A. Merchant, et al.
COVID-19 vaccine hesitancy among pregnant women attending antenatal clinics in Pakistan: a multicentric, prospective, survey-based study
Viruses, 14 (11) (2022), Article 2344
Crossref
View in ScopusGoogle Scholar[23]
H. Blakeway, S. Prasad, E. Kalafat, P.T. Heath, S.N. Ladhani, K. Le Doare, et al.
COVID-19 vaccination during pregnancy: coverage and safety
Am J Obstet Gynecol, 226 (2) (2022), pp. 236.e1-236.e14
View PDFView articleGoogle Scholar[24]
M.K. Kiefer, R. Mehl, M.M. Costantine, A. Johnson, J. Cohen, T.L. Summerfield, et al.
Characteristics and perceptions associated with COVID-19 vaccination hesitancy among pregnant and postpartum individuals: a cross-sectional study
BJOG Int J Obstet Gynaecol, 129 (8) (2022), pp. 1342-1351
Crossref
View in ScopusGoogle Scholar[25]
A. Gibson, C. Rand, C. Olson-Chen
Attitudes toward COVID-19 vaccination among pregnant persons in urban hospital-affiliated practices: exploring themes in vaccine hesitancy
Matern Child Health J, 27 (10) (2023), pp. 1855-1863
Crossref
View in ScopusGoogle Scholar[26]
F. Licata, M. Romeo, C. Riillo, G. Di Gennaro, A. Bianco
Acceptance of recommended vaccinations during pregnancy: a cross-sectional study in Southern Italy
Front Public Health, 11 (2023), Article 1132751
View in Scopus
Google Scholar
[27]
V. Gianfredi, A. Berti, P. Stefanizzi, M. D’Amico, V. De Lorenzo, L. Moscara, et al.
COVID-19 vaccine knowledge, attitude, acceptance and hesitancy among pregnancy and breastfeeding: systematic review of hospital-based studies
Vaccines, 11 (11) (2023)
Google Scholar
[28]
X. Qiu, H. Bailey, C. Thorne
Barriers and facilitators associated with vaccine acceptance and uptake among pregnant women in high income countries: a mini-review
Front Immunol, 12 (2021), Article 626717
View in Scopus
Google Scholar[29]
S. Kilada, N. French, E. Perkins, D. Hungerford
Pregnant women’s attitudes and behaviours towards antenatal vaccination against Influenza and COVID-19 in the Liverpool City Region, United Kingdom: cross-sectional survey
Vaccine X, 1 (15) (2023), Article 100387
View PDFView articleView in ScopusGoogle Scholar[30]
L.M. Irgens
The Medical Birth Registry of Norway. Epidemiological research and surveillance throughout 30 years
Acta Obstet Gynecol Scand, 79 (6) (2000), pp. 435-439
View in Scopus
Google Scholar
[31]
L. Trogstad, G. Ung, M. Hagerup-Jenssen, I. Cappelen, I.L. Haugen, B. Feiring
The Norwegian immunisation register – SYSVAK
Eurosurveillance, 17 (16) (2012), Article 20147
Google Scholar
[32]
G. Murzakanova, S. Räisänen, A.F. Jacobsen, K.B. Sole, L. Bjarkø, K. Laine
Adverse perinatal outcomes in 665,244 term and post-term deliveries—a Norwegian population-based study
Eur J Obstet Gynecol Reprod Biol, 247 (2020), pp. 212-218
View PDFView articleView in ScopusGoogle Scholar[33]
I.J. Bakken, A.M.S. Ariansen, G.P. Knudsen, K.I. Johansen, S.E. Vollset
The Norwegian Patient Registry and the Norwegian Registry for Primary Health Care: research potential of two nationwide health-care registries
Scand J Public Health, 48 (1) (2020), pp. 49-55
Crossref
View in ScopusGoogle Scholar[34]
Norwegian Institute of Public Health (NIPH). Coronavirus vaccine – information for the public. Coronavirus vaccine [Internet]. [cited 2023 Aug 14]. Available from: https://www.fhi.no/en/id/corona/coronavirus-immunisation-programme/coronavirus-vaccine/#about-risk-groups-and-childrenadolescents-with-underlying-conditions
.
Google Scholar
[35]
O. Harel, E.M. Mitchell, N.J. Perkins, S.R. Cole, E.J. Tchetgen Tchetgen, B. Sun, et al.
Multiple imputation for incomplete data in epidemiologic studies
Am J Epidemiol., 187 (3) (2018), pp. 576-584
Crossref
View in ScopusGoogle Scholar
[36]
J.R. Carpenter, M.G. Kenward
Multiple imputation and its application
(1st ed.), Wiley, Chichester, West Sussex, UK (2013)
[Statistics in practice]
Google Scholar
[37]
D.W. Hosmer, S. Lemeshow, R.X. Sturdivant
Applied Logistic Regression
(3rd ed.), Wiley, Hoboken (2013)
[Wiley Series in Probability and Statistics]
Google Scholar
[38]
G. Zou
A modified Poisson regression approach to prospective studies with binary data
Am J Epidemiol, 159 (7) (2004), pp. 702-706
View in Scopus
Google Scholar[39]
A.J. Siegler, N. Luisi, E.W. Hall, H. Bradley, T. Sanchez, B.A. Lopman, et al.
Trajectory of COVID-19 vaccine hesitancy over time and association of initial vaccine hesitancy with subsequent vaccination
JAMA Netw Open, 4 (9) (2021), Article e2126882
Crossref
View in ScopusGoogle Scholar[40]
E.C. Anderson, P.S. Blair, A. Finn, J. Ingram, G. Amirthalingam, C. Cabral
Maternal vaccination provision in NHS maternity trusts across England
Vaccine, 41 (49) (2023), pp. 7359-7368
View PDFView articleView in ScopusGoogle Scholar[41]
P. Buekens, M. Berrueta, A. Ciapponi, A. Bardach, A. Mazzoni, F. Rodriguez-Cairoli, et al.
Safe in pregnancy: a global living systematic review and meta-analysis of COVID-19 vaccines in pregnancy
Vaccine, 42 (7) (2024), pp. 1414-1416
View PDFView articleView in ScopusGoogle Scholar[42]
T. Nasrin, F. Tauqeer, L.D. Bjørndal, S. Kittel-Schneider, A. Lupattelli
Partner support for women’s antidepressant treatment and its association with depressive symptoms in pregnant women, mothers, and women planning pregnancy
Arch Womens Ment Health, 27 (4) (2024), pp. 557-566
Crossref
View in ScopusGoogle Scholar
[43]
E. Maisonneuve, E. Gerbier, F. Tauqeer, L. Pomar, G. Favre, U. Winterfeld, et al.
Determinants of vaccination and willingness to vaccinate against COVID-19 among pregnant and postpartum women during the third wave of the pandemic: a European multinational cross-sectional survey
Viruses, 15 (5) (2023)
Google Scholar
[44]
K.T. Paul, B.M. Zimmermann, P. Corsico, A. Fiske, S. Geiger, S. Johnson, et al.
Anticipating hopes, fears and expectations towards COVID-19 vaccines: a qualitative interview study in seven European countries
SSM - Qual Res Health, 1 (2) (2022), Article 100035
View PDFView articleView in ScopusGoogle Scholar[45]
H. Blakeway, S. Prasad, E. Kalafat, P.T. Heath, S.N. Ladhani, K. Le Doare, et al.
COVID-19 vaccination during pregnancy: coverage and safety
Am J Obstet Gynecol, 226 (2) (2022), pp. 236.e1-236.e14
View PDFView articleGoogle Scholar[46]
L. Ha, C. Levian, N. Greene, I. Goldfarb, A. Hirsch, M. Naqvi
Association between acceptance of routine pregnancy vaccinations and COVID-19 vaccine uptake in pregnant patients
J Infect, 87 (6) (2023), pp. 551-555
View PDFView articleView in ScopusGoogle Scholar[47]
D. Ramonfaur, D.E. Hinojosa-González, R.G. Rodríguez, A.L. Melchor, A. Rodríguez-Ramírez, G.P. Rodríguez-Gómez, et al.
Determinants of COVID-19 vaccine hesitancy among pregnant persons
J Am Pharm Assoc, 63 (4) (2023), pp. 1191-1196
View PDFView articleView in ScopusGoogle Scholar[48]
N. Pooley, S.S. Abdool Karim, B. Combadière, E.E. Ooi, R.C. Harris, S.C. El Guerche, et al.
Durability of vaccine-induced and natural immunity against COVID-19: a narrative review
Infect Dis Ther, 12 (2) (2023), pp. 367-387
Crossref
View in ScopusGoogle Scholar[49]
J.A. Sterne, I.R. White, J.B. Carlin, M. Spratt, P. Royston, M.G. Kenward, et al.
Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls
BMJ, 338 (2009), Article b2393
Crossref
Google Scholar |
16 | https://www.nature.com/articles/s41392-022-00996-y | "Signal Transduction and Targeted Therapy\nvolume 7, Article number: 146 (2022)\n Cite th(...TRUNCATED) |
17 | https://link.springer.com/article/10.1186/s12929-020-00695-2 | "\nCoronavirus vaccine development: from SARS and MERS to COVID-19\n\n Review\n Open access\n (...TRUNCATED) |
18 | https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.602256/full | "COVID-19: Coronavirus Vaccine Development Updates\nJing Zhao&#x;Jing Zhao1†Shan Zhao&#x;Shan Zhao(...TRUNCATED) |
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 m(...TRUNCATED) |
20 | https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.585354/full | "REVIEW article\nFront. Immunol., 14 October 2020\nSec. Vaccines and Molecular Therapeutics\nVolume (...TRUNCATED) |
End of preview. Expand
in Data Studio
README.md exists but content is empty.
- Downloads last month
- 75