Research in context
SARS-CoV-2 infection, infections, COVID-19 infection, infection, T-cell
ADENOVIRUS, VIRUS, SARS-COV-2 INFECTION, CNS INFECTIONS, INFECTIONS, COVID-19 INFECTION, INFECTION, CYTOTOXICITY, INFECTION INDUCED

Antibodies induced by SARS-CoV-2 infection or vaccines are correlated with prevention of infection as well as the attenuation of clinical severity of COVID-19 infection through virus neutralisation and Fc effector functions. The recombinant replication-defective chimpanzee adenovirus SARS-CoV-2 glycoprotein vaccine (AZD1222) is being widely used across Africa, where vaccine coverage remains low but approximately 90% of the population has been infected by SARS-CoV-2. Previous findings show that a single AZD1222 dose in previously SARS-CoV-2 infected individuals elicits similar antibody responses compared with two doses in SARS-CoV-2 naive individuals. There is little data on the durability, breadth, and capacity to mediate Fc effector functions of antibodies that result from AZD1222 vaccination following SARS-CoV-2 infection (hybrid immunity), particularly in the era of dominance of COVID-19 due to infections by the omicron variant of concern (VOC).We did a literature search on PubMed for reports from Nov 1, 2020 up to Aug 21, 2022 using the keywords (“COVID-19” OR “SARS-CoV-2”) AND (“vaccine*” OR “vaccination*”) AND “Hybrid Immunity” AND “Omicron”, with no restrictions on language. We identified 51 studies reporting hybrid immunity after COVID-19 vaccination. We identified 16 observational studies reporting on hybrid immunity, which included analysis against the omicron VOC. COVID-19 vaccination, which used AZD1222, BBV152 (inactivated COVID-19 vaccine), BNT162.b2, and mRNA-1273 vaccines following infection with SARS-CoV-2 resulted in significantly higher anti-spike protein (anti-S), anti-receptor binding domain (anti-RBD), antibody concentration and neutralisation activity titres against wild-type virus compared with vaccine-only induced immunity. Also, hybrid immunity was associated with higher amounts of neutralising activity against omicron, albeit lower relative to wild-type virus, compared with those with vaccine-only induced immunity following two doses of AZD1222 or BBV152 and 2–3 doses of mRNA. The cross-sectional observational studies, however, varied in the number of vaccine doses (2–3), time period between last dose of vaccine, and sampling timepoint (21 to 224 days) and neutralising activity testing was restricted to wild-type virus, omicron BA.1 or BA.2, and delta.
We expanded the observations of previous studies to include analysis of hybrid compared with AZD1222-only induced immunity on the longitudinal kinetics of anti-S, anti-RBD, antibody dependent cellular cytotoxicity (ADCC) and neutralising antibody activity against wild-type (D614G), beta, delta, A.VOI.V2, gamma, BA.1, BA.4, and SARS-CoV from 28 days after the first dose of AZD1222 through to 180 days. Similar to earlier observations, our data show little increase of anti-S IgG, anti-RBD IgG, neutralising antibody, or ADCC following a second dose of AZD1222 within 4 weeks of the first dose in individuals infected with SARS-CoV-2 before the first dose, compared with immune responses after the second AZD1222 dose in those without SARS-CoV-2 infection before vaccination. Hybrid compared with vaccine-only induced immunity showed increased ability to neutralise VOCs, including the highly immune-evasive omicron BA.1 and BA.4 sub-lineages, which have dominated global infections in the first half of 2022, as well as SARS-CoV. Furthermore, neutralising antibodies titres remained higher at 142 days after the second dose (D180) in individuals with hybrid compared with vaccine-only induced immunity against many VOCs, but not for delta, BA.1, or BA.4.
The low increase in antibody responses in individuals after a second dose of AZD1222 in those infected with SARS-CoV-2 before the first dose of vaccine, calls into question the utility of a second dose as soon as 4 weeks after the first dose in populations with a high previous rate of SARS-CoV-2 infection. Furthermore, hybrid immunity was associated with heightened neutralising activity against all VOCs including BA.1 and BA.4. Although there was waning of antibody neutralising activity against Delta, BA.1 and BA.4 by day 180 including in those with hybrid immunity, there is likely to be memory B cell responses against these variants in individuals with hybrid immunity. Our data indicate that even a single dose of AZD1222 at the general population level in Africa where there is high SARS-CoV-2 seropositivity and COVID-19 vaccine rollout is lagging, might be a valuable, cost-effective intervention to significantly enhance the magnitude and quality of antibody responses to SARS-CoV-2.Infection with SARS-CoV-2 before COVID-19 vaccination (ie, hybrid immunity) is associated with robust anti-S IgG and NAb against wild-type virus after a single dose of AZD1222, AD26.CoVs.S, and mRNA (ie, BNT162.b2 and mRNA-1273) vaccines.COVID-19 vaccine and infection induced protection against severe COVID-19 is potentially mediated by T-cell induced immunity, which is less affected by mutations in the VOCs that have evolved to date.There is little knowledge on the effects of hybrid immunity on NAb against a range of variants, including against omicron BA.1 and BA.4. Furthermore, there is a paucity of data on the effect of hybrid immunity on durability of NAb against wild-type virus and subsequent variants or against SARS-CoV, by 180 days after vaccination. COVID-19 vaccination using AZD1222, BBV152 (inactivated COVID-19 vaccine), BNT162.b2, and mRNA-1273 messenger RNA (mRNA) vaccines following infection with SARS-CoV-2 was associated with higher concentrations of NAb against omicron, albeit lower against wild type, compared with vaccine-only induced immunity following two doses of AZD1222 or BBV152 and 2–3 doses of mRNA.The main focus of this analysis was to evaluate the effect of SARS-CoV-2 infection before the first dose of AZD1222 on the post-vaccine antibody kinetics through to day 180. We report on the antibody kinetics of anti-S IgG, anti-receptor binding domain (anti-RBD) IgG, NAb against wild type, multiple VOCs (including omicron BA.1, BA.4) and SARS-CoV, and Fc effector function to wild-type and delta VOC.