Discussion
infection, SARS-CoV-2 infection, infected by SARS-CoV-2 compared, SARS-CoV-2 infections
VIRUS, SARS-COV-2 INFECTION, ASYMPTOMATIC COVID-19, INFECTION, INFECTION INDUCED
The findings of our study show that SARS-CoV-2 infections, before vaccination primed the immune system for a more robust humoral immune response to the AZD1222 primary series compared with individuals who were SARS-CoV-2 naive when vaccinated. Similar observations were reported by other studies on AZD1222 vaccine as an effective booster after initial priming with SARS-CoV-2 infection.Furthermore, a second dose of AZD1222 within 4 weeks of the first dose in individuals who were baseline seropositive, did not result in a further increase in anti-S IgG, anti-RBD IgG, Nab, or ADCC. In contrast there were substantial increases in antibody concentrations following the second dose of AZD1222 in individuals who were seronegative at baseline. Similar observations were reported by others after the primary series for AZD1222 for anti-S and NAb to wild type virus,The baseline anti-N IgG seropositive compared with seronegative AZD1222 recipients maintained higher concentrations of anti-S and anti-RBD IgG through to day 180. Also, a greater percentage of vaccine recipients with hybrid immunity had NAb above the PRRT against symptomatic COVID-19 due to D614G, beta, A.VOI.V2, and gamma through to day 180. Although a higher percentage of the seropositive group compared with the seronegative group also had NAb titres above the PRRT against symptomatic COVID-19 due to delta (92·0% The higher potential vaccine effectiveness even against variants showing relative resistance to NAb activity imputed from our analysis, is corroborated from real world vaccine effectiveness in which hybrid immunity with mRNA vaccines had higher vaccine effectiveness against BA.1 and BA.2 infection (52–57%) compared with only two doses of mRNA vaccine induced immunity.We previously reported from the same study the lack of vaccine efficacy against mild–moderate symptomatic COVID-19 due to the beta variant (vaccine efficacy 10%; 95% CI −79 to 55%) in individuals who were anti-N IgG seronegative at enrolment. The lack of AZD1222 vaccine effectiveness against beta is consistent with our observation that none of the baseline seronegative group had NAb above the PRRT against beta variant symptomatic COVID-19 at day 42. In contrast, the percentage with NAb above the PRRT in the seropositive group was 71·7% at day 28 and remained high through to day 180 (51·9%). This illustrates the need for exercising caution in extrapolating from studies done early on in the pandemic when a lower percentage of the populations were infected by SARS-CoV-2 compared with the present when the population is broadly SARS-CoV-2 experienced.Notably, most individuals with hybrid immunity (92% at day 28 and day 42) had NAb against delta titres above the PRRT compared with only 9% of those with vaccine-only induced immunity. The final analysis of study recorded vaccine efficacy of 77·1% (95% CI 30·4–94·4) against the delta variant, with the cases having accrued 9–10 months after the second dose of AZD1222, independent of baseline anti-N IgG serostatus; and vaccine efficacy against wild-type virus was 91% (35–100).We had unmasked the study and offered dosing of the placebo group and a third dose to the vaccinated group before the onset of the omicron dominant wave. Consequently, we cannot extrapolate whether the high percentage of individuals with hybrid immunity who had NAb above the PRRT against BA.1 at day 42 (84%) translated into vaccine effectiveness against mild–moderate COVID-19 due to omicron BA.1. Notably, 70% of COVID-19 unvaccinated adults in Gauteng Province (South Africa), where most sites involved in this study were based, were seropositive before the omicron dominant wave in South Africa.Limitations of our study include that we focused only on vaccine and infection induced binding and NAb responses, which are important contributors to protecting against SARS-CoV-2 infection and mild-moderate COVID.Overall, these data indicate that vaccine effectiveness against symptomatic COVID-19 is likely to differ at an individual and population level depending on previous SARS-CoV-2 infection. Also, the low boost in antibody responses following a second dose of a vaccine in previously infected individuals suggests a low value at the population level (excluding immunocompromised individuals) of a second dose of vaccine 4 weeks later in settings where there has been a high rate of past SARS-CoV-2 infections. It is, however, possible that a longer interval between the first two doses could confer benefit in individuals with past SARS-CoV-2 infection. This is pertinent in many low-income African countries where COVID-19 vaccine rollout is still lagging, but 79% of the population had been infected with SARS-CoV-2 by mid-November, 2021, before the circulation of the highly transmissible omicron variant.