Predictive models of immune protection from COVID-19 are urgently needed to identify correlates of protection to assist in the future deployment of vaccines. To address this, we analyzed the relationship between in vitro neutralization levels and the observed protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using data from seven current vaccines and from convalescent cohorts. We estimated the neutralization level for 50% protection against detectable SARS-CoV-2 infection to be 20.2% of the mean convalescent level (95% confidence interval (CI) = 14.4-28.4%). The estimated neutralization level required for 50% protection from severe infection was significantly lower (3% of the mean convalescent level; 95% CI = 0.7-13%, P = 0.0004). Modeling of the decay of the neutralization titer over the first 250 d after immunization predicts that a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained. Neutralization titers against some SARS-CoV-2 variants of concern are reduced compared with the vaccine strain, and our model predicts the relationship between neutralization and efficacy against viral variants. Here, we show that neutralization level is highly predictive of immune protection, and provide an evidence-based model of SARS-CoV-2 immune protection that will assist in developing vaccine strategies to control the future trajectory of the pandemic.

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The coronavirus disease 2019 (COVID-19) pandemic has resulted in significant morbidity and mortality worldwide. Community-level immunity, acquired through infection or vaccination, is necessary to control the pandemic as the virus continues to circulate (1). mRNA vaccines encoding a stabilized version of the full-length SARS-CoV-2 Spike protein have been widely administered and clinical trial data demonstrated up to 95% efficacy in preventing symptomatic COVID-19 (2, 3). These mRNA vaccines induce potent humoral immune responses, with neutralizing antibody titers proposed as the major correlate of protection (4-6). Current evidence suggests that circulating antibodies persist for at least 6 months post-vaccination (7), though there is some decay from peak levels achieved after the second dose. This decline from peak antibody levels may be associated with an increase in infections over time compared to the initial months post-vaccination (8, 9). Yet, vaccine-induced immunity remains highly effective at preventing severe disease, hospitalization, and death even at later timepoints when antibody levels may decline (10)(11)(12).Previous research has largely focused on responses early in the course of vaccination, with transcriptional analysis identifying potential links between myeloid cell responses and neutralizing antibodies (13).

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The durability of infection-induced SARS-CoV-2 immunity has major implications for reinfection and vaccine development. Here, we show a comprehensive profile of antibody, B cell and T cell dynamics over time in a cohort of patients who have recovered from mild-moderate COVID-19. Binding and neutralising antibody responses, together with individual serum clonotypes, decay over the first 4 months post-infection. A similar decline in Spike-specific CD4+ and circulating T follicular helper frequencies occurs. By contrast, S-specific IgG+ memory B cells consistently accumulate over time, eventually comprising a substantial fraction of circulating the memory B cell pool. Modelling of the concomitant immune kinetics predicts maintenance of serological neutralising activity above a titre of 1:40 in 50% of convalescent participants to 74 days, although there is probably additive protection from B cell and T cell immunity. This study indicates that SARS-CoV-2 immunity after infection might be transiently protective at a population level. Therefore, SARS-CoV-2 vaccines might require greater immunogenicity and durability than natural infection to drive long-term protection.