Evolution of immune responses to SARS-CoV-2 in mild-moderate COVID-19

Abstract

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.

Decay of Fc-dependent antibody functions after mild to moderate COVID-19

“…antibodies against S and RBD for the lower affinity polymorphisms of FcgRIIIa (F158) and FcgRIIa (R131) were broadly similar to their higher affinity counterparts (Figure S1A), with dimeric FcgR-binding antibodies against RBD decaying faster than for S. Consistent with our previous report that S1-specific IgG decays faster than S2-specific IgG, 8 FcgR binding activity with antibodies against the S1 subunit decayed faster than that of S2 (FcgRIIIa, t 1/2 of 84 versus 227 days; FcgRIIa, t 1/2 of 65 versus 317 days; Figure S1B).…”

“…7 However, the duration of protection from re-infection in humans conferred by neutralizing antibodies is not known. Several studies now show neutralizing antibodies decline rapidly during early convalescence, 2,8,9 with the magnitude of the antibody response positively correlating with disease severity. 10,11 Following mild COVID-19, many subjects mount modest neutralizing antibody responses that decline to undetectable levels within 60 days, despite the maintenance of S-and RBD-specific immunoglobulin G (IgG) binding antibodies.…”

“…Importantly, two recent challenge studies demonstrated that certain RBD-specific mAbs rely on Fc effector functions to mediate protection against SARS-CoV-2 in mice. 17,18 We previously reported that binding antibodies to SARS-CoV-2 S exhibit substantially longer half-lives than the neutralizing antibody response, 8 suggesting that Fc-mediated antibody function may extend the protective window beyond that inferred from neutralizing activity alone. At present, analyses of Fc-mediated functions of SARS-CoV-2 antibodies within COVID-19 convalescent subjects have focused upon cross-sectional analyses or short-term longitudinal studies up to 1 to 2 months post-symptom onset.…”

Divergent trajectories of antiviral memory after SARS-Cov-2 infection

“…However, since the magnitude of T and B cell responses correlate with each other 11 , dissecting the role of these immune subsets in protection from re-infection or severe disease on re-exposure is challenging. Several groups have now reported that SARS-CoV-2 specific T and B cells decline after acute disease 12,13,14,15,16 , but there is high heterogeneity between individuals in the levels of measurable immunity in different compartments it is unclear how or if the kinetics of this decline correlate with protection from subsequent infection. Concerns have been raised that SARS-CoV-2 re-infection associated with waning immunity is plausible, particularly since the seasonal coronaviruses, closely related to SARS-CoV-2, commonly re-infect the same host 17,18 .…”

Understanding the Challenges and Uncertainties of Seroprevalence Studies for SARS-CoV-2

“…Indeed, as vaccinated individuals should also have detectable antibody levels, seroprevalence can provide a snapshot of the extent of COVID-19 immunity in the population at a given point in time, arising either from vaccination or from past infection [ 31 ]. While public health authorities will likely have reliable estimates of vaccine coverage in the population, there are concerns about infection- and vaccine-induced protection from COVID-19 declining over time [ 32 , 33 ], or about the prevalence of vaccine “nonresponders” who do not develop antibodies. As such, vaccine coverage in the population may not provide sufficient information about population immunity for public health authorities: carrying out routine serosurveillance in this setting could potentially address this gap.…”