Evolution of antibody immunity to SARS-CoV-2

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected 78 million individuals and is responsible for over 1.7 million deaths to date. Infection is associated with the development of variable levels of antibodies with neutralizing activity, which can protect against infection in animal models 1,2. Antibody levels decrease with time, but, to our knowledge, the nature and quality of the memory B cells that would be required to produce antibodies upon reinfection has not been examined. Here we report on the humoral memory response in a cohort of 87 individuals assessed at 1.3 and 6.2 months after infection with SARS-CoV-2. We find that titres of IgM and IgG antibodies against the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 decrease significantly over this time period, with IgA being less affected. Concurrently, neutralizing activity in plasma decreases by fivefold in pseudotype virus assays. By contrast, the number of RBD-specific memory B cells remains unchanged at 6.2 months after infection. Memory B cells display clonal turnover after 6.2 months, and the antibodies that they express have greater somatic hypermutation, resistance to RBD mutations and increased potency, indicative of continued evolution of the humoral response. Immunofluorescence and PCR analyses of intestinal biopsies obtained from asymptomatic individuals at 4 months after the onset of coronavirus disease 2019 (COVID-19) revealed the persistence of SARS-CoV-2 nucleic acids and immunoreactivity in the small bowel of 7 out of 14 individuals. We conclude that the memory B cell response to SARS-CoV-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence. Antibody responses to SARS-CoV-2 were initially characterized in a cohort of individuals convalescing from COVID-19 at approximately 40 days (1.3 months) after infection 1. Between 31 August and 16 October 2020, 100 participants returned for a 6-month follow-up study visit. Although the initial criteria allowed enrolment of the close contacts of individuals with SARS-CoV-2 infection confirmed by reverse-transcription PCR (RT-PCR) 1 , 13 of the contacts did not seroconvert and were excluded from further analyses. The remaining 87 participants with RT-PCR-confirmed SARS-CoV-2 infection and/ or seroconversion returned for analysis at approximately 191 days (6.2 months; range of 165 to 223 days) after the onset of symptoms. In this cohort, symptoms lasted for a median of 12 days (range of 0 to 44 days) during the acute phase, and 10 (11%) of the participants were hospitalized. Consistent with other reports 3,4 , 38 (44%) of the participants reported persistent long-term symptoms attributable to COVID-19 (Methods, Supplementary Tables 1, 2). The duration and severity of symptoms during acute disease was significantly greater among participants with persistent post-acute symptoms at the second study visit (Extended Data Fig. 1m-q). Importantly, all 87 participants tested negative for SARS-CoV-2 at the 6-month follow...

mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants

“…In anti-RBD ELISAs the mean half-maximal effective concentration (EC50) was higher than that observed in infected individuals after 6.2 months but not significantly different from antibodies obtained 1.3 months after infection (Extended Data Fig. 6a, and Table 5 and 7,8 ). To examine memory B cell antibodies for binding to circulating SARS-CoV-2 variants and antibody resistant mutants we performed ELISAs using mutant RBDs 12,15,[28][29][30][31] .…”

“…In addition, antibodies that share the same combination of IGHV and IGLV genes in vaccinees comprised 39% of all the clonal sequences (Extended Data Fig. 4b) and 59% when combined with naturally infected individuals 7,8 (Fig. 2f), and some of these antibodies were nearly identical (Extended Data Table 3 and 4).…”

“…Although circulating antibodies derived from plasma cells wane over time, long-lived immune memory can persist in expanded clones of memory B cells 7,20 . We used flow cytometry to enumerate the circulating SARS-CoV-2 RBD-specific memory B cells elicited by mRNA immunization 7,8 (Fig. 2a, Extended Data Fig.…”

“…6d-n and Table 5). SARS-CoV-2 S pseudotyped viruses were used to measure the neutralizing activity of all 127 antibodies 7,8,10 (Fig. 3a, Extended Data Table 5).…”

SARS-CoV-2 binding and neutralizing antibody levels after vaccination with Ad26.COV2.S predict durable protection in rhesus macaques

“…It is conceivable that this would translate into durable protection against COVID-19 in vaccinated humans, where protection may be even more durable as infection with SARS-CoV-2 is likely to trigger an anamnestic response. 17 Due to the incubation time between infection and development of symptoms, humans may indeed benefit from an anamnestic response while this will have no added value in our macaque infection model due to the relatively high challenge virus inoculum, and rapid clearance of the virus. In macaques, durable protection could be predicted based on humoral immune response levels.…”