RESUMO
BackgroundSARS-CoV-2 serology is used to identify prior infection at individual and at population level. Extended longitudinal studies with multi-timepoint sampling to evaluate dynamic changes in antibody levels are required to identify the time horizon in which these applications of serology are valid, and to explore the longevity of protective humoral immunity. MethodsHealth-care workers were recruited to a prospective cohort study from the first SARS-CoV-2 epidemic peak in London, undergoing weekly symptom screen, viral PCR and blood sampling over 16-21 weeks. Serological analysis (n=12,990) was performed using semi-quantitative Euroimmun IgG to viral spike S1 domain and Roche total antibody to viral nucleocapsid protein (NP) assays. Comparisons were made to previously reported pseudovirus neutralising antibody measurements. FindingsA total of 157/729 (21.5%) participants developed positive SARS-CoV-2 serology by one or other assay, of whom 31.0% were asymptomatic and there were no deaths. Peak Euroimmun anti-S1 and Roche anti-NP measurements correlated (r=0.57, p<0.0001) but only anti-S1 measurements correlated with near-contemporary pseudovirus neutralising antibody titres (measured at 16-18 weeks, r=0.57, p<0.0001). By 21 weeks follow-up, 31/143 (21.7%) anti-S1 and 6/150 (4.0%) anti-NP measurements reverted to negative. Mathematical modelling suggested faster clearance of anti-S1 compared to anti-NP (median half-life of 2.5 weeks versus 4.0 weeks), earlier transition to lower levels of antibody production (median of 8 versus 13 weeks), and greater reductions in relative antibody production rate after the transition (median of 35% versus 50%). InterpretationMild SARS-CoV-2 infection is associated with heterogenous serological responses in Euroimmun anti-S1 and Roche anti-NP assays. Anti-S1 responses showed faster rates of clearance, more rapid transition from high to low level production rate and greater reduction in production rate after this transition. The application of individual assays for diagnostic and epidemiological serology requires validation in time series analysis. FundingCharitable donations via Barts Charity Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed, medRxiv, and bioRxiv for ["antibody" OR "serology"] AND ["SARS-CoV-2" OR "COVID-19"]. The available literature highlights widespread use of serology to detect recent SARS-CoV-2 infection in individual patients and in population epidemiological surveys. Antibody to virus spike protein S1 domain is widely reported to correlate with neutralising antibody titres. The existing assays have good sensitivity to detect seroconversion within 14 days of incident infection, but the available longitudinal studies have reported variable rates of decline in antibody levels and reversion to undetectable levels in some people over 3 months. High frequency multi-time point serology data for different antibody targets or assays in longitudinal cohorts from the time of incident infection to greater than 3 months follow up are lacking. Added value of this studyWe combine detailed longitudinal serology using the Euroimmun anti-S1 and Roche anti-nucleocapsid protein (NP) assays in 731 health care workers from the time of the first SARS-CoV-2 epidemic peak in London, UK. In 157 seroconverters (using either assay) we show substantial heterogeneity in semiquantitative antibody measurements over time between individuals and between assays. Mathematical modelling of individual participant antibody production and clearance rates in individuals with at least 8 data points over 21 weeks showed anti-S1 antibodies to have a faster clearance rate, earlier transition from the initial antibody production rate to lower rates, and greater reduction in antibody production rate after this transition, compared to anti-NP antibodies as measured by these assays. As a result, Euroimmun anti-S1 measurements peaked earlier and then reduced more rapidly than Roche anti-NP measurements. In this study, these differences led to 21% anti-S1 sero-reversion, compared to 4% anti-NP sero-reversion over 4-5 months. Implications of all of the available evidenceThe rapid decline in anti-S1 antibodies measured by the Euroimmun assay following infection limits its application for diagnostic and epidemiological screening. If generalisable, these data are consistent with the hypothesis that anti-S1 mediated humoral immunity may not be sustained in some people beyond the initial post-infective period. Further work is required to understand the mechanisms behind the heterogeneity in antibody kinetics between individuals to SARS-CoV-2. Our data point to differential mechanisms regulating humoral immunity against these two viral targets.
RESUMO
Studies of adaptive immunity to SARS-CoV-2 include characterisation of lethal, severe and mild cases1-8. Understanding how long immunity lasts in people who have had mild or asymptomatic infection is crucial. Healthcare worker (HCW) cohorts exposed to and infected by SARS-CoV-2 during the early stages of the pandemic are an invaluable resource to study this question9-14. The UK COVIDsortium is a longitudinal, London hospital HCW cohort, followed from the time of UK lockdown9,10 ; weekly PCR, serology and symptom diaries allowed capture of asymptomatic infection around the time of onset, so duration of immunity could be tracked. Here, we conduct a cross-sectional, case-control, sub-study of 136 HCW at 16-18 weeks after UK lockdown, with 76 having had laboratory-confirmed SARS-CoV-2 mild or asymptomatic infection. Neutralising antibodies (nAb) were present in 90% of infected HCW sampled after the first wave; titres, likely to correlate with functional protection, were present in 66% at 16-18 weeks. T cell responses tended to be lower in asymptomatic infected HCW than those reporting case-definition symptoms of COVID-19, while nAb titres were maintained irrespective of symptoms. T cell and antibody responses were discordant. HCW lacking nAb also showed undetectable T cells to Spike protein but had T cells of other specificities. Our findings suggest that the majority of HCW with mild or asymptomatic SARS-CoV-2 infection carry nAb complemented by multi-specific T cell responses for at least 4 months after mild or asymptomatic SARS-CoV-2 infection.
