Dynamics and significance of the antibody response to SARS-CoV-2 infection

Abstract

Background: Characterizing the humoral immune response to SARS-CoV-2 and developing accurate serologic assays are needed for diagnostic purposes and estimating population-level seroprevalence.

Methods: We measured the kinetics of early antibody responses to the receptor-binding domain (RBD) of the spike (S) protein of SARS-CoV-2 in a cohort of 259 symptomatic North American patients infected with SARS-CoV-2 (up to 75 days after symptom onset) compared to antibody levels in 1548 individuals whose blood samples were obtained prior to the pandemic.

Results: Between 14-28 days from onset of symptoms, IgG, IgA, or IgM antibody responses to RBD were all accurate in identifying recently infected individuals, with 100% specificity and a sensitivity of 97%, 91%, and 81% respectively. Although the estimated median time to becoming seropositive was similar across isotypes, IgA and IgM antibodies against RBD were short-lived with most individuals estimated to become seronegative again by 51 and 47 days after symptom onset, respectively. IgG antibodies against RBD lasted longer and persisted through 75 days post-symptoms. IgG antibodies to SARS-CoV-2 RBD were highly correlated with neutralizing antibodies targeting the S protein. No cross-reactivity of the SARS-CoV-2 RBD-targeted antibodies was observed with several known circulating coronaviruses, HKU1, OC 229 E, OC43, and NL63.

Conclusions: Among symptomatic SARS-CoV-2 cases, RBD-targeted antibodies can be indicative of previous and recent infection. IgG antibodies are correlated with neutralizing antibodies and are possibly a correlate of protective immunity.

Figures

Figure 1.. Measurements of IgG, IgM, and IgA against SARS-CoV-2 spike protein receptor binding domain among pre-pandemic controls and PCR positive cases.

Each dot represents a unique measurement of an isotype (Row A: IgG, Row B: IgM, Row C: IgA) in pre-pandemic controls (left panels) and PCR positive cases (right panels). The blue line is a loess smooth non-parametric function. Black dashed lines indicate the maximum concentration (μg/mL) found among pre-pandemic controls (IgG: 0.57, IgM: 2.63, IgA: 2.02). Horizontal jitter was introduced into the pre-pandemic controls. The limit of detection (μg/mL) was 0.04 for IgG, 0.28 for IgM, and 0.3 for IgA.

Figure 2.. Parametric and non-parametric model estimates of time to seroconversion and seroreversion for each isotype.

A) The isotype cut-offs chosen for seroconversion were the maximum concentration (μg/mL) found among pre-pandemic controls (IgG: 0.57, IgM: 2.63, IgA: 2.02). The solid line represents the estimated cumulative distribution function of the time to seroconversion or reversion with 100 bootstrapped fits shown as transparent lines. The parametric accelerated failure time models assume a Weibull time-to-event distribution. Non-parametric estimates shown in grey were calculated using the Turnbull method. Only 1 individual seroreverted for IgG, so no model is included. B) The table indicates the estimated average number of days since onset of symptoms it takes for a percentage of cases to seroconvert or serorevert. Bootstrap 95% confidence intervals are shown in parentheses.

Figure 3.. SARS-CoV-2 pseudovirus neutralization antibody titers in symptomatic PCR positive cases and correlation with anti-RBD IgG responses.

A) Each point represents a measurement of 50% neutralizing titer (NT50). Lines connect measurements from the same individual and a loess smooth function is shown in blue. B) The overall repeated measures correlation coefficient (r) is shown. Lines represent simple linear models for each time period.