Extended Data Fig. 8: Analyses of spike IgG and receptor binding domain (RBD) IgG as correlates of risk and as correlates of protection.

Analyses were performed in baseline SARS-CoV-2 seronegative per-protocol vaccine recipients. A, B) Covariate-adjusted cumulative incidence of COVID-19 by 54 days post D29 by vaccinated baseline SARS-CoV-2 seronegative per-protocol subgroups defined by D29 (A) anti-spike IgG or (B) anti-RBD IgG concentration above a threshold, with reverse cumulative distribution function (CDF) of D29 marker level overlaid in green. The blue dots are point estimates at each COVID-19 primary endpoint linearly interpolated by solid black lines; the gray shaded area is pointwise 95% confidence intervals (CIs). The estimates and CIs were adjusted using the assumption that the true threshold-response is nonincreasing. The upper boundary of the green shaded area is the estimate of the reverse cumulative distribution function (CDF) of D29 marker level in baseline SARS-CoV-2 seronegative per-protocol vaccine recipients. The vertical red dashed line is the D29 marker threshold above which no COVID-19 endpoints were observed (in the time frame of 1 through 54 days post D29). C, D) Covariate-adjusted cumulative incidence of COVID-19 by 54 days post D29 by D29 (C) anti-spike IgG or (D) anti-RBD IgG concentration, estimated using (solid purple line) a Cox model or (solid blue line) a nonparametric method. Each point on the curve represents the covariate-adjusted cumulative COVID-19 incidence at the given D29 ID50 titer value. The dotted black lines indicate bootstrap point-wise 95% CIs. The upper and lower horizontal gray lines are the overall cumulative incidence of COVID-19 from 1 to 54 days post D29 in placebo and vaccine recipients, respectively. E, F) Vaccine efficacy (solid purple line) by D29 (E) anti-spike IgG or (F) anti-RBD IgG concentration, estimated using a Cox proportional hazards implementation of Gilbert et al⁴⁴. Each point on the curve represents the vaccine efficacy at the given D29 ID50 titer value. The dashed black lines indicate bootstrap point-wise 95% CIs. Vaccine efficacy (solid blue line) by D29 (E) anti-spike IgG concentration or (F) anti-RBD IgG concentration, estimated using a nonparametric implementation of Gilbert et al.⁴⁴ (see SAP). Each point on the curve represents the vaccine efficacy at the given D29 ID50 titer value. The blue shaded area represents the 95% CIs. In C-F, curves are plotted over the range from Positivity Cut-off/2 to the 97.5th percentile = (C, E) 238 BAU/ml for Spike IgG or (D, F) 173 BAU/ml for RBD IgG; In C-F, the green histogram is an estimate of the density of D29 marker and the horizontal gray line is the overall vaccine efficacy from 1 to 54 days post D29, with the dotted gray lines indicating the 95% CIs. Baseline covariates adjusted for were baseline risk score and geographic region.

Source data