Immune correlates analysis of the mRNA-1273 COVID-19 vaccine efficacy clinical trial

Abstract

In the coronavirus efficacy (COVE) phase 3 clinical trial, vaccine recipients were assessed for neutralizing and binding antibodies as correlates of risk for COVID-19 disease and as correlates of protection. These immune markers were measured at the time of second vaccination and 4 weeks later, with values reported in standardized World Health Organization international units. All markers were inversely associated with COVID-19 risk and directly associated with vaccine efficacy. Vaccine recipients with postvaccination 50% neutralization titers 10, 100, and 1000 had estimated vaccine efficacies of 78% (95% confidence interval, 54 to 89%), 91% (87 to 94%), and 96% (94 to 98%), respectively. These results help define immune marker correlates of protection and may guide approval decisions for messenger RNA (mRNA) COVID-19 vaccines and other COVID-19 vaccines.

Fig. 1.. Anti-spike IgG concentration and pseudovirus neutralization ID₅₀ titer by COVID-19 outcome status.

(A) Anti-spike IgG concentration. (B) Pseudovirus neutralization ID50 titer. Data points are from baseline-negative per-protocol vaccine recipients in the day 29 marker or day 57 marker case-cohort set. The violin plots contain interior box plots with upper and lower horizontal edges representing the 25th and 75th percentiles of antibody level and middle line representing the 50th percentile. The vertical bars represent the distance from the 25th (or 75th) percentile of antibody level and the minimum (or maximum) antibody level within the 25th (or 75th) percentile of antibody level minus (or plus) 1.5 times the interquartile range. Each side shows a rotated probability density (estimated by a kernel density estimator with a default Gaussian kernel) of the data. Positive response rates were computed with inverse probability of sampling weighting. Pos.Cut, positivity cut-off; LoD, limit of detection; ULoQ, upper limit of quantitation. ULOQ = 10,919 for ID₅₀ (above all data points). Positive response for spike IgG was defined by IgG > 10.8424 BAU/ml. Positive response for ID₅₀ was defined by value > LOD (2.42). Post–day 57 cases are COVID-19 end points starting 7 days after day 57 through the end of the blinded follow-up (last COVID-19 end point was 126 days after dose 2); intercurrent cases are COVID-19 end points starting 7 days after day 29 through 6 days after day 57.

Fig. 2.. COVID-19 risk by antibody marker level.

The plots and table show covariate-adjusted cumulative incidence of COVID-19 by low, medium, and high tertiles of day 57 IgG concentration or pseudovirus neutralization titer in baseline SARS-CoV-2–negative per-protocol participants. (A) Anti-spike IgG concentration. (B) ID₅₀ titer. (C) IgG (spike and RBD) and pseudovirus neutralization titer (ID₅₀ and ID₈₀). The overall P value is from a generalized Wald test of whether the hazard rate of COVID-19 differed across the low, medium, and high subgroups. Baseline covariates are adjusted for baseline risk score, at risk status, and community of color status. Pt. Est., point estimate; FDR, false discovery rate; FWER, family-wise error rate.

Fig. 3.. Hazard ratio of COVID-19 as antibody marker level increases.

The table and plots show covariate-adjusted hazard ratios of COVID-19 per 10-fold increase in each day 57 antibody marker in baseline-negative per-protocol vaccine recipients overall and in subgroups. (A) Inferences for IgG (spike and RBD) and pseudovirus neutralization titer (ID₅₀ and ID₈₀). (B) Forest plots for spike IgG. (C) Forest plots for ID₅₀. Baseline covariates are adjusted for baseline risk score, at risk status, and community (Comm.) of color status.

Fig. 4.. Further analyses of day 57 ID₅₀ level as a correlate of risk and as a correlate of protection.

(A) Covariate-adjusted cumulative incidence of COVID-19 by 100 days after day 57 by vaccinated baseline SARS-CoV-2–negative per-protocol subgroups defined by day 57 ID₅₀ level above a threshold, with reverse cumulative distribution function (CDF) of day 57 ID₅₀ level overlaid in green. The red dots are point estimates at 35 threshold values equally spaced over quantiles of the observed marker values, linearly interpolated by solid black lines. The gray shaded area is pointwise 95% CIs. The upper boundary of the green shaded area is the estimate of the reverse CDF of day 57 ID₅₀ level in baseline SARS-CoV-2–negative per-protocol vaccine recipients. The vertical red dashed line is the day 57 ID₅₀ threshold above which no post–day 57 COVID-19 end points occurred. (B) Covariate-adjusted cumulative incidence of COVID-19 by 100 days after day 57 by day 57 ID₅₀ level. The dotted black lines indicate bootstrap pointwise 95% CIs. The upper and lower horizontal gray lines are the overall cumulative incidence of COVID-19 from 7 to 100 days after day 57 in placebo and vaccine recipients, respectively. (C) Vaccine efficacy (VE) (solid black line) by day 57 ID₅₀ level, estimated using the method of Gilbert, Fong, and Carone (28). The dashed black lines indicate bootstrap pointwise 95% CIs. The horizontal gray line is the overall vaccine efficacy from 7 to 100 days after day 57, with the dotted gray lines indicating the 95% CIs [this number, 92.8%, differs from the 94.1% reported in (6), which was based on counting COVID-19 end points starting 14 days after day 29]. In (B) and (C), the green histograms are an estimate of the density of day 57 ID₅₀ level in baseline-negative per-protocol vaccine recipients. Baseline covariates are adjusted for baseline risk score, at risk status, and community of color status.