Immune Correlates Analysis of the mRNA-1273 COVID-19 Vaccine Efficacy Trial

Abstract

Background: In the Coronavirus Efficacy (COVE) trial, estimated mRNA-1273 vaccine efficacy against coronavirus disease-19 (COVID-19) was 94%. SARS-CoV-2 antibody measurements were assessed as correlates of COVID-19 risk and as correlates of protection.

Methods: Through case-cohort sampling, participants were selected for measurement of four serum antibody markers at Day 1 (first dose), Day 29 (second dose), and Day 57: IgG binding antibodies (bAbs) to Spike, bAbs to Spike receptor-binding domain (RBD), and 50% and 80% inhibitory dilution pseudovirus neutralizing antibody titers calibrated to the WHO International Standard (cID50 and cID80). Participants with no evidence of previous SARS-CoV-2 infection were included. Cox regression assessed in vaccine recipients the association of each Day 29 or 57 serologic marker with COVID-19 through 126 or 100 days of follow-up, respectively, adjusting for risk factors.

Results: Day 57 Spike IgG, RBD IgG, cID50, and cID80 neutralization levels were each inversely correlated with risk of COVID-19: hazard ratios 0.66 (95% CI 0.50, 0.88; p=0.005); 0.57 (0.40, 0.82; p=0.002); 0.42 (0.27, 0.65; p<0.001); 0.35 (0.20, 0.61; p<0.001) per 10-fold increase in marker level, respectively, multiplicity adjusted P-values 0.003-0.010. Results were similar for Day 29 markers (multiplicity adjusted P-values <0.001-0.003). For vaccine recipients with Day 57 reciprocal cID50 neutralization titers that were undetectable (<2.42), 100, or 1000, respectively, cumulative incidence of COVID-19 through 100 days post Day 57 was 0.030 (0.010, 0.093), 0.0056 (0.0039, 0.0080), and 0.0023 (0.0013, 0.0036). For vaccine recipients at these titer levels, respectively, vaccine efficacy was 50.8% (-51.2, 83.0%), 90.7% (86.7, 93.6%), and 96.1% (94.0, 97.8%). Causal mediation analysis estimated that the proportion of vaccine efficacy mediated through Day 29 cID50 titer was 68.5% (58.5, 78.4%).

Conclusions: Binding and neutralizing antibodies correlated with COVID-19 risk and vaccine efficacy and likely have utility in predicting mRNA-1273 vaccine efficacy against COVID-19.

Trial registration number: COVE ClinicalTrials.gov number, NCT04470427.

Figure 1:

(A) Anti-Spike IgG concentration and (B) pseudovirus neutralization cID50 titer by COVID-19 outcome status. Data points are from baseline negative per-protocol vaccine recipients selected into the case-cohort set. The violin plots contain interior box plots with upper and lower horizontal edges the 25^th and 75^th percentiles of antibody level and middle line the 50^th percentile. 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 cID50 (above all data points). Post Day 57 cases are COVID-19 endpoints starting 7 days post Day 57 visit; Intercurrent cases are COVID-19 endpoints starting 7 days post Day 29 visit through 6 days post Day 57 visit. cID50: ID50 nAb titer calibrated to the WHO International Standard.

Figure 2.

Covariate-adjusted cumulative incidence of COVID-19 by Low, Medium, High tertile of Day 57 IgG concentration or pseudovirus neutralization titer. (A) Anti-Spike IgG concentration; (B) cID50 titer; (C) IgG (Spike, RBD) and (cID50, cID80). 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. cID50, cID80: ID50 or ID80 nAb titer calibrated to the WHO International Standard.

Figure 3.

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, RBD) and (cID50, cID80); (B) Forest plots for Spike IgG; (C) Forest plots for cID50. cID50, cID80: ID50 or ID80 neutralizing antibody titer calibrated to the WHO International Standard. Comm. of color = all participants other than White Non-Hispanic.

Figure 4.

(A) Covariate-adjusted cumulative incidence of COVID-19 by 100 days post Day 57 by subgroups defined by Day 57 cID50 level above a threshold, with reverse cumulative distribution function of Day 57 cID50 level overlaid in green. The gray shaded area is pointwise 95% confidence intervals (CIs). The upper boundary of the green shaded area is the estimate of the reverse cumulative distribution function (CDF) of the marker in baseline SARS-CoV-2 negative per-protocol vaccine recipients. (B) Covariate-adjusted cumulative incidence of COVID-19 by 100 days post Day 57 by Day 57 cID50 level. The dotted lines indicate bootstrap point-wise 95% CIs. (C) Vaccine efficacy by Day 57 cID50 level, estimated using the method of Gilbert, Fong, and Carone. The dashed lines indicate bootstrap point-wise 95% CIs. In (B) and (C), covariate adjustment was based on an inverse probability samplingweighted Cox model; the green histograms are an estimate of the density of Day 57 cID50 level in baseline negative per-protocol vaccine recipients. LOD, limit of detection. cID50: ID50 nAb titer calibrated to the WHO International Standard.