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

Gilbert, Peter B.; Montefiori, David C.; McDermott, Adrian; Fong, Youyi; Benkeser, David; Deng, Weiping; Zhou, Honghong; Houchens, Christopher R.; Martins, Karen; Jayashankar, Lakshmi; Castellino, Flora; Flach, Britta; Lin, Bob C.; O’Connell, Sarah; McDanal, Charlene; Eaton, Amanda; Sarzotti-Kelsoe, Marcella; Lu, Yiwen; Yu, Chenchen; Borate, Bhavesh; van der Laan, Lars W. P.; Hejazi, Nima; Huynh, Chuong; Miller, Jacqueline; El Sahly, Hana M.; Baden, Lindsey R.; Baron, Mira; De La Cruz, Luis; Gay, Cynthia; Kalams, Spyros; Kelley, Colleen F.; Kutner, Mark; Andrasik, Michele P.; Kublin, James G.; Corey, Lawrence; Neuzil, Kathleen M.; Carpp, Lindsay N.; Pajon, Rolando; Follmann, Dean; Donis, Ruben O.; Koup, Richard A.

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