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Immune Correlates Analysis of the mRNA-1273 COVID-19 Vaccine Efficacy Trial
Peter B Gilbert1, David C Montefiori1, Adrian McDermott1
1Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA (P.B.G., Y.F., Y.L., C.Y., B.B., L.v.d.L., M.P.A., J.G.K., L.C., L.N.C.); the Vaccine Research Center (A.M., B.F., B.C.L., S.O., R.A.K.) and the Biostatistics Research Branch (D.F.), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; the Department of Surgery and Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC (C.M., A.E., M.S.-K., D.C.M.); the Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA (D.B.); the Biomedical Advanced Research and Development Authority, Washington, DC (C.R.H., K.M., L.J., F.C., C.H., R.O.D.); Graduate Group in Biostatistics, University of Berkeley, Berkeley, CA (N.H.); Moderna, Inc., Cambridge, MA (W.D., H.Z., J.M., R.P.); Baylor College of Medicine, Houston, TX (H.M.E.S.); Brigham and Women's Hospital, Boston, MA (L.R.B.); Palm Beach Research Center, West Palm Beach, FL (M.B.); Keystone Vitalink Research, Greenville, SC (L.D.L.C.); University of North Carolina, Chapel Hill, NC (C.G.); Vanderbilt University Medical Center, Nashville, TN (S.K.); Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine and the Grady Health System, Atlanta, GA (C.F.K.); Suncoast Research Group, Miami, FL (M.K.); and the Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD (K.M.N.).
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.
