1. Introduction
RBD
CORONAVIRUS, GILBERT
Current address: Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37203, USA.Current address: Sanofi Vaccines R&D, 1541 Avenue Marcel Mérieux, 69280 Marcy l’Etoile, France.The Members of the Immune Assays; Moderna, Inc.; CoVPN/COVE; and USG/CoVPN Biostatistics Teams are listed in the The COVE trial randomized participants to receive two doses of mRNA-1273 vaccine or placebo on Days 1 and 29 (D1, D29). Anti-SARS-CoV-2 Spike IgG binding antibodies (bAbs), anti-receptor binding domain IgG bAbs, 50% inhibitory dilution neutralizing antibody (nAb) titers, and 80% inhibitory dilution nAb titers were measured at D29 and D57. We assessed these markers as correlates of protection (CoPs) against COVID-19 using stochastic interventional vaccine efficacy (SVE) analysis and principal surrogate (PS) analysis, frameworks not used in our previous COVE immune correlates analyses. By SVE analysis, hypothetical shifts of the D57 Spike IgG distribution from a geometric mean concentration (GMC) of 2737 binding antibody units (BAU)/mL (estimated vaccine efficacy (VE): 92.9% (95% CI: 91.7%, 93.9%)) to 274 BAU/mL or to 27,368 BAU/mL resulted in an overall estimated VE of 84.2% (79.0%, 88.1%) and 97.6% (97.4%, 97.7%), respectively. By binary marker PS analysis of Low and High subgroups (cut-point: 2094 BAU/mL), the ignorance interval (IGI) and estimated uncertainty interval (EUI) for VE were [85%, 90%] and (78%, 93%) for Low compared to [95%, 96%] and (92%, 97%) for High. By continuous marker PS analysis, the IGI and 95% EUI for VE at the 2.5th percentile (519.4 BAU/mL) vs. at the 97.5th percentile (9262.9 BAU/mL) of D57 Spike IgG concentration were [92.6%, 93.4%] and (89.2%, 95.7%) vs. [94.3%, 94.6%] and (89.7%, 97.0%). Results were similar for other D29 and D57 markers. Thus, the SVE and PS analyses additionally support all four markers at both time points as CoPs. In the coronavirus efficacy (COVE) phase 3 clinical trial of the mRNA-1273 COVID-19 vaccine, participants were randomized 1:1 to receive mRNA-1273 vaccine (In Gilbert et al. [Here, we report the results from additional CoP analyses of the COVE trial, completing the suite of pre-specified blinded-phase immune correlates analyses of the D29 and D57 antibody markers and COVID-19. Specifically, we evaluated each of the four markers, Spike IgG, RBD IgG, nAb-ID50, and nAb-ID80, measured at D29 or D57, as a CoP against COVID-19 defined using two additional causal inference frameworks for CoP assessment as specified in the master protocol SAP: the stochastic interventional vaccine efficacy (SVE) framework and principal surrogate (PS) framework (within the principal stratification framework of causal inference [