Comparing antibody assays as correlates of protection against COVID-19 in the COVE mRNA-1273 vaccine efficacy trial
David Benkeser, David C. Montefiori, Adrian B. McDermott, Youyi Fong, Holly Janes, Weiping Deng, Honghong Zhou, Christopher R. Houchens, Karen Martins, Lakshmi Jayashankar, Flora Castellino, Britta Flach, Bob C. Lin, Sarah O’Connell, Charlene McDanal, Amanda Eaton, Marcella Sarzotti‐Kelsoe, Yiwen Lu, Chenchen Yu, Bhavesh Borate, Lars W. P. van der Laan, Nima S. Hejazi, Avi Kenny, Marco Carone, Brian D. Williamson, Jennifer Garver, Erin Altonen, Thomas L. Rudge, Chuong Huynh, Jacqueline M. Miller, Hana M. El Sahly, Lindsey R. Baden, Sharon E. Frey, Elissa Malkin, Stephen A. Spector, Michele P. Andrasik, James G. Kublin, Lawrence Corey, Kathleen M. Neuzil, Lindsay N. Carpp, Rolando Pajón, Dean Follmann, Rubén O. Donis, Richard A. Koup, Peter B. Gilbert, on behalf of the Immune Assays, Coronavirus Vaccine Prevention Network (CoVPN)/Coronavirus Efficacy (COVE), United States Government (USG)/CoVPN Biostatistics Teams
Abstract
The best assay or marker to define mRNA-1273 vaccine–induced antibodies as a correlate of protection (CoP) is unclear. In the COVE trial, participants received two doses of the mRNA-1273 COVID-19 vaccine or placebo. We previously assessed IgG binding antibodies to the spike protein (spike IgG) or receptor binding domain (RBD IgG) and pseudovirus neutralizing antibody 50 or 80% inhibitory dilution titer measured on day 29 or day 57, as correlates of risk (CoRs) and CoPs against symptomatic COVID-19 over 4 months after dose. Here, we assessed a new marker, live virus 50% microneutralization titer (LV-MN 50 ), and compared and combined markers in multivariable analyses. LV-MN 50 was an inverse CoR, with a hazard ratio of 0.39 (95% confidence interval, 0.19 to 0.83) at day 29 and 0.51 (95% confidence interval, 0.25 to 1.04) at day 57 per 10-fold increase. In multivariable analyses, pseudovirus neutralization titers and anti-spike binding antibodies performed best as CoRs; combining antibody markers did not improve correlates. Pseudovirus neutralization titer was the strongest independent correlate in a multivariable model. Overall, these results supported pseudovirus neutralizing and binding antibody assays as CoRs and CoPs, with the live virus assay as a weaker correlate in this sample set. Day 29 markers performed as well as day 57 markers as CoPs, which could accelerate immunogenicity and immunobridging studies.