LAUSR

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-MN50), and compared and combined markers in multivariable analyses. LV-MN50 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. Description A single measurement of either binding or pseudovirus neutralizing antibodies is the best correlate of protection for the mRNA-1273 vaccine. Connecting correlates of protection Correlates of protection are immunological markers, such as quantity of antibodies, that associate with the level of vaccine protection. Identifying such correlates is important for measuring the performance of vaccines. Here, Benkeser et al. aimed to identify the best correlates of protection against COVID-19 in recipients of the mRNA-1273 vaccine. Using immune markers including live virus neutralizing antibody titers in samples from participants of the COVE mRNA-1273 vaccine efficacy trial, the authors found that a single pseudovirus neutralizing antibody titer or a single spike protein–binding antibody concentration was the best correlate of protection for the vaccine. Higher pseudovirus neutralizing antibody titers and higher spike protein–binding antibody concentrations associated with greater vaccine protection from COVID-19. Together, these data will help to guide future vaccine development and will aid in immunobridging studies. —CM