Immune correlates analysis in NextCOVE trial for a next-generation mRNA-1283 COVID-19 vaccine.

SARS-CoV-2 neutralizing antibodies (nAbs) are strongly inversely associated with COVID-19 risk and have correlated with vaccine efficacy across multiple clinical trials conducted during the COVID-19 pandemic. As SARS-CoV-2 continues to evolve in the endemic era, it is important to determine whether nAb levels remain a valid statistical correlate of protection and potential surrogate endpoints for emerging variants. The next-generation COVID-19 vaccine, mRNA-1283, has recently received regulatory approval worldwide. In the Phase 3 NextCOVE trial (NCT05815498), which enrolled more than 10,000 participants aged ≥12 y, mRNA-1283 (10 µg; bivalent ancestral plus Omicron BA.4/BA.5) met the non-inferiority criterion for relative vaccine efficacy (rVE) versus mRNA-1273 (50 µg; bivalent) and elicited higher nAb responses. In this correlate analysis of the NextCOVE trial, we evaluated Day 29 nAbs against ancestral D614G, BA.4/BA.5, and XBB.1.5 variants as correlates of risk (CoRs) and correlates of protection (CoPs) for COVID-19 after vaccination with mRNA-1283 or mRNA-1273. Across multiple statistical frameworks, higher Day 29 nAb levels were consistently associated with lower COVID-19 risk and higher estimated rVE. The estimated hazard ratios per 10-fold increase in Day 29 nAbs against D614G, BA.4/BA.5, and XBB.1.5 were 0.70 (95% confidence interval [CI]: 0.48-1.02; p = .064), 0.49 (95% CI: 0.41-0.58; p < .001), and 0.41 (95% CI: 0.35-0.49; p < .001), respectively. These findings indicate that nAb levels, particularly against variants antigenically similar to circulating strains, remain associated with stronger contemporaneous protection against COVID-19.