Analysis of Antibody Markers as Immune Correlates of Risk of Severe COVID-19 in the PREVENT-19 Efficacy Trial of the NVX-CoV2373 Recombinant Protein Vaccine

Background: We previously showed that ancestral-specific anti-Spike binding IgG concentration and 50% inhibitory dilution neutralizing antibody titer (nAb-ID50) measured at 2 weeks postdose 2 (∼peak) were inverse correlates of risk (CoRs) of COVID-19 over 2 months post ∼peak in the PREVENT-19 trial of the NVX-CoV2373 vaccine; there were not sufficient data to assess CoRs of severe COVID-19. Methods: Here, we assessed, in the same vaccinated cohort, Delta- and ancestral-specific Spike IgG and nAb-ID50 at ∼peak and over time as CoRs of severe COVID-19 and of Delta COVID-19 over 3.5–10 months post ∼peak (287 breakthrough Delta cases, including 8 severe; 446 noncases). Results: Peak antibody levels were much higher for noncases versus severe cases (all inferred Delta), with nAb-ID50 Delta geometric mean 209.5 arbitrary units (AU)/mL (95% CI: 176.1, 249.1) versus 9.6 AU/mL (95% CI: 2.4, 38.6), respectively. Frequency of detectable nAb-ID50 titer was 98.3% (97.2, 99.0) for noncases versus 62.5% (22.3, 93.9) for severe cases. All markers were inverse CoRs of severe COVID-19, with a ∼peak hazard ratio (HR) of 0.13 (95% CI: .03, .57) per 10-fold nAb-ID50 Delta increase. Severe COVID-19 risk through 305 days postday 35 was 0.0338 (0.0043, 0.206) at the nAb-ID50 Delta 2.5th percentile (8.4 AU/mL), and 0.002 (0.0000, 0.0108) and 0.0002 (0.0000, 0.0035) at the 50th and 95th percentiles (210, 2522 AU/mL). Conclusions: Postvaccination NVX-CoV2373 antibody levels are stronger predictors of severe COVID-19 than any-severity Delta COVID-19. Low antibody responses indicate vulnerability to severe COVID-19.