Search

Background: Stochastic interventional vaccine efficacy (SVE) analysis is a new approach to correlate of protection (CoP) analysis of a phase III trial that estimates how vaccine efficacy (VE) would change under hypothetical shifts of an immune marker. Methods: We applied nonparametric SVE methodology to the COVE trial of messenger RNA-1273 vs placebo to evaluate post-dose 2 pseudovirus neutralizing antibody (nAb) titer against the D614G strain as a CoP against COVID-19. Secondly, we evaluated the ability of these results to predict VE against variants based on shifts of geometric mean titers to variants vs D614G. Prediction accuracy was evaluated by 13 validation studies, including 12 test-negative designs. Results: SVE analysis of COVE supported post-dose 2 D614G titer as a CoP: estimated VE ranged from 66.9% (95% confidence interval: 36.2, 82.8%) to 99.3% (99.1, 99.4%) at 10-fold decreased or increased titer shifts, respectively. The SVE estimates only weakly predicted variant-specific VE estimates (concordance correlation coefficient 0.062 for post 2-dose VE). Conclusion: SVE analysis of COVE supports nAb titer as a CoP for messenger RNA vaccines. Predicting variant-specific VE proved difficult due to many limitations. Greater anti-Omicron titers may be needed for high-level protection against Omicron vs anti-D614G titers needed for high-level protection against pre-Omicron COVID-19.

Assessment of immune correlates of severe COVID-19 has been hampered by the low numbers of severe cases in COVID-19 vaccine efficacy (VE) trials. We assess neutralizing and binding antibody levels at 4 weeks post-Ad26.COV2.S vaccination as correlates of risk and of protection against severe-critical COVID-19 through 220 days post-vaccination in the ENSEMBLE trial (NCT04505722), constituting ~4.5 months longer follow-up than our previous correlates analysis and enabling inclusion of 42 severe-critical vaccine-breakthrough cases. Neutralizing antibody titer is a strong inverse correlate of severe-critical COVID-19, with estimated hazard ratio (HR) per 10-fold increase 0.35 (95% CI: 0.13, 0.90). In a multivariable model, HRs are 0.31 (0.11, 0.89) for neutralizing antibody titer and 1.22 (0.49, 3.02) for anti-Spike binding antibody concentration. VE against severe-critical COVID-19 rises with neutralizing antibody titer: 63.1% (95% CI: 40.0%, 77.3%) at unquantifiable [<4.8975 International Units (IU)50/ml], 85.2% (47.2%, 95.3%) at just-quantifiable (5.2 IU50/ml), and 95.1% (81.1%, 96.9%) at 90th percentile (30.2 IU50/ml). At the same titers, VE against moderate COVID-19 is 32.5% (11.8%, 48.4%), 33.9% (19.1%, 59.3%), and 60.7% (40.4%, 76.4%). Protection against moderate vs. severe disease may require higher antibody levels, and very low antibody levels and/or other immune responses may associate with protection against severe disease. In this study, the authors report that post-vaccination neutralizing and binding antibody levels in the ENSEMBLE trial associate with Ad26.COV2.S vaccine efficacy (VE) against severe-critical COVID-19, with substantial VE even at unquantifiable neutralizing antibody titer. [ABSTRACT FROM AUTHOR]