Nat Microbiol. 2022 Dec; 7(12):1996-2010.

PubMed ID: 36357712

Immune correlates analysis of the ENSEMBLE single Ad26.COV2.S dose vaccine efficacy clinical trial

Fong Y, McDermott AB, Benkeser D, Roels S, Stieh DJ, Vandebosch A, Le Gars M, Van Roey GA, Houchens CR, Martins K, Jayashankar L, Castellino F, Amoa-Awua O, Basappa M, Flach B, Lin BC, Moore C, Naisan M, Naqvi M, Narpala S, O'Connell S, Mueller A, Serebryannyy L, Castro M, Wang J, Petropoulos CJ, Luedtke A, Hyrien O, Lu Y, Yu C, Borate B, van der Laan LWP, Hejazi NS, Kenny A, Carone M, Wolfe DN, Sadoff J, Gray GE, Grinsztejn B, Goepfert PA, Little SJ, Paiva de Sousa L, Maboa R, Randhawa AK, Andrasik MP, Hendriks J, Truyers C, Struyf F, Schuitemaker H, Douoguih M, Kublin JG, Corey L, Neuzil KM, Carpp LN, Follmann D, Gilbert PB, Koup RA, Donis RO, Immune Assays Team, the Coronavirus Vaccine Prevention Network (CoVPN)/ENSEMBLE Team, the United States Government (USG)/CoVPN Biostatistics Team

Measuring immune correlates of disease acquisition and protection in the context of a clinical trial is a prerequisite for improved vaccine design. We analysed binding and neutralizing antibody measurements 4 weeks post vaccination as correlates of risk of moderate to severe-critical COVID-19 through 83 d post vaccination in the phase 3, double-blind placebo-controlled phase of ENSEMBLE, an international randomized efficacy trial of a single dose of Ad26.COV2.S. We also evaluated correlates of protection in the trial cohort. Of the three antibody immune markers we measured, we found most support for 50% inhibitory dilution (ID50) neutralizing antibody titre as a correlate of risk and of protection. The outcome hazard ratio was 0.49 (95% confidence interval 0.29, 0.81; P = 0.006) per 10-fold increase in ID50; vaccine efficacy was 60% (43%, 72%) at non-quantifiable ID50 (<2.7 IU50 ml-1) and increased to 89% (78%, 96%) at ID50 = 96.3 IU50 ml-1. Comparison of the vaccine efficacy by ID50 titre curves for ENSEMBLE-US, the COVE trial of the mRNA-1273 vaccine and the COV002-UK trial of the AZD1222 vaccine supported the ID50 titre as a correlate of protection across trials and vaccine types.