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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 (ID 50 ) 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 ID 50 ; vaccine efficacy was 60% (43%, 72%) at non-quantifiable ID 50 (<2.7 IU 50  ml -1 ) and increased to 89% (78%, 96%) at ID 50  = 96.3 IU 50  ml -1 . Comparison of the vaccine efficacy by ID 50 titre curves for ENSEMBLE-US, the COVE trial of the mRNA-1273 vaccine and the COV002-UK trial of the AZD1222 vaccine supported the ID 50 titre as a correlate of protection across trials and vaccine types., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)