HPV binding antibodies as a correlate of protection

BackgroundHuman papillomavirus (HPV) is the major cause of cervical cancer globally. Current vaccines have shown high efficacy at preventing HPV infection and other surrogate disease endpoints in randomised controlled trials (RCT). However, uptake is limited by accessibility and cost. Rapid clinical evaluation is critical for shortening time-to-market and encouraging the development and deployment of affordable vaccines. We aim to establish a validated correlate of protection, to support vaccine developers and decision makers for vaccine development, approval, dose schedules and deployment decisions. MethodsWe utilised three existing Cochrane Systematic Reviews of RCTs of HPV vaccines and extended these to 30 September 2023. We identified and extracted data from trials where both efficacy and immunogenicity (HPV-specific antibodies) were reported. Antibody binding concentrations to HPV types not targeted by the vaccine were sourced from a separate immunogenicity study. We linked antibody binding concentrations from each RCT to the corresponding vaccine efficacy data, matching by study, vaccine arm, number of doses, and HPV type (all available HPV types). We use a Bayesian framework in a model-based meta-analysis to examine the association between antibody binding concentrations and vaccine efficacy. FindingsCombining data on both vaccine-targeted and non-targeted HPV types, we find an association between type-specific antibody binding concentrations and vaccine efficacy against the three HPV outcomes tested: incident infection, persistent infection and grade 2 or 3 cervical intraepithelial neoplasia (CIN2+). We also compared this association with data from studies of natural infection, which had shown an association between antibody binding concentrations and risk of infection. This demonstrated that the association between vaccine-induced antibodies and vaccine efficacy was well aligned with the existing HPV literature on correlates of risk from natural exposure. Finally, using our correlate of protection, we predict robust long-term protection from a single dose of the vaccine against the oncogenic HPV types targeted by the vaccines. InterpretationsHPV type-specific antibody binding concentrations correlate with protection against incident HPV infection, persistent HPV infection, and CIN2+ outcomes. This relationship is consistent regardless of whether antibodies were obtained via natural exposure or vaccination. This suggests that antibody binding concentrations are a reliable surrogate of vaccine efficacy for HPV and suggests their use in vaccine assessment and as a public health decision tool. FundingThis work is supported by National Health and Medical Research Council of Australia and the University of New South Wales.