Dengue vaccines: The role of a correlate of protection in evaluating vaccine safety and risk.

Dengue remains a significant global health challenge, with incidence rising and over half the world's population at risk. Vaccines could play an important role in controlling dengue, but without a validated correlate of protection (CoP), vaccine development relies on large, costly, and complex phase 3 field efficacy trials that are often underpowered for evaluating efficacy and safety by individual DENV serotypes in individuals who have never been infected with a dengue virus (i.e., DENV-naïve individuals). A validated CoP would help developers make informed decisions about the best vaccine candidates for testing in costly phase 3 field trials. A CoP might enable licensure of dengue vaccines based on efficacy endpoint trials of shorter duration and use of immunogenicity data to bridge efficacy data to other populations, which could accelerate the pathway from vaccine trials to operational dengue vaccination programs. Recognizing the urgent need for vaccine development and licensure, a group of experts in dengue vaccinology convened in San Juan, Puerto Rico, from March 14-15, 2024, to define a research agenda for establishing a CoP. The meeting brought together experts from academia, government, U.S. regulatory agencies, and public health organizations who identified key barriers to CoP validation, discussed lack of assay standardization and limited regulatory consensus, and identified the most promising CoP candidates. Experts agreed that neutralizing antibodies to unique epitopes on each serotype (i.e., type-specific antibodies) are the most promising biomarker for DENV-naïve individuals (the most challenging subgroup for establishing safety and efficacy) and emphasized the need for harmonized assays and validation studies using clinical trial samples. The group also discussed the role of alternative trial modalities, such as human challenge studies and nonhuman primate models, in supplementing regulatory submissions where phase 3 efficacy data may be incomplete. This article outlines the key research priorities identified at the meeting and provides a framework for advancing CoP validation to accelerate dengue vaccine development, licensure, and implementation. By aligning scientific, regulatory, and industry efforts around these priorities, the field can move more quickly toward broad access to safe and effective dengue vaccines.