Evaluation of inactivated and live attenuated, tetravalent dengue vaccine prime-boost strategies in a randomized, open-label, phase I study: implications for understanding immune correlates of protection.

UNLABELLED: Vaccines that elicit balanced, protective immunity to all four dengue virus (DENV) types are needed to reduce the global burden of dengue disease. Achieving this goal has been a challenge for dengue vaccine developers, particularly when immunizing dengue immunologically naïve individuals. In this randomized, phase I, open-label study of 40 healthy adults, we evaluated a heterologous, tetravalent purified inactivated vaccine (PIV) prime and a tetravalent live attenuated vaccine (LAV) boost. We compared a 0, 90 day PIV/LAV prime-boost schedule to a 0, 180 day schedule. These two PIV/LAV regimens elicited similar, high, and balanced cellular and humoral immune responses to DENV 1-4, although the condensed schedule was associated with more severe adverse events. In a subsequent clinical trial [K. E. Lyke, J. V. Chua, M. Koren, H. Friberg, et al., Lancet Infect Dis 24:896-908, 2024, https://doi.org/10.1016/S1473-3099(24)00100-2], the PIV/LAV vaccinees were challenged with DENV-1 and most were unprotected and experienced more pronounced dengue fever-like illness than unvaccinated controls. These outcomes underscore critical gaps in our understanding of mechanistic correlates of dengue vaccine-mediated protection and disease risk. IMPORTANCE: Dengue vaccine research and development has been complicated by several factors, including an incomplete understanding of immunologic correlates of protection and immune-mediated risk of severe disease. High and balanced immunity elicited by the tetravalent purified inactivated vaccine (PIV)/live attenuated vaccine (LAV) prime-boost vaccine strategy was predicted to provide protection from dengue virus type 1 (DENV-1) challenge in a subsequent clinical study, but vaccinees were unprotected and had an unexpected increase in symptom severity compared to unvaccinated controls. Evidence of exposure to a specific DENV type by viral genome detection (e.g., by quantitative RT-PCR) in acute samples or measurement of post-exposure, type-specific antibody responses (e.g., by serum antibody depletion) are known correlates of protection. However, current methods of measuring type-specific antibody are not ideal for evaluating groups of vaccinees, even in relatively small clinical trials. Newer, high-throughput methods of determining DENV type-specific immune responses and discovery of other correlates of protection are needed to more reliably evaluate dengue vaccine candidates.