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

Abstract

ABSTRACT 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. 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.