Immunogenicity of the dengue vaccine CYD-TDV in a dengue virus serotype 1 immune population

Mosquito-borne flaviviruses, including the dengue viruses (DENV1-4), are a major global public health threats that require multidisciplinary control approaches. The live-attenuated CYD-TDV (Dengvaxia®), is the first dengue vaccine approved by the US FDA in 2019 and an important new tool for controlling dengue illness in endemic countries. However, CYD-TDV is an imperfect vaccine with significant limitations. Randomized, placebo- controlled trials found the vaccine was only protective when given to subjects with pre-existing DENV immunity, while vaccinated DENV naïve subjects were more likely to be hospitalized with subsequent DENV. Thus the FDA only approved the vaccine for individuals aged 9-16 years with laboratory confirmed prior DENV infection, hampering the role the vaccine can play in controlling DENV and highlighting the need for ongoing vaccine development and improvement. It remains unclear why this vaccine is more immunogenic in DENV immune compared to DENV naïve individuals. While pre-existing MBCs are expected to drive the more broadly cross- reactive antibody response, it is possible that vaccine virus enhancement via pre-existing circulating antibodies and immune cells also are required to elicit an effective immune response. Under this hypothesis, immune enhancement, like that seen in severe dengue disease, driven by antibody complexes with vaccine virus and DENV cross-reactive CD8+ cells, drives post-vaccine innate immune response to generate a more broad and potent antibody response. This hypothesis to date remains largely unexplored. Thus, to address the knowledge gap, we will leverage the CYD-TDV rollout in the pre-immune vaccinee population in Puerto Rico to prospectively characterize pre- and post-vaccination antibodies, leukocytes, and inflammatory pathways. Results from these investigations are expected to precisely identify the mechanisms leading to vaccine efficacy in some groups and propose novel approaches for future vaccine refinement and deployment. Two Aims will be carried out. In Aim 1 we Characterize the pre- and post-vaccination DENV type-specific and cross-reactive serum antibody populations and DENV-specific MBC frequencies in DENV pre-immune vaccinees. We test the hypothesis that pre-existing DENV MBCs will direct the CYD-TDV antibody response in a unique and predictable manner. Specifically, we predict that pre-existing DENV1 immunity will lead to significantly higher DENV1 type-specific antibody titers post vaccination with a DENV2-4 cross-reactive antibody response distributed in a pre-vaccination DENV MBC-specific manner. In Aim 2 we evaluate acute innate and adaptive immune responses following CYD- TDV vaccination. Here we test the hypothesis that there is a dose-response relationship between acute post- vaccination inflammatory markers of enhancement and the potency and breadth of post-vaccination DENV antibodies. Specifically, we will test the strength, direction, and significance of the relationship between post- vaccination viral load, inflammatory cytokine levels, natural killer cell, monocyte, and neutrophil activation, and T-cell activation, specificity, and potency of DENV-specific antibodies post-vaccination.