PROJECT 2: Linking Vaccine Induced Antibody Responses to Protective or Disease Enhancing Immunity (University of North Carolina, Chapel Hill). SUMMARY Vaccination is the most promising and cost-effective strategy for controlling the global pandemic caused by the four dengue virus (DENV) serotypes. DENV vaccines based on tetravalent live attenuated (TV-DLAV) formulations are at different stages of clinical development. Recently, DENV vaccines have faced major setbacks in clinical studies, such as poorly balanced immune responses across the four DENV serotypes, variable vaccine efficacy depending on the baseline immune status of children, vaccine responses that are more effective against strains that closely match the vaccine strain and, most significantly, vaccine-primed severe dengue disease upon exposure to wild-type DENVs. It has been challenging to understand and solve these problems because we still lack robust immune correlates that predict DENV vaccine efficacy and safety. The overall approach of Project 2 is to characterize antibody (Ab) responses in people who receive TV-DLAV. To link vaccine-induced Ab responses to specific outcomes such as protection, vaccine failure and vaccine-primed severe disease, our studies utilize samples from vaccinated people with known outcomes upon exposure to wild- type DENVs. We will test the hypothesis that in people with no prior immunity to DENVs who are vaccinated, durable protection will require the induction of Abs to type-specific (TS) tertiary and quaternary structure epitopes on each DENV serotype (Specific Aim 1.1). In children who are seronegative at baseline, we will test if low- avidity cross-reactive (XR) Abs induced by vaccination increase the risk of severe dengue disease (Specific Aim 1.2). In people with pre-existing immunity to DENV, we will explore if vaccine efficacy is linked to the activation of DENV-specific memory B cells and the induction of cross-protective Ab responses, similar to protective responses in natural 2 DENV infections (Specific Aim 2). We will also conduct studies to define the impact of genotypic variation within each DENV serotype on vaccine efficacy (Specific Aim 3). This project will define immune correlates and mechanisms of vaccine efficacy and safety in people with different levels of baseline immunity to DENV. Project 2 is highly synergistic with the other Projects and Cores in this P01. We will generate reagents (chimeric epitope transplant flaviviruses and recombinant antigens) for use by other Projects (Projects 1 & 4), share clinical samples (Core C, Projects 1 & 3), compare Ab responses to vaccines and natural DENV infections (Projects 1 and 4) and integrate the analysis (Core B) of the Ab and T cell response to DENV vaccines (Project 3).
(PROJECT 2) Dengue is the leading mosquito-transmitted viral infection of humans. Vaccines offer the best hope for prevention and control of dengue; however, dengue vaccine development has been challenging because we do not understand specific properties of human antibodies linked to safe and effective vaccine responses. In this project, we will characterize the properties of antibodies in people who received dengue vaccines and developed effective or suboptimal immune responses, and we will identify the properties of antibodies linked to durable protection or vaccine failure. Further, we will generate critical reagents used by the entire Program Project and will share methods and analytic approaches across P01 Projects and Cores. Overall, our discoveries will advance the search for an effective dengue vaccine.
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