(PROJECT 2) Vaccines represent the best hope for preventing and controlling dengue, yet vaccine development is complicated by the presence of four dengue virus (DENV) serotypes, unbalanced serotype-specific immunity in vaccine recipients, and the possibility of immune-enhanced dengue disease. The three leading dengue vaccine candidates are based on tetravalent live attenuated dengue vaccine (TV-DLAV) formulations, which are currently being tested in clinical trials. For Project 2, we propose to characterize the antibody and B cell responses in people receiving DENVax, a leading TV-DLAV licensed by Takeda Vaccines, Inc. We use DENVax as a model platform to dissect B cell and antibody responses associated with simultaneous exposure to 4 attenuated DENVs. Our group and others have discovered new quaternary structure epitopes on the surface of DENVs that are targeted by strongly neutralizing, serotype-specific antibodies in people exposed to natural DENV infections. We hypothesize that in DENV-nave individuals who receive DENVax (Specific Aim 1), neutralization will be mediated by serotype-specific antibody responses that target these quaternary structure epitopes. Our preliminary studies demonstrate that people exposed to natural secondary DENV infections develop serotype cross-reactive neutralizing antibodies that are qualitatively different from antibodies induced after primary exposure. We propose that similar cross-neutralizing antibodies will be induced when DENV-exposed individuals receive DENVax (Specific Aim 2). Antibody genes will be sequenced to determine if these cross-neutralizing antibodies are derived from somatically mutated memory B cells (MBCs) clones that secrete high affinity antibodies. Currently, there are no established immune correlates of protection from dengue disease.
Aim 3 will analyze samples from DENVax Phase 3 efficacy trials to identify antibody responses associated with protection from disease. In this P01, Projects 2 and 3 will analyze the same vaccine samples to obtain a comprehensive view of both the B and T cell response to TV-DLAVs. Moreover, samples collected for Projects 1 and 2 will be matched and characterized using the same assays to directly compare antibody responses to natural DENV infection and vaccination.
(PROJECT 2) Antibody and T cell responses are critical for protection from dengue virus infection and disease, although under some conditions, human immune responses have been implicated in severe dengue disease as well. In this project, we will characterize the properties of antibodies and B cells produced in DENV-nave and previously DENV-exposed people vaccinated with a tetravalent dengue vaccine candidate currently being tested in human clinical trials. The studies are designed to identify specific properties of beneficial antibodies induced by vaccination. Our findings will lead to improved methods for evaluating existing vaccines and the rational design of new vaccines.
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