Project 3: Immunological imprinting of T cell responses following dengue virus natural infections and live attenuated dengue virus vaccination

University Of California Berkeley, Berkeley CA

Investigators

Linked publications & trials

Abstract

SUMMARY Dengue is a major global public health problem, with 50-100 million cases annually, and it is caused by four related dengue virus serotypes (DENV1-4). While immune responses are necessary for control, clearance and prevention of infection, they can also contribute to poor clinical outcomes. The Overall theme of this Program Project is to investigate the magnitude and quality of immune responses, the impact of pre-existing immunity, and mechanisms of protection, enhanced disease, and vaccine safety. In Project 3, we will address the central issue of how DENV-specific pre-existing T cell immunity influences immunity against a subsequent DENV infection with a different serotype or live virus vaccine, analyzing the imprinted memory response. We have developed methods to accurately measure magnitude, frequency, and phenotype of DENV-specific T cells. In Aim 1, we will study the antigens targeted by DENV-specific T cells and whether this repertoire changes after a subsequent DENV infection. For example, does a subsequent infection with a different serotype expand the repertoire, or does the T cell response focus on conserved regions? Well-defined samples from pediatric dengue studies in Nicaragua (Core C) will allow us to answer to what degree effector responses are multi-specific, and how narrow or diverse the T cell receptor (TCR) repertoire of DENV-specific T cells is (i.e., how much specialization the different T cells have undergone). Importantly, the longitudinal samples will allow us to follow CD4 and CD8 memory T cell subsets over time to establish how long the imprinted memory phenotype remain. The serotype and serotype sequences studied align with Project 1. In Aim 2, we will examine how pre-existing immune imprinting (naïve, primary and secondary) influence the DENV-specific CD4 and CD8 T cell response against a monovalent DENV3 vaccine developed by the NIH in a vaccine challenge study (Core C). This will address another important component of response quality; namely, its cross-reactivity among DENV serotypes and the influence on the subsequent vaccine response. In Aim 3, we will work with Project 2 and Core C to characterize the response against the suboptimal first licensed DENV vaccine (Dengvaxia®). Since Dengvaxia® is based on the yellow fever 17D vaccine backbone containing just the DENV prM and E genes, the majority of the CD4 and CD8 T cell epitopes in the vaccine are from yellow fever virus and not DENV. Using clinical samples collected from children in the Philippines (DENV-naïve, primary or secondary) vaccinated with Dengvaxia® , we will study whether children vaccinated with Dengvaxia® have suboptimal T cell and antibody responses because of T cell epitope mismatches between the DENV complex and yellow fever virus. Importantly, together with data from the other Projects, our findings willl have direct implications for DENV vaccine design, testing and deployment.