Immuno-proteomic interrogation of antigen presentation during Dengue and Zika infections reveals novel targets for the design of broad acting T-cell vaccines

Abstract

Abstract The recent outbreak of Zika virus (ZIKV) infection across the Americas has raised dire concerns about its potential long-term health effects including its negative impact on neuronal, psychological and motor development in affected individuals. Emerging evidence pointing to Alzheimer’s-like damage to the adult brain further highlights the urgent need for efficacious prophylactic measures. Zika-affected regions are often endemic to the related Dengue virus (DENV). Antibodies against the two viruses are crossreactive and cause antibody-mediated enhancement (ADE) of infection. This confounds the design of traditional vaccines that elicit humoral antibody-mediated responses. T cell vaccines mediated by cytotoxic CD8+ T cells that recognize conserved viral epitopes presented on the major histocompatibility complex (MHC-I) of infected cells are unencumbered by ADE and can supplement or substitute traditional vaccines. In order to identify robust T cell vaccine candidates, we first used an immunoproteomic approach and isolated over 100 novel DENV and ZIKA epitopes presented by infected B lymphocytes in vitro. These viral peptides were not predicted to be epitopes by computational programs typically used for epitope discovery, which discard >95% of all predictions. Focussing on epitopes derived from polyprotein regions strictly conserved between the two viruses, we validated the presentation of these epitopes in primary dendritic cells and assayed their ability to stimulate robust T cell responses in ex vivo ELISpot assays. Together these discoveries let us assay the immunogenic potentials of an unprecedented range of DENV and ZIKV antigens which have the potential to serve as broad acting and effective Zika vaccine candidates.