Crosseactivity of flaviviruses specific CD8+T cell responses across different viral species

Abstract

Abstract Several flaviviruses, including Dengue Virus (DENV), Zika Virus (ZIKV), Japanese Encephalitis Virus (JEV), West Nile Virus (WNV), and Yellow Fever Virus (YFV), share significant sequence homology and often circulate in the same geographical regions. Significant levels of cross-reactivity could in turn result in pre-existing T cell immunity modulating T cell responses to subsequent flavivirus infections or vaccination. Whether and to what extent cross-reactivity at the level of CD8 responses is detected is currently unclear. Thus we designed pools of epitopes and predicted HLA binding peptides derived from DENV, ZIKV, JEV, WNV and YFV. We then used PBMC of individuals vaccinated with DENV or YF to test their potential to recall antigen specific CD8 memory T cell response in an Intracellular Cytokine Staining (ICS) assay. Significant cross-reactivity of CD8 T cell responses against several of the pools was observed both in the case of DENV and YF vaccinees, but the extent of cross-reactivity varied as a function of the flavivirus species considered, and the cross-reactive responses were significantly lower than the responses to the autologous virus. Phenotypic analyses showed a suboptimal expression of activation markers in cross-reactive responses. We are currently characterizing cross-reactive responses at the single epitope level, and in PBMCs from donors naturally exposed to flaviviruses. Characterization of the extent and functionality of CD8 cross-reaction across different flaviviruses will contribute to the understanding of immunity in the natural infection, and has particular implications for vaccine efficacy and safety in endemic settings.