Pre-existing Immunity to Japanese Encephalitis Virus Alters CD4 T Cell Responses to Zika Virus Inactivated Vaccine

Abstract

The epidemic spread of Zika virus (ZIKV), associated with devastating neurologic syndromes, has driven the development of multiple ZIKV vaccines candidates. An effective vaccine should induce ZIKV-specific T cell responses, which are shown to improve the establishment of humoral immunity and contribute to viral clearance. Here we investigated how previous immunization against Japanese encephalitis virus (JEV) and yellow fever virus (YFV) influences T cell responses elicited by a Zika purified-inactivated virus (ZPIV) vaccine. We demonstrate that three doses of ZPIV vaccine elicited robust CD4 T cell responses to ZIKV structural proteins, while ZIKV-specific CD4 T cells in pre-immunized individuals with JEV vaccine, but not YFV vaccine, were more durable and directed predominantly toward conserved epitopes, which elicited Th1 and Th2 cytokine production. In addition, T cell receptor repertoire analysis revealed preferential expansion of cross-reactive clonotypes between JEV and ZIKV, suggesting that pre-existing immunity against JEV may prime the establishment of stronger CD4 T cell responses to ZPIV vaccination. These CD4 T cell responses correlated with titers of ZIKV-neutralizing antibodies in the JEV pre-vaccinated group, but not in flavivirus-naïve or YFV pre-vaccinated individuals, suggesting a stronger contribution of CD4 T cells in the generation of neutralizing antibodies in the context of JEV-ZIKV cross-reactivity.

Cross-Reactive Immunity among Five Medically Important Mosquito-Borne Flaviviruses Related to Human Diseases

“…(3) Study in humans In a phase 1 clinical trial of a ZIKV vaccine, participants preimmunized with the JEV vaccine maintained more durable ZIKV-specific CD4 + T cell responses, with more obviousness in conserved epitopes among flaviviruses, suggesting that prior JEV immunity altered the immunogenicity of subsequent ZIKV vaccine [46].…”

Broadly neutralizing antibodies against Zika virus from dengue patients with prior exposure to Japanese encephalitis virus

“…Our current knowledge of cross-immunity to ZIKV is mainly derived from infection of DENV 9 or other aviviruses such as WNV 25 and YFV 26 , and were limited to investigating the interrelationships of two avivirus serocomplexes 27 . Although a few studies investigated the interplay of avivirus immunity in the context of JEV, which is endemic in SEAsia, these studies focused on animal immunization or ex vivo stimulation using PBMCs from JEV-experienced donors 28,29 . Here, we purport key insights for developing broadly neutralizing antibodies against aviviruses using various approaches, including serological or epidemiological information, huMAbs isolation with structure-guided epitope mapping and murine vaccination model.…”

The Japanese Encephalitis Antigenic Complex Viruses: From Structure to Immunity

“…Similar experiments in mice using recombinant vaccinia virus that carried the genes for the E and NS1 proteins of MVEV showed complete protection with a subsequent challenge with MVEV by eliciting generation of neutralizing antibodies, rather than a CD8+ immune response when E protein was used; passive transfer of MVEV-infected human sera also conferred protection with a subsequent MVEV challenge [ 204 ]. Cross-protection due to neutralizing antibodies resulting from CD4 T cell expansion following infection after JEV immunization, but not with YF immunization, has also been reported against ZIKV and DENV [ 205 , 206 , 207 ]. Li et al reported cross-protection against all four serotypes of DENV following JEV immunization, using more than one JEV vaccine [ 208 ].…”