The pre-existing cellular immunity to Japanese encephalitis virus heterotypically protects mice from Zika virus infection

Zika virus (ZIKV) and Japanese encephalitis virus (JEV) are closely related flaviviruses, ZIKV circulates in the population that has been JEV vaccinated in Southeast Asian countries. This alerts that a pre-existing immunity to JEV would impact ZIKV infection and/or pathogenesis. Herein we showed that the pre-existing immunity to JEV SA14-14-2 vaccination provided an ample protection against non-lethal or lethal dose of ZIKV infection in mice. This was in sharp contrast to the passive immunization of JEV antibodies, which failed to affect ZIKV infection or pathogenesis in mice, albeit these antibodies exhibited cross-reactivity and antibody dependent enhancement (ADE) of ZIKV infection in vitro. Furthermore, we determined that JEV vaccine-elicited CD8+ T cells were required to mediate the heterotypic protection of ZIKV infection, which cross-reacted to ZIKV E and NS5 antigens (E294-302 and NS52839-2848). Adoptive transfer of these CD8+ T cells could partially protect the mice from ZIKV challenge. Therefore, although short of epidemiological evidence, these results suggested that cross-reactive CD8+ T cells activated by JEV vaccination could protect potential ZIKV infection in human populations.