CD8+ T cells mediate an NS3-based vaccine protection against Zika virus

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Abstract Zika virus (ZIKV), a member of the flaviviridae family, is associated with severe congenital malformations in infants born to infected mothers, and with neurological disorders, such as Guillain–Barré syndrome, in infected adults. To date, the development of anti-flavivirus vaccines has focused predominantly on the induction of neutralizing antibodies. Paradoxically, a suboptimal antibody response may enhance disease severity upon subsequent flaviviral infection through a phenomenon known as antibody-dependent enhancement. Thus, alternative approaches to ZIKV vaccine design are necessary. Here, we report induction of a protective anti-ZIKV CD8+ T cell response in the HLA-B*0702 Ifnar1−/− transgenic mouse model using an alphavirus-based replicon RNA vaccine expressing ZIKV nonstructural protein NS3, a potent T cell antigen. The NS3 vaccine did not induce an antibody response, but elicited polyfunctional CD8+ T cells that were necessary and sufficient for controlling viral burden and preventing death in lethally infected adult mice. In addition, the NS3 vaccine prevented fetal growth restriction and death in infected pregnant mice. These data identify CD8+ T cells as the major mediators of the ZIKV NS3 vaccine-induced protection and suggest a new strategy to develop safe and effective anti-flavivirus vaccines that avoid inadvertent antibody-dependent enhancement.