Development of ZIKV vaccines has focused on the induction of neutralising antibodies, despite concerns of antibody-dependent enhancement of flavivirus infections. This poses a serious concern and a challenge due to the high level of DENV seroprevalence in areas where ZIKV is circulating. Alternative vaccine strategies that utilise T cell immunity, should be considered and explored.
We have developed a DNA vaccine expressing secreted ZIKV NS1 protein that is highly immunogenic, with vaccine efficacy T cell mediated, and dependant on secretion of NS1. We evaluated NS1 DNA vaccine in the pregnancy model of ZIKV infection and demonstrate protection of fetuses from intrauterine growth restriction, microcephaly, and brain damage. NS1 vaccination of male IFNAR-/- mice protected males against ZIKV-induced testicular damage and prevented viral persistence in the testes. Adoptive transfer studies demonstrated that protection is T cell mediated.
Considering that T cell- based vaccines do not provide sterilising immunity, inclusion of additional antigens in vaccine can provide enhanced protection. This may be particularly important during infection in pregnancy, to reduce any possibility of vertical ZIKV transmission. Therefore, we comprehensively evaluated in vivo ZIKV-specific effector, early and late-memory T cell responses after infection. Complementing and supporting the published data from human studies we show that NS3 and NS4 are the dominant antigenic targets of T cell responses post-infection. We next evaluated if the immunogenicity and efficacy of NS1 DNA vaccine is enhanced by the inclusion of NS4 and NS3 antigens.
ZIKV NS1 DNA vaccine progressed to NHP studies in rhesus macaques with vaccine delivered intradermally using PharmaJet Tropis device. Evaluation has shown that the vaccine is highly immunogenic and protective against ZIKV infection.
Taken together our results have important implications for the development of protective and safe T cell-based ZIKV vaccines, that can abrogate the risk of antibody dependant enhancement of flavivirus disease.