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 and demonstrated that vaccine is highly immunogenic, inducing strong T cell responses and anti-NS1 antibodies, but that vaccine efficacy is T cell mediated, and dependant on efficient secretion of NS1. Here we present data that shows that NS1 DNA vaccine is immunogenic in the immunocompetent C57BL6 pregnancy model of ZIKV infection and protects fetuses from intrauterine growth restriction, microcephaly, and brain damage. We show that NS1 DNA vaccination of male IFNAR-/- mice protects mice against ZIKV-induced damage to the testes and prevents viral persistence in the testes. Adoptive transfer studies demonstrated that this protection is T cell mediated.
Considering that T cell- based vaccines do not provide sterilising immunity, inclusion of additional antigens in a ZIKV vaccine may provide enhanced protection and efficacy. This may be particularly important during infection in pregnancy, to reduce any possibility of vertical transmission of ZIKV from mother to fetus. Therefore, we comprehensively evaluated in vivo and in real time ZIKV-specific effector, early and late memory T cell responses after ZIKV infection. Complementing and supporting the published data from human studies we show that ZIKV NS3 and NS4 are the dominant antigenic targets of T cell responses post-infection. Thus, we next evaluated if the immunogenicity and efficacy of the NS1 DNA vaccine is enhanced by the inclusion of ZIKV NS4 and NS3 antigens.
ZIKV NS1 DNA vaccine has progressed to non-human primate studies in rhesus macaques with vaccine delivered intradermally using PharmaJet Tropis device. Early 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.