Zika virus (ZIKV), a mosquito-borne human pathogen, causes dire congenital brain developmental abnormalities in children of infected mothers. The global health crisis precipitated by this virus has led to a concerted effort to develop effective
therapies and prophylactic measures although, unfortunately, not very successfully. The error-prone nature of
RNA viral genome replication tends to promote evolution of novel viral strains, which could cause epidemics and pandemics. As such, our objective was to develop a safe and effective replication-deficient ZIKV vector-based
vaccine candidate. We approached this by generating a ZIKV vector containing only the nonstructural (NS) 5'-untranslated (UTR)-NS-3' UTR sequences, with the structural
proteins capsid (C), precursor membrane (prM), and envelope (E) (CprME) used as a packaging system. We efficiently packaged replication-deficient Zika
vaccine particles in human producer cells and verified
antigen expression in vitro. In vivo studies showed that, after inoculation in neonatal mice, the Zika
vaccine candidate (ZVAX) was safe and did not produce any replication-competent revertant viruses. Immunization of adult, nonpregnant mice showed that ZVAX protected mice from lethal challenge by limiting viral replication. We then evaluated the safety and efficacy of ZVAX in pregnant mice, where it was shown to provide efficient maternal and fetal protection against Zika disease. Mass cytometry analysis showed that vaccinated pregnant animals had high levels of splenic CD8+ T cells and effector memory T cell responses with reduced proinflammatory cell responses, suggesting that endogenous expression of NS
proteins by ZVAX induced cellular immunity against ZIKV NS
proteins. We also investigated humoral immunity against ZIKV, which is potentially induced by
viral proteins present in ZVAX virions. We found no significant difference in
neutralizing antibody titer in vaccinated or unvaccinated challenged animals; therefore, it is likely that cellular immunity plays a major role in ZVAX-mediated protection against
ZIKV infection. In conclusion, we demonstrated ZVAX as an effective inducer of protective immunity against ZIKV, which can be further evaluated for potential prophylactic application in humans. IMPORTANCE This research is important as it strives to address the critical need for effective prophylactic measures against the outbreak of Zika virus (ZIKV) and outlines an important
vaccine technology that could potentially be used to induce immune responses against other pandemic-potential viruses.