INVESTIGATING DETERMINANTS OF IMMUNOGENICITY AND SAFETY IN ZIKA LIVE ATTENUATED VACCINES

Abstract

Zika virus (ZIKV) emerged into prominence during the 2016 outbreak as a cause of fetal demise and malformations. Vaccine development thus proceeded with great haste. While multiple vaccine candidates are in clinical development, their fate is uncertain due to incomplete understanding of the determinants of vaccine immunogenicity. Here, we demonstrate that a vaccine’s replicative ability shapes adaptive immune responses elicited and that cellular immunity are required for protection against systemic ZIKV dissemination. As replicative vaccine carries safety concerns, this thesis also examined the host response that borders attenuated and pathogenic infection. We found metabolic dysregulation to be a tipping point of Zika pathogenesis; pathogenic but not attenuated ZIKV infection disrupted glycolysis, TCA cycle and oxidative phosphorylation that collectively activated the inflammatory response. Remarkably, metabolic supplementation could reduce inflammation and restore fetal development even with pathogenic ZIKV infection, suggesting a potential prophylactic application.