Impact of Fusion Loop Mutations in Zika Envelope Protein-Based Vaccines on Antibody- and Cell-Mediated Protection 4637

Abstract Description Zika virus (ZIKV) can cause severe neurological injury in humans, and there are currently no effective vaccines. A challenge associated with vaccine development is that flavivirus-cross-reactive antibodies (Abs), under certain conditions, may precipitate severe disease through the process known as Ab-dependent enhancement (ADE). Thus, ZIKV vaccine developers have generated envelope (E) protein-based vaccines with mutant fusion loop (FL) epitope, as wild type (WT) FL epitope induces a dominant ADE-promoting, poorly neutralizing Ab (nAb) response. However, little is known about the mechanism of protection conferred by FL mutant (FLM) E-based vaccines. We evaluated the mechanism by which DNA and replicon RNA vaccines expressing WT vs FLM prM-E afford protection against ZIKV in mice. Both vaccines induced high levels of in vitro nAbs in the serum and polyfunctional CD4+ and CD8+ T cell responses in the spleen, and significantly reduced infectious ZIKV in tissues. However, passive transfer experiments demonstrated that Abs generated from the FLM prM-E vaccine do not protect. Instead, T cell depletion experiments showed that the FLM prM-E vaccine-mediated protection required CD8+ T cells. Thus, our results suggest that FLM E protein-based ZIKV vaccines may not afford protective immunity via the expected mechanism (ie, nAbs), and instead elicit suboptimal Ab responses in vivo. Our findings have significant implications for the development of safe and efficient ZIKV vaccines. Funding Sources This work is supported by NIH R01AI180196, NIH R01AI153500, NIH R01 AI163188 and Conrad Prebys Foundation. Topic Categories Viral Immunology (VIR)