Novel Non-Segmented Negative-Sense Rna Virus-Based Vaccine Platforms For Zika Virus

Abstract Zika virus (ZIKV) is a mosquito-borne flavivirus that can cause Congenital Zika Syndrome (including microcephaly), Guillain-Barré syndrome, and other severe neurological disorders. Despite major efforts, there is no FDA-approved vaccine for ZIKV. Current efforts to develop ZIKV subunit vaccines have been exclusively focused on pre-membrane (prM) and envelope (E) proteins. However, the role of other viral proteins such as nonstructural protein 1 (NS1) in protection is poorly understood. Here, we developed two novel ZIKV vaccine candidates using non-segmented negative-sense RNA viruses (vesicular stomatitis virus, VSV; measles virus, MeV) as a vector. ZIKV prM-E-NS1 or prM-E gene was inserted into the attenuated VSV or MeV vector, and recombinant viruses expressing prM-E-NS1 or prM-E were recovered. The VSV- and MeV-based vaccine candidates were highly attenuated, induced strong ZIKV-specific antibody and T cell immune responses in animal models, and provided complete protection against ZIKV challenge in both immunocompetent and immunodeficient mice. Compared with vaccine candidates expressing only prM-E, ones with NS1 induced significantly higher levels of antibody and/or T cell responses and provided better protection against ZIKV infection, suggesting that NS1 plays a regulatory role in immune response and protection. In addition, we found that NS1, alone, is capable of conferring protection against ZIKV infection even though it did not induce neutralizing antibody. Our results demonstrated that prM-E-NS1 was superior to prM-E as a vaccine antigen. In summary, we have developed safe and highly efficacious ZIKV vaccine candidates, which are ready for pre-clinical trials in nonhuman primates and humans in the future.