ENVELOPED VIRUS-LIKE PARTICLES (eVLPs) EXPRESSING MODIFIED FORMS OF ZIKA VIRUS PROTEINS E AND NS1 PROTECT MICE FROM ZIKA VIRUS INFECTION

Abstract

While Zika virus (ZIKV) infection induces mild disease in the majority of cases, it has been identified as responsible for microcephaly and severe neurological disorders in recent 2015-2016 outbreaks in South America and the Caribbean. Since then, several prophylactic vaccine strategies have been studied. Here, we describe the development of a ZIKV candidate vaccine consisting of bivalent enveloped virus-like particles (eVLPs) expressing a modified form of E and truncated NS1 (EG/NS1) proteins. In EG/NS1, the E transmembrane/cytoplasmic tail has been replaced with those domains from the VSV G protein and a {beta}-domain of NS1 was fused in-frame to Gag from Moloney murine leukemia virus (MLV). Immunization of BALB/C mice demonstrated that bivalent EG/NS1 and monovalent EG eVLPs induced comparable levels of antibody (Ab) titers but that EG/NS1 induced much higher neutralizing activity, comparable to naturally acquired anti-ZIKV immunity. In contrast, monovalent NS1 eVLPs did not induce a significant anti-NS1 Ab response but promoted strong T cell immunity that was also elicited with EG/NS1 eVLPs. ZIKV challenge studies in C57BL/6-IFNR-/- mice demonstrated that EG/NS1 eVLPs conferred 100% protection against clinical disease after ZIKV challenge compared to 80% protection after EG eVLP vaccination, with protection against challenge correlating with neutralizing antibody titers and overt signs of infection.\n\nAuthor SummaryZika virus has caused rapidly spreading epidemics with potentially severe neurological symptoms including microcephaly in new born babies. Rapid progress has been made with several candidate vaccines under clinical evaluation but no vaccine or treatment is yet available. In this context, we have produced and tested recombinant virus-like particles that incorporate one or two Zika virus proteins, E and NS1 that have been modified for optimal efficacy. Our immunogenicity studies in mice showed a synergistic effect of both proteins in the bivalent vaccine. NS1 induced a strong T cell response enhancing the neutralizing antibody production induced by the E protein. In challenge experiments, the bivalent vaccine protected 100% of mice from clinical signs of Zika virus infection. These products could be further used to explore Zika virus correlates of protection and evaluated as vaccine candidates.