Rift Valley fever virus (RVFV) belongs to the NIAID Category A list pathogens and the CDC list ofpotential bioterrorism agents. RVFV belong to the genus Phlebovirus, in the family Bunyaviridae, a large andwidely diverse group of enveloped RNA viruses containing three RNA genome segments. Rift Valley fever isan endemic disease of sub-Saharan Africa that has emerged in explosive mosquito-borne epidemicsresulting in massive economic loss in herds of sheep and cattle, but also causes hemorrhagic fever,encephalitis, retinal vasculitis, and lesser disease in humans. RVFV has been exported to Egypt and theArabian peninsula, where it threatens to spread further. RVFV introduction in North America will panic thegeneral population and the effects on livestock could be economically devastating. In a new continentallocation RVFV would likely maintain reservoirs of infection common to those found in Africa, whilesimultaneously potentially establishing new amplifiers in novel wild-animal hosts, thereby leading to higherlevels of viremia in RVFV-infected humans; such an epidemic would be ripe with the possibility of humansserving as amplifiers. For the protection of American citizens a human vaccine is essential for controllingRVFV, whereas an RVFV vaccine applicable for inception of massive vaccination of people does not exist.Two live attenuated RVFV strains, MP-12 and clone 13 have potential as vaccine candidates. This presentapplication aims to develop new MP-12-based, live RVFV human vaccine candidates using an RVFVreverse genetics system, which was recently developed by our group. There is considerable evidence thathumoral immunity is necessary and sufficient for protection against RVFV and RVFV is considered to beserologically monotypic. We hypothesize that safe, nonpathogenic MP-12-derived viruses eliciting stronghumoral immune responses, particularly against two envelope proteins, Gn and Gc, are ideal for advancedRVFV vaccine studies. In this application, we will generate advanced MP-12-derived vaccine candidates byintroducing mutations in L and M segment RNAs. To this end, we will first examine the virulence in mice ofreassortant viruses between wt RVFV and MP-12 and test for a humoral immune response after infection ofthe mice by these viruses. Selected reassortant viruses will be further modified to improve immunizationefficacies using a mouse model system. Our recent study showed that a single nucleotide substitution in theGn gene substantially affected the virulence of wt RVFV in mice. We will investigate how a single nucleotidesubstitution could affect the wt RVFV virulence. We expect that the data obtained from the proposed studieswill be groundbreaking for the generation of live human RVFV vaccines and will further our understanding ofRVFV pathogenicity at a molecular level.
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