Toward Control of Rift Valley Fever Virus Replication

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Rift Valley fever virus (RVFV) belongs to the NIAID Category A list pathogens and the CDC list of potential bioterrorism agents. RVFV belong to the genus Phlebovirus, in the family Bunyaviridae, a large and widely diverse group of enveloped RNA viruses containing three RNA genome segments. Rift Valley fever is an endemic disease of sub-Saharan Africa that has emerged in explosive mosquito-borne epidemics resulting 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 the Arabian peninsula, where it threatens to spread further. RVFV introduction in North America will panic the general population and the effects on livestock could be economically devastating. In a new continental location RVFV would likely maintain reservoirs of infection common to those found in Africa, while simultaneously potentially establishing new amplifiers in novel wild-animal hosts, thereby leading to higher levels of viremia in RVFV-infected humans; such an epidemic would be ripe with the possibility of humans serving as amplifiers. For the protection of American citizens a human vaccine is essential for controlling RVFV, 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 present application aims to develop new MP-12-based, live RVFV human vaccine candidates using an RVFV reverse genetics system, which was recently developed by our group. There is considerable evidence that humoral immunity is necessary and sufficient for protection against RVFV and RVFV is considered to be serologically monotypic. We hypothesize that safe, nonpathogenic MP-12-derived viruses eliciting strong humoral immune responses, particularly against two envelope proteins, Gn and Gc, are ideal for advanced RVFV vaccine studies. In this application, we will generate advanced MP-12-derived vaccine candidates by introducing mutations in L and M segment RNAs. To this end, we will first examine the virulence in mice of reassortant viruses between wt RVFV and MP-12 and test for a humoral immune response after infection of the mice by these viruses. Selected reassortant viruses will be further modified to improve immunization efficacies using a mouse model system. Our recent study showed that a single nucleotide substitution in the Gn gene substantially affected the virulence of wt RVFV in mice. We will investigate how a single nucleotide substitution could affect the wt RVFV virulence. We expect that the data obtained from the proposed studies will be groundbreaking for the generation of live human RVFV vaccines and will further our understanding of RVFV pathogenicity at a molecular level.