New Opportunities Projects
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Toward control of Rift Valley Fever Virus replication
Collaborating Institution: University of Texas Medical Branch at Galveston (UTMB), Galveston, TX
Principal Investigator: Shinji Makino, D.V.M., Ph.D.
Co-Investigators: a) John C. Morrill, D.V.M., Ph.D., UTMB, Galveston, TX b) C.J. Peters, M.D., UTMB, Galveston, TX
Expected Product: A new live human vaccine for Rift Valley fever based on MP-12
Description: Rift Valley fever virus (RVFV) belongs to the NIAID Category A list pathogens and the CDC list of potential bioterrorism agents. RVFV belongs to the genus Phlebovirus, in the family Bunyaviridae, a large and widely diverse group of enveloped RNA viruses containing three RNA genome segments, and is an endemic disease of sub-Saharan Africa that has emerged in explosive mosquito-borne epidemics. RVFV infection has resulted 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. Introduction of RVFV into North America will cause panic in 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, leading to higher levels of viremia in RVFV-infected humans; the possibility of humans serving as amplifiers in such an epidemic is highly likely. For the protection of American citizens, a human vaccine is essential for controlling RVFV; however, an RVFV vaccine that could be used in the mass 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 and deleting the pre-Gn region of M gene. We will investigate the humoral immune response after infection of mice with these viruses and efficacies of immunization of these modified mutant viruses against wild-type RVFV challenge. We expect that the data obtained from the proposed studies will be groundbreaking for the generation of live human RVFV vaccines and will further the understanding of RVFV pathogenicity at a molecular level.
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