Rift Valley fever virus (RVFV), which belongs to the genus Phlebovirus, family Bunyaviridae, is one of the most important emerging viruses. It is listed as an NIAID category A pathogen. RVFV is transmitted by mosquitoes and causes severe disease in both humans and livestock. A proportion of infected humans develop hemorrhagic fever, encephalitis or retinal vasculitis;the offspring of infected ruminants often die in utero. RVFV is endemic in sub-Saharan African countries, but other countries are preparing for potential introductions of RVFV due to climate change, air transport, and/or bioterrorism. The only truly effective countermeasure is vaccination. RVFV has a tripartite negative-stranded RNA genome composed of the S-, M- and L-segments. The genome encodes 4 major structural proteins (N, Gn, Gc and L), 2 nonstructural proteins (NSs and NSm) and a 78-kD protein whose function is poorly characterized. A candidate live-attenuated vaccine, MP-12, was developed by 12 serial passages of the wild-type ZH548 strain in human diploid MRC-5 cells in the presence of a chemical mutagen. Our preliminary data in the mouse model suggest that MP-12 is attenuated by the combined effect of partially attenuated M- and L-segments. The current MP-12 vaccine poses a significant risk for use in humans because attenuation of the virus is not complete, and reversion of either the M- or L- segment could potentially increase the virulence of MP-12. Therefore, it is essential to characterize the mechanism of MP-12 attenuation to further improve its safety. My long term goal is to establish effective countermeasures against highly virulent negative-stranded RNA viruses, with special emphasis on vaccination. The central hypothesis is that the current candidate MP-12 vaccine can be further improved for safety by introducing mutations into either the S- or M-segment by reverse genetics while retaining immunogenicity. The overall objective is to characterize existing attenuation mutations in the MP-12 genome, and improve the safety of MP-12 by incorporating further attenuation mutations into the S- or M-segment. The three specific aims are proposed as follows:
Specific Aim 1 : To identify and characterize attenuation mutations of MP-12, Specific Aim 2: To attenuate the MP-12 S-segment without reducing the immunogenicity of MP-12, and Specific Aim 3: To attenuate the MP-12 M-segment by modifying the cytoplasmic domains of Gn or Gc. The proposed study will harness the advantage of using of reverse genetics for vaccine development, and develop a next generation of live-attenuated RVFV vaccine candidates that are highly immunogenic and very safe.
Rift Valley fever virus MP-12 strain, a live-attenuated vaccine candidate, has a potential risk to increase the virulence by a few mutations. We will identify and characterize the attenuation mutations of existing MP-12 vaccine and generate further attenuated but immunogenic second generation MP-12 vaccines.
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|Nishiyama, Shoko; Slack, Olga A L; Lokugamage, Nandadeva et al. (2016) Attenuation of pathogenic Rift Valley fever virus strain through the chimeric S-segment encoding sandfly fever phlebovirus NSs or a dominant-negative PKR. Virulence 7:871-881|
|Phoenix, Inaia; Nishiyama, Shoko; Lokugamage, Nandadeva et al. (2016) N-Glycans on the Rift Valley Fever Virus Envelope Glycoproteins Gn and Gc Redundantly Support Viral Infection via DC-SIGN. Viruses 8:|
|Phoenix, Inaia; Lokugamage, Nandadeva; Nishiyama, Shoko et al. (2016) Mutational Analysis of the Rift Valley Fever Virus Glycoprotein Precursor Proteins for Gn Protein Expression. Viruses 8:|
|Nishiyama, Shoko; Lokugamage, Nandadeva; Ikegami, Tetsuro (2016) The L, M, and S Segments of Rift Valley Fever Virus MP-12 Vaccine Independently Contribute to a Temperature-Sensitive Phenotype. J Virol 90:3735-44|
|Ly, Hoai J; Ikegami, Tetsuro (2016) Rift Valley fever virus NSs protein functions and the similarity to other bunyavirus NSs proteins. Virol J 13:118|
|Ikegami, Tetsuro; Hill, Terence E; Smith, Jennifer K et al. (2015) Rift Valley Fever Virus MP-12 Vaccine Is Fully Attenuated by a Combination of Partial Attenuations in the S, M, and L Segments. J Virol 89:7262-76|
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