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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI087643-02
Application #
8206484
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
Repik, Patricia M
Project Start
2010-12-15
Project End
2015-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
2
Fiscal Year
2012
Total Cost
$382,500
Indirect Cost
$132,500
Name
University of Texas Medical Br Galveston
Department
Pathology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Ly, Hoai J; Lokugamage, Nandadeva; Ikegami, Tetsuro (2016) Application of Droplet Digital PCR to Validate Rift Valley Fever Vaccines. Methods Mol Biol 1403:207-20
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
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:
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:
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
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
Lihoradova, Olga; Ikegami, Tetsuro (2014) Countermeasure development for Rift Valley fever: deletion, modification or targeting of major virulence factor NSs. Future Virol 9:27-39
Kalveram, Birte; Lihoradova, Olga; Indran, Sabarish V et al. (2013) Rift Valley fever virus NSs inhibits host transcription independently of the degradation of dsRNA-dependent protein kinase PKR. Virology 435:415-24
Indran, Sabarish V; Lihoradova, Olga A; Phoenix, Inaia et al. (2013) Rift Valley fever virus MP-12 vaccine encoding Toscana virus NSs retains neuroinvasiveness in mice. J Gen Virol 94:1441-50
Kalveram, Birte; Ikegami, Tetsuro (2013) Toscana virus NSs protein promotes degradation of double-stranded RNA-dependent protein kinase. J Virol 87:3710-8

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