The Phlebovirus genus of the Bunyaviridae family is a group of arthropod-borne viruses, having mosquitoes and flies as the usual vectors and a wide variety of animals as primary hosts. Over fifty currently known members defining this group are widely distributed in both hemispheres. The Phlebovirus genus contains a spectrum of important pathogens that can cause fatal disease in humans and domestic animals. Our research plan focuses on creating a vaccine against the Rift Valley fever virus (RVFV). This virus can be transmitted by a wide variety of mosquitoes and spread to distant geographical sites to initiate epizootics. Most recently, RVFV caused a massive epidemic in sub-Saharan Africa in 1997-98 and spread across the Red Sea to Saudi Arabia and Yemen, causing devastating disease outbreaks in sheep and cattle. The RVFV has potential for use in bioterrorism, and its projected effect on U.S. agricultural interests would likely be immense. There is no treatment for humans or vaccine for the livestock that are such important amplifiers of the virus. An experimental vaccine exists for humans, but the number of doses is limited, and there are no prospects for future manufacture. We propose to develop a prototype recombinant vaccine against RVFV infection based on Sindbis virus replicons expressing structural proteins of RVFV. Replicons will be packaged into viral particles composed by structural proteins of Sindbis and other alpha viruses. Immunization by these particles will efficiently protect against RVFV infection, and it will be possible to manufacture this vaccine on an industrial scale. This vaccine will combine the efficiency of live attenuated vaccines and safety of the subunit vaccines. In this proposal we will identify i) the optimal strategy for expression of structural proteins of RVFV by recombinant Sindbis virus, ii) a system for delivery of recombinant genomes into antigen-presenting cells, and iii) the manufacturing procedure for large-scale production of the recombinant viruses. The study will be important for creating a general strategy for development of vaccines against emerging infections, vaccines that require fast design and large-scale production for immediate use. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI053135-01
Application #
6556801
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
Laughlin, Catherine A
Project Start
2003-04-15
Project End
2007-03-31
Budget Start
2003-04-15
Budget End
2004-03-31
Support Year
1
Fiscal Year
2003
Total Cost
$302,000
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
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Michel, Gilles; Petrakova, Olga; Atasheva, Svetlana et al. (2007) Adaptation of Venezuelan equine encephalitis virus lacking 51-nt conserved sequence element to replication in mammalian and mosquito cells. Virology 362:475-87
Shustov, Alexandr V; Mason, Peter W; Frolov, Ilya (2007) Production of pseudoinfectious yellow fever virus with a two-component genome. J Virol 81:11737-48
Frolova, Elena; Gorchakov, Rodion; Garmashova, Natalia et al. (2006) Formation of nsP3-specific protein complexes during Sindbis virus replication. J Virol 80:4122-34
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Volkova, Eugenia; Gorchakov, Rodion; Frolov, Ilya (2006) The efficient packaging of Venezuelan equine encephalitis virus-specific RNAs into viral particles is determined by nsP1-3 synthesis. Virology 344:315-27
Petrakova, Olga; Volkova, Eugenia; Gorchakov, Rodion et al. (2005) Noncytopathic replication of Venezuelan equine encephalitis virus and eastern equine encephalitis virus replicons in Mammalian cells. J Virol 79:7597-608
Fayzulin, Rafik; Gorchakov, Rodion; Petrakova, Olga et al. (2005) Sindbis virus with a tricomponent genome. J Virol 79:637-43
Gorchakov, Rodion; Frolova, Elena; Williams, Bryan R G et al. (2004) PKR-dependent and -independent mechanisms are involved in translational shutoff during Sindbis virus infection. J Virol 78:8455-67