In the US, extensive reservoirs of the rabies virus exist in many diverse wild animal species that continue to pose a serious risk of lethal infection of humans and cause an economic burden exceeding $1 billion annually. Previous experience with rabies control in foxes in Europe has clearly demonstrated that oral immunization with live vaccines is the only practical approach to eradicating rabies in free-ranging animals. However, unlike Europe where vulpine rabies was the only major reservoir, the Americas harbor a variety of species including raccoons, skunks, coyotes, and bats that serve as the primary reservoirs of rabies. Each of these animal reservoirs carries an antigenically distinct virus variant. Because the currently available modified-live rabies virus vaccines have either safety problems or do not induce sufficient protective immunity, particularly in wildlife species, die overall goal of this proposal is the development of recombinant rabies virus vaccines that are very safe and highly effective in particular wildlife species. Based on preliminary data indicating that the potency of a vaccine is significantly increased if the G protein of the vaccine strain is identical to that of the target virus, we propose to use a reverse genetics approach to engineer viruses that contain G proteins from virus strains associated with relevant wildlife species. Our preliminary data also indicate that an increased ability of rabies virus to induce apoptosis leads to enhanced immunogenicity of the virus and to reduced pathogenicity. Moreover, our recent evidence indicates that the immunogenicity can also be enhanced by immunostimulatory cytokines. Thus, we will construct recombinant viruses that express genes encoding proapoptotic proteins and cytokines in order to stimulate immunity or otherwise interfere with viral pathogenesis in order to enhance their efficacy and safety. In addition to the practical implications of this approach for vaccine development, information derived from studying these viruses will provide a better understanding of factors that stimulate immunity against rabies and may provide a strategy based on co-expression of immunostimulatory proteins that finds broad application to other vaccines. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI060686-04
Application #
7371050
Study Section
Special Emphasis Panel (ZRG1-VMD (01))
Program Officer
Cassetti, Cristina
Project Start
2005-03-01
Project End
2010-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
4
Fiscal Year
2008
Total Cost
$253,935
Indirect Cost
Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Schutsky, Keith; Curtis, Dana; Bongiorno, Emily K et al. (2013) Intramuscular inoculation of mice with the live-attenuated recombinant rabies virus TriGAS results in a transient infection of the draining lymph nodes and a robust, long-lasting protective immune response against rabies. J Virol 87:1834-41
Li, Jianwei; Ertel, Adam; Portocarrero, Carla et al. (2012) Postexposure treatment with the live-attenuated rabies virus (RV) vaccine TriGAS triggers the clearance of wild-type RV from the Central Nervous System (CNS) through the rapid induction of genes relevant to adaptive immunity in CNS tissues. J Virol 86:3200-10
Li, Jianwei; Faber, Milosz; Dietzschold, Bernhard et al. (2011) The role of toll-like receptors in the induction of immune responses during rabies virus infection. Adv Virus Res 79:115-26
Faber, M; Dietzschold, B; Li, J (2009) Immunogenicity and safety of recombinant rabies viruses used for oral vaccination of stray dogs and wildlife. Zoonoses Public Health 56:262-9
Faber, Milosz; Li, Jianwei; Kean, Rhonda B et al. (2009) Effective preexposure and postexposure prophylaxis of rabies with a highly attenuated recombinant rabies virus. Proc Natl Acad Sci U S A 106:11300-5
Dietzschold, Bernhard; Li, Jianwei; Faber, Milosz et al. (2008) Concepts in the pathogenesis of rabies. Future Virol 3:481-490
Pulmanausahakul, Rojjanaporn; Li, Jianwei; Schnell, Matthias J et al. (2008) The glycoprotein and the matrix protein of rabies virus affect pathogenicity by regulating viral replication and facilitating cell-to-cell spread. J Virol 82:2330-8
Li, Jianwei; McGettigan, James P; Faber, Milosz et al. (2008) Infection of monocytes or immature dendritic cells (DCs) with an attenuated rabies virus results in DC maturation and a strong activation of the NFkappaB signaling pathway. Vaccine 26:419-26
Faber, Milosz; Faber, Marie-Luise; Li, Jianwei et al. (2007) Dominance of a nonpathogenic glycoprotein gene over a pathogenic glycoprotein gene in rabies virus. J Virol 81:7041-7
Blanton, Jesse D; Self, Joshua; Niezgoda, Michael et al. (2007) Oral vaccination of raccoons (Procyon lotor) with genetically modified rabies virus vaccines. Vaccine 25:7296-300

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