Viral encephalitis is a compelling bioterror disease target. Most of the causative agents, such as Nipah (NV), West Nile (WNV), Japanese encephalitis (JE) and Rabies viruses are accessible in nature, can infect via aerosol delivery, a means suitable for weaponization, and cause a lethal outcome in at least some infected individuals. The clinical course of these RNA virus infections is usually non-specific such that diagnosis is often delayed until after virus reaches the CNS and existing therapies are no longer effective. The most lethal viral encephalitis is rabies, with few documented survivors of the disease until recently. While rabies virus is a Category C bioterror agent due to the availability of vaccines that are protective either prior to, or in the first days following exposure, the current reagents fail to clear the virus from the CNS. We have recently constructed a live-attenuated rabies vaccine virus, designated TriGAS, that has a unique safety profile and the capacity to clear an existing wild-type rabies virus from the CNS in mice. The primary objective of this project is translational, to determine if TriGAS administration, with or without passively administered rabies virus neutralizing antibodies, is likely to trigger non- cytolytic clearance of rabies virus from the human CNS. TriGAS therapy will be optimized in mice, validated in dogs, and preclinically correlated with biomarkers of protective immunity in TriGAS-infected human brain tissues in vitro. Cerebrospinal fluid and serum samples from patients who either died of or recovered from CNS rabies infection will be studied to determine whether aspects critical to the development of a protective immune response differ between humans and the animal models. If so, TriGAS will be engineered to mitigate the difference, for example by expressing a chemokine or cytokine. TriGAS will be engineered to express glycoproteins from other viruses capable of causing encephalitis, potentially to serve as a vaccine vector for the clearance of multiple viruses from the CNS. The secondary objective of the project is therefore to determine if TriGAS expressing NV, WNV, and JE glycoproteins have similar safety profiles and evidence of efficacy as the parent virus, the goal being to develop a single vaccine that can safely clear several types of encephalitis viruses from CNS tissues.

Public Health Relevance

Virus infections of the brain are a major health concern, particularly with respect to bioterrorism, because there is no specific treatment of established infections. Rabies is a classic example. This project will examine whether a new vaccine that shows potential for clearing rabies virus from the nervous system is likely to be safe and effective in humans and can be modified for use in other epidemic virus infections of the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI093369-04
Application #
8660277
Study Section
Special Emphasis Panel (ZAI1-NLE-M (J3))
Program Officer
Cassetti, Cristina
Project Start
2011-06-01
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
4
Fiscal Year
2014
Total Cost
$945,437
Indirect Cost
$140,951
Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Willoughby Jr, Rodney E (2015) Rabies: Rare Human Infection - Common Questions. Infect Dis Clin North Am 29:637-50
Barkhouse, Darryll A; Faber, Milosz; Hooper, D Craig (2015) Pre- and post-exposure safety and efficacy of attenuated rabies virus vaccines are enhanced by their expression of IFNγ. Virology 474:174-80
Yang, Yang; Huang, Ying; Gnanadurai, Clement W et al. (2015) The inability of wild-type rabies virus to activate dendritic cells is dependent on the glycoprotein and correlates with its low level of the de novo-synthesized leader RNA. J Virol 89:2157-69
Gnanadurai, C W; Huang, C T; Kumar, D et al. (2015) Novel Approaches to the Prevention and Treatment of Rabies. Int J Virol Stud Res 3:8-16
Lebrun, Aurore; Portocarrero, Carla; Kean, Rhonda B et al. (2015) T-bet Is Required for the Rapid Clearance of Attenuated Rabies Virus from Central Nervous System Tissue. J Immunol 195:4358-68
Chai, Qingqing; She, Ruiping; Huang, Ying et al. (2015) Expression of neuronal CXCL10 induced by rabies virus infection initiates infiltration of inflammatory cells, production of chemokines and cytokines, and enhancement of blood-brain barrier permeability. J Virol 89:870-6
Barkhouse, Darryll A; Garcia, Samantha A; Bongiorno, Emily K et al. (2015) Expression of interferon gamma by a recombinant rabies virus strongly attenuates the pathogenicity of the virus via induction of type I interferon. J Virol 89:312-22
Gnanadurai, Clement W; Yang, Yang; Huang, Ying et al. (2015) Differential Host Immune Responses after Infection with Wild-Type or Lab-Attenuated Rabies Viruses in Dogs. PLoS Negl Trop Dis 9:e0004023
Huang, Ying; Chen, Zhenhai; Huang, Junhua et al. (2015) Parainfluenza virus 5 expressing the G protein of rabies virus protects mice after rabies virus infection. J Virol 89:3427-9
Caicedo, Yolanda; Paez, Andres; Kuzmin, Ivan et al. (2015) Virology, immunology and pathology of human rabies during treatment. Pediatr Infect Dis J 34:520-8

Showing the most recent 10 out of 17 publications