The program project application of PowderJect Vaccines, Inc. (PJV) and the University of Pittsburgh entails the evaluation of a therapeutic DNA vaccine regimen for human immunodeficiency virus (HIV) infection using the simian immunodeficiency virus (SIV) model in rhesus macaques. The therapeutic DNA vaccine to be evaluated is a single, CMV promoter-based DNA vaccine vector encoding the gag, RT, and nef products of the 17e Fr clone of SIVmac239. This vaccine will be delivered using the clinically-proven particle-mediated (gene gun) delivery device that has been shown to elicit Th1 humoral and cellular responses in man and monkeys. The design of the SIV DNA vaccine vector is intended to closely mimic a clinical HIV-1 DNA vaccine vector that is on a clinical track for human evaluation via the joint clinical development efforts of GlaxoSmithKline (GSK) and PJV. Therefore, the activities described in this application are an integral part of the GSK/PJV clinical co-development efforts for prophylactic and therapeutic AIDS vaccines and will serve three important functions to promote clinical success. First, these activities will provide non-human primate model validation of the immunogenicity and therapeutic vaccine potential of GSK's clinical DNA vaccine vector strategy in the highly relevant SIV/rhesus monkey model. Our recent DNA vaccine trials in the rhesus model using earlier vectors have proven our ability to induce significant prophylactic and therapeutic effects via particle-mediated DNA vaccine technology, in addition, these activities will allow for the evaluation of an exciting new DNA vaccine adjuvant vector encoding the heat-labile enterotoxin of E. coli. This adjuvant vector has been proven safe in an extensive nonhuman primate safety trial and dramatically augments Th1 cellular immune responses to a variety of model antigens in mice and monkeys. Finally, activities described in this application will provide important mechanistic data regarding the induction of systemic and mucosal immunity and virus load containment following therapeutic DNA vaccination (with and without adjuvant) in the rhesus SIV model. Specifically, the proposed therapeutic DNA vaccine trials will allow for determination of the importance of the strength and quality of systemic cellular responses, the role of mucosal immunity and importance of gut viral reservoirs, and the importance of DC / T cell interactions in therapeutic DNA vaccine efficacy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI055944-05
Application #
7009291
Study Section
Special Emphasis Panel (ZAI1-AM-A (M1))
Program Officer
Gupta, Kailash C
Project Start
2003-07-01
Project End
2007-12-31
Budget Start
2006-01-01
Budget End
2007-12-31
Support Year
5
Fiscal Year
2006
Total Cost
$776,346
Indirect Cost
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Murphey-Corb, Michael; Rajakumar, Premeela; Michael, Heather et al. (2012) Response of simian immunodeficiency virus to the novel nucleoside reverse transcriptase inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine in vitro and in vivo. Antimicrob Agents Chemother 56:4707-12
Muthuswamy, Ravikumar; Urban, Julie; Lee, Je-Jung et al. (2008) Ability of mature dendritic cells to interact with regulatory T cells is imprinted during maturation. Cancer Res 68:5972-8
Lee, Je-Jung; Foon, Kenneth A; Mailliard, Robbie B et al. (2008) Type 1-polarized dendritic cells loaded with autologous tumor are a potent immunogen against chronic lymphocytic leukemia. J Leukoc Biol 84:319-25
Pegu, Amarendra; Qin, Shulin; Fallert Junecko, Beth A et al. (2008) Human lymphatic endothelial cells express multiple functional TLRs. J Immunol 180:3399-405