It is the primary objective of this program to elucidate correlates of immune-mediated protection against HIV-1 infection using pre-clinical animal models. To this end, Project 1 will determine humoral and cell-mediated immune responses to an attenuated SIV, termed SIVGY that induces protective immunity to subsequent challenge with a heterologous pathogenic SIV. Project 3 will determine immune responses elicited by different prime-boost vaccine regimens using combinations of DNA vaccines, E1-deleted adenovirus (Ad) vectors and poxvirus vectors. Project 2 will use passive immunization with neutralizing antibodies to determine baseline parameters of antibody-mediated protection with the long-term to develop vaccines that induce B and T cells. Project 3 will assess the role of vaccine-induced mucosal T cells in limiting the spread of SIV. It is the secondary objective of this program to determine if vaccine-induced immune responses including those induced by Ad vectors can be detrimental and if further modifications of E1-deleted Ad vectors can improve both their safety and immunogenicity/efficacy. To this end, Project 3 will test the hypothesis that CD4+ T cell responses induced by viral vector vaccines against the transgene product or components of the vector facilitate disease progression upon SIV infection of nonhuman primates. Project 1 will attempt to improve the efficacy and safety profile of Ad vector vaccines by generating and testing 2nd generation E1-deleted Ad vectors that will have an additional deletion of E2a to reduce synthesis of the highly immunogenic structural antigens of Ad vectors. The application is subdivided into the following 3 Projects and 2 Cores. Project 1 (H. Ertl): Vaccine-Induced Correlates of Protection Project 2 (R. Ruprecht): Neutralizing Antibody Coverage for CTL Vaccines Project 3 (G. Silvestri): Mucosal T Cell Responses and Protection from Simian AIDS Core A (H. Ertl): Administrative Core Core B (X. Zhou): Vector Core

Public Health Relevance

The overall goal of the Program is to further our knowledge on correlates of protection against HIV-1 using pre-clinical animal models. This, in turn, will help to design an efficacious vaccine to HIV-1. Efforts to develop a vaccine against this pathogen are of interest to public health considering the global impact of HIV-1 infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI082282-02
Application #
7924012
Study Section
Special Emphasis Panel (ZAI1-EC-A (J2))
Program Officer
Pensiero, Michael N
Project Start
2009-09-01
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2012-08-31
Support Year
2
Fiscal Year
2010
Total Cost
$2,749,162
Indirect Cost
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Emmer, Kristel L; Wieczorek, Lindsay; Tuyishime, Steven et al. (2016) Antibody responses to prime-boost vaccination with an HIV-1 gp145 envelope protein and chimpanzee adenovirus vectors expressing HIV-1 gp140. AIDS 30:2405-2414
Sholukh, Anton M; Byrareddy, Siddappa N; Shanmuganathan, Vivekanandan et al. (2014) Passive immunization of macaques with polyclonal anti-SHIV IgG against a heterologous tier 2 SHIV: outcome depends on IgG dose. Retrovirology 11:8
Kurupati, Raj; Tuyishime, Steve; Kossenkov, Andrew V et al. (2013) Correlates of relative resistance against low-dose rectal simian immunodeficiency virus challenges in peripheral blood mononuclear cells of vaccinated rhesus macaques. J Leukoc Biol 93:437-48
Sholukh, Anton M; Mukhtar, Muhammad M; Humbert, Michael et al. (2012) Isolation of monoclonal antibodies with predetermined conformational epitope specificity. PLoS One 7:e38943
Lasaro, Marcio O; Sazanovich, Marina; Giles-Davis, Wynetta et al. (2011) Active immunotherapy combined with blockade of a coinhibitory pathway achieves regression of large tumor masses in cancer-prone mice. Mol Ther 19:1727-36
Small, Juliana C; Ertl, Hildegund C J (2011) Viruses - from pathogens to vaccine carriers. Curr Opin Virol 1:241-5
Lakhashe, Samir K; Silvestri, Guido; Ruprecht, Ruth M (2011) No acquisition: a new ambition for HIV vaccine development? Curr Opin Virol 1:246-53
Lasaro, Marcio O; Ertl, Hildegund C J (2010) Targeting inhibitory pathways in cancer immunotherapy. Curr Opin Immunol 22:385-90