This program focuses on vaccine candidates for HIV-1 based on two replication-defective chimpanzee (chimp) adenovirus (Ad) vectors, termed AdC6 and AdC7. The program has four interlinked goals. Our first goal is to pursue clinical development of AdC6 and AdC7 vectors expressing gag of HIV-1 to test the safety of each vector in dose-escalation phase I trials, and to assess the immunogenicity of both vectors combined in a heterologous prime boost regimen in a phase IIA trial. Clinical trials will be conducted under the auspices of the NIAID-sponsored HIV Vaccine Trials Network (HVTN). Our second goal is to further optimize the AdC6 and AdC7 vectors for later stage clinical trials. Our third goal is a research objective to define the quality of T cell responses to AdC6/AdC7 prime boost regimens in both experimental animals and human vaccine recipients. Evidence is mounting that different vaccine regimens not only influence the magnitude but also the quality of the ensuing cellular immune responses, and that this quality substantially influences progression of HIV-1 infections toward disease. Vaccine-induced correlates of protection against HIV-1 associated illness remain poorly defined, which has made it difficult to compare the clinical potential of the vectors considered as platforms for a candidate HIV vaccine.
We aim to carefully define pertinent characteristics of the cellular immune responses elicited by chimp Ad vector prime boost regimens in preclinical models, and how such characteristics correlate with protection against challenge with model pathogens. Our fourth goal is to elucidate the effect of pre-existing T cells to conserved antigens of Ads on the performance of chimp Ad vectors as vaccine carriers. The prevalence of such T cells will be determined in human cohorts from the US and Africa. Their effect on vaccine-induced T cell responses will first be assessed in experimental animals and then in human vaccine recipients. Definition of the characteristics of effective immune responses in animals with comparison studies in human vaccine recipients will advance our understanding of the correlates of immune protection to be pursued in future efforts of AIDS vaccine development.
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|Tuyishime, Steven; Haut, Larissa H; Zhu, Caihong et al. (2014) Enhancement of recombinant adenovirus vaccine-induced primary but not secondary systemic and mucosal immune responses by all-trans retinoic acid. Vaccine 32:3386-92|
|Small, Juliana C; Haut, Larissa H; Bian, Ang et al. (2014) The effect of adenovirus-specific antibodies on adenoviral vector-induced, transgene product-specific T cell responses. J Leukoc Biol 96:821-31|
|Cervasi, Barbara; Carnathan, Diane G; Sheehan, Katherine M et al. (2013) Immunological and virological analyses of rhesus macaques immunized with chimpanzee adenoviruses expressing the simian immunodeficiency virus Gag/Tat fusion protein and challenged intrarectally with repeated low doses of SIVmac. J Virol 87:9420-30|
|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|
|Zhou, Dongming; Zhou, Xiangyang; Bian, Ang et al. (2010) An efficient method of directly cloning chimpanzee adenovirus as a vaccine vector. Nat Protoc 5:1775-85|
|Haut, Larissa H; Lin, Shih W; Tatsis, Nia et al. (2010) Robust genital gag-specific CD8+ T-cell responses in mice upon intramuscular immunization with simian adenoviral vectors expressing HIV-1-gag. Eur J Immunol 40:3426-38|
|Hutnick, Natalie A; Carnathan, Diane; Demers, Korey et al. (2010) Adenovirus-specific human T cells are pervasive, polyfunctional, and cross-reactive. Vaccine 28:1932-41|
|Makedonas, George; Hutnick, Natalie; Haney, Danielle et al. (2010) Perforin and IL-2 upregulation define qualitative differences among highly functional virus-specific human CD8 T cells. PLoS Pathog 6:e1000798|
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