This Project is designed to pursue clinical development of two replication-defective chimpanzee (chimp)adenovirus (Ad) vectors, termed AdC6 and AdC7. We developed the chimp Ad vectors to circumvent preexistingneutralizing antibodies, which are commonly found in humans to human serotypes of adenovirusesand which reduce uptake of the corresponding Ad vectors and hence their ability to induce transgeneproduct-specific immune responses. Neutralizing antibodies to AdC6 and AdC7 are rare in humans residingin the US or Asia, and lower in Sub-Saharan Africans than antibodies against other Ad vectors currently intesting. AdC6 and AdC7 vectors expressing antigens of HIV-1 or SIV induce potent and sustained T cellmediated immune responses in experimental animals, which increase upon sequential use of the two vectorsin prime boost regimens. In rhesus macaques primed with AdC7 vectors or Ad vectors of the humanserotype 5 (AdHuS) and then challenged with SHIV89.6P, AdC7 primed NHPs showed better control of viralload and less loss of CD4+ T cells compared to animals primed with the AdHuS vectors. Similar to AdHuS,AdC6 and AdC7 vectors are genetically stable, exhibit suitable growth characteristics, and production andquality control of vectors have been established. We are proposing to develop AdC6 and AdC7 vectors forinitial early phase human clinical trials that express gag of HIV-1 clade B (AdCGHIVgag, AdC7HIVgag).Clinical data on AdHuS based HIV-1 gag vaccines are available and this will allow for a comparison with thechimp Ad vectors. Pre-clinical development and testing of AdC6 and AdC7 vectors expressing additionalsequences of HIV-1 for their potential use in future large scale clinical trials will be pursued by Project 2 ofthis application.In this application we plan to initiate two phase I trials which will address the safety andtolerability of the AdC6 and AdC7 vectors in separate dose escalation trials in human volunteers. In addition,since we do not expect that a single dose of a vaccine, as can be tested in the phase I trials, will result inimpressive HIV-1 antigen-specific immune responses, we are proposing a phase IIA trial in which the twochimp Ad vectors are tested in a prime boost regimen, using each vector twice in a 4-dose regimen in humanvolunteers. We will conduct the clinical trials through HVTN, which is best poised to recruit and enroll humanvolunteers, conduct the trial in adherence to Good Clinical Practice (GCP) guidelines for ethical conduct ofresearch involving human subjects and requisite standards and reporting requirements of U.S. Food andDrug Administration (FDA) and National Institutes of Health (NIH), ensure trial compliance, and assessvaccine safety and immunogenicity using sophisticated and validated assays. Studies by HVTN will becomplemented by studies of Project 3, which will assess in human volunteers the quality of vaccine-inducedgag-specific T cell responses in relationship to pre-existing immunity to the vaccine carrier.
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