This clinical research project is for clinical trials related to preventive HIV vaccines conducted at the VRC Clinic at the NIH Clinical Center. These consist of a screening protocol and clinical trials to evaluate candidate preventive HIV-1 vaccines including: DNA vaccine constructs, a recombinant adenoviral vector serotype 5(rAd5) vaccine, and a recombinant adenoviral vector serotype 35 (rAd35) vaccine. Studies have been designed to evaluate dose, immunogenicity, route of administration, device for administration and prime-boost regimens. A brief summary of each study to date follows. The screening protocol, VRC 000 (02-I-0127), facilitates recruitment and screening of healthy, HIV-negative subjects for investigational preventive HIV vaccine clinical trials. Educational materials on vaccines are reviewed with and provided to subjects before enrollment into a study. Prior to the establishment of the VRC Clinic, a Phase I study VRC 001 (01-I-0079) of a clade B, single plasmid DNA vaccine developed by VRC was conducted through collaboration with other intramural investigators. A manuscript describing results wss published in FY07 J Acquir Immune Defic Syndr, 2007. 44(5): p. 601-5. VRC 004 (03-I-0022) was the first Phase I clinical trial of a multiclade 4-plasmid DNA vaccine, VRC-HIVDNA009-00-VP, which expresses a Gag-Pol-Nef polyprotein from clade B HIV-1 and Env glycoproteins from clades A, B and C. This study evaluated the 2 mg, 4 mg and 8 mg dosage. In FY07 a manuscript describing results was published J Infect Dis, 2006. 194(12): p. 1650-60. The long-term follow-up for the protocol was completed during FY08. VRC 006 (04-I-0128) was the first Phase I clinical trial of an investigational recombinant serotype 5 adenoviral vector (rAd5) vaccine, VRC-HIVADV014-00-VP, for the prevention of HIV infection. This vaccine is composed of 4 adenoviral vectors (in a 3:1:1:1 ratio) that encode for the HIV-1 Gag/Pol polyprotein from clade B and HIV-1 Env glycoproteins from clades A, B, and C, respectively. This study evaluated three dosages. In FY07 a manuscript describing results was published J Infect Dis, 2006. 194(12): p. 1638-49. The long-term follow-up for the protocol was completed during FY09. VRC 007 (04-I-0254) was the first Phase I clinical trial of a multiclade 6-plasmid HIV-1 DNA vaccine, VRC-HIVDNA016-00-VP, which expresses Gag, Pol and Nef proteins from clade B HIV-1 and Env glycoproteins from clades A, B and C. The 4 mg dosage was evaluated. In FY07 a manuscript describing study results was published Vaccine, 2007. 25(20): p. 4085-92. VRC 008 (05-I-0148) is a Phase I study of the prime-boost vaccination regimen consisting of 3 vaccinations with the 6-plasmid DNA vaccine followed by a boost with the rAd5 vaccine. This study evaluated the safety and immunogenicity of both Biojector and needle/syringe as injection devices for the DNA vaccine, as well as safety and immunogenicity of two different dosages for the rAd5 booster. The study was designed to enroll equal numbers of subjects with low and high antibody titers to adenovirus serotype 5 at enrollment in order to gain a better understanding of whether pre-existing antibody affects the safety and immunogenicity of the rAd5 booster. During FY08 week 94 long-term follow-up evaluations were completed and analysis of the primary immunogenicity assays were completed. VRC 009 (05-I-0081) is a Phase I study of the rAd5 vaccine as a booster vaccination in subjects previously immunized with the 4 mg or 8 mg dose of the 4-plasmid multiclade DNA vaccine in the VRC 004 study. Ten subjects enrolled. During FY07 statistical analysis of the study was completed and a manuscript of study results from VRC 009 and 010 combined is under review. VRC 010 (05-I-0140) is a Phase I study of the rAd5 vaccine as a booster vaccination in subjects previously immunized with 4 mg of the 6-plasmid multiclade DNA vaccine in the VRC 007 study. Only a small number of subjects were eligible to participate;4 subjects enrolled and completed the 24 weeks of follow-up. During FY07 statistical analysis of the study was completed and a manuscript of study results from VRC 009 and 010 combined is under review. VRC 011 (06-I-0149) is a Phase I study to evaluate the intramuscular, subcutaneous and intradermal routes of administration for priming vaccinations with either three injections of the 6-plasmid DNA vaccine or one injection of the rAd5 vaccine. In all schedules a rAd5 booster injection is administered IM. Sixty subjects were enrolled;equal numbers of subjects had negative and positive antibody titers to adenovirus serotype 5 at enrollment in order to gain a better understanding of whether pre-existing antibody affects the safety and immunogenicity of the regimens. Follow-up of study participants was completed during FY 09. VRC 012 (07-I-0167) is a Phase I study to evaluate a novel prototype adenoviral vector serotype 35 vaccine (rAd 35-EnvA) at three dosages in Part I of the study and then in Part II of the study heterologous prime-boost schedules with an rAd5-EnvA vaccine will be evaluated. During FY08 the Part I enrollments and vaccinations were completed. The enrollments and study vaccinations for Part II of the study are ongoing in FY09. VRC 015 (08-I-0171) is a Phase I study to evaluate the safety and immunogenicity of both Biojector and needle/syringe as injection devices for the recombinant serotype 5 adenoviral vector (rAd5) vaccine, VRC-HIVADV014-00-VP. The enrollments and study vaccinations are ongoing during FY09. HVTN 505 (09-I-0163) is a multicenter Phase II study of the VRC candidate DNA prime-rAd5 boost HIV vaccine regimen for which the VRC Clinical Trials Core is participating as a site. After Phase I/II safety and immunogenicity evaluations of the vaccines were completed, this study was developed to begin a new phase of evaluation. It is designed to see whether or not the vaccines have an effect on HIV viral load in vaccine recipients as compared to placebo recipients who later acquire HIV infection during about 3 years of follow-up.
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