This clinical research project is for clinical trials related to active immunity (preventive vaccines) and passive immunity (monoclonal antibodies) directed against HIV that are conducted by the VRC Clinical Trials Program (CTP). The clinical trials to evaluate candidate preventive HIV-1 vaccines have included: 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 and device of administration, and prime-boost regimens. The CTP has also advanced clinical trials of monoclonal antibodies aimed at passive immunization against HIV. In FY16, the CTP continued evaluation of broadly neutralizing monoclonal antibody (MAb) VRC01 and began evaluation of an enhanced MAb VRC01LS. A brief summary of each study to date follows. VRC 001 (01-I-0079) evaluated a clade B, single plasmid DNA vaccine developed by the VRC in collaboration with other intramural investigators. Results published: 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. Results 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. Results 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. Results published: Vaccine, 2007. 25(20):p.4085-92. VRC 008 (05-I-0148) was 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. Results published: PLoS One, 2013; 8(4):e59340. VRC 009 (05-I-0081) was 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. Similarly, VRC 010 (05-I-0140) was 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. Results from VRC 009 and 010 published: PLoS One, Feb 2010, 5(2):p.1-15 VRC 011 (06-I-0149) was 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. Results published: PLoS One, 2014 Mar 12;9(3). VRC 012 (07-I-0167) was 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 were completed in FY10. Results in Press: PLoS One. VRC 015 (08-I-0171) was 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 were completed in FY10; long-term follow-up was completed in FY14. Results published: PLoS One. 2014 Sep 29;9(9). VRC 016 (11-I-0197) was a Phase Ib descriptive study to evaluate the kinetics and pattern of early innate and adaptive immune responses to the rAd5 vaccine, VRC-HIVADV014-00-VP, alone and after priming with a DNA vaccine. This study was developed and initiated in FY11 and all follow-up completed in FY14. HVTN 505 (09-I-0163) was a multicenter Phase 2b efficacy 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 1/2 safety and immunogenicity evaluations of the vaccines were completed, this study was developed in collaboration with the Division of AIDS and HVTN and designed to see whether or not the vaccines have efficacy in prevention of HIV or an effect on HIV viral load in vaccine recipients as compared to placebo recipients who acquire HIV infection during 2 years of follow-up. Study enrollments were completed in FY13. Study vaccinations were discontinued in April 2013 based on DSMB recommendations when study results showed that prospectively defined efficacy futility criteria had been met. Long term follow-up is ongoing. Results published: N Engl J Med. 2013 Nov 28;369(22):2083-92. VRC 602 (14-I-0019) was a Phase 1 dose-escalation study of the safety and pharmacokinetics of human monoclonal antibody VRC01, administered intravenously or subcutaneously to healthy adults. The study was initiated in FY14 with follow-up was on-going in FY15. Results published: Clin Exp Immunol. 2015 Dec;182(3):289-301. VRC 606 (16-I-0018) is the first study of a new generation of highly potent and broadly neutralizing HIV-1 human MAb, VRC01LS, targeted against the HIV-1 CD4 binding site. The study examines safety, tolerability and pharmacokinetics. VRC01LS is being administered to healthy adults by the intravenous and subcutaneous routes. The study was initiated and is on-going in FY16.
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