Phase I Safety and Immunogenicity Evaluations of an Alphavirus Replicon HIV-1 Subtype C gag Vaccine in Healthy HIV-1-Uninfected Adults

Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Clinical and vaccine Immunology: CVI (Impact Factor: 2.47). 08/2012; 19(10):1651-1660. DOI: 10.1128/CVI.00258-12
Source: PubMed


On the basis of positive preclinical data, we evaluated the safety and immunogenicity of an alphavirus replicon HIV-1 subtype C gag vaccine (AVX101), expressing a nonmyristoylated form of Gag, in two double-blind, randomized, placebo-controlled clinical trials in healthy HIV-1-uninfected adults. Escalating doses of AVX101 or placebo were administered subcutaneously to participants in the United States and Southern Africa. Because of vaccine stability issues, the first trial was halted prior to completion of all dose levels and a second trial was implemented. The second trial was also stopped prematurely due to documentation issues with the contract manufacturer. Safety and immunogenicity were evaluated through assessments of reactogenicity, reports of adverse events, and assessment of replication-competent and Venezuelan equine encephalitis (VEE) viremia. Immunogenicity was measured using the following assays: enzyme-linked immunosorbent assay (ELISA), chromium 51 ((51)Cr)-release cytotoxic T lymphocyte (CTL), gamma interferon (IFN-γ) ELISpot, intracellular cytokine staining (ICS), and lymphoproliferation assay (LPA). Anti-vector antibodies were also measured. AVX101 was well tolerated and exhibited only modest local reactogenicity. There were 5 serious adverse events reported during the trials; none were considered related to the study vaccine. In contrast to the preclinical data, immune responses in humans were limited. Only low levels of binding antibodies and T-cell responses were seen at the highest doses. This trial also highlighted the difficulties in developing a novel vector for HIV.

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    • "Phase I trials of HIV-1C candidate vaccines, based upon modified vaccinia Ankara and recombinant adeno-associated virus vaccine vector candidates have been conducted in India [2] [3], but generated modest immune responses. Similarly, the phase I trial of an alphavirus replicon HIV-1C gag vaccine (AVX101) generated low levels of binding antibodies and T-cell responses [4]. Alternative approaches need to be explored in order to provide a better HIV-1C vaccine vector candi- date. "
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