Phase I safety and immunogenicity evaluations of an alphavirus replicon HIV-1 subtype C gag vaccine in healthy HIV-1-uninfected adults
Clinical and Vaccine Immunology
Fred Hutchinson Cancer Research Center, Seattle, WA, United States; Division of AIDS, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, United States; AlphaVax, Inc., Research Triangle Park, NC, United States; Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Nelson R. Mandela School of Medicine, Durban, South Africa; Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States; Bill and Melinda Gates Foundation, Seattle, WA, United States; Applied Genetic Technologies Corporation, Alachua, FL, United States; Weill Cornell Medical College, New York, NY, United States; Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
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 ( 51Cr)-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. Copyright © 2012, American Society for Microbiology. All Rights Reserved.
avx 101; gamma interferon; Human immunodeficiency virus antibody; Human immunodeficiency virus vaccine; interleukin 2; placebo; unclassified drug; adult; Alpha virus; antibody response; antibody titer; article; CD4+ T lymphocyte; CD8+ T lymphocyte; controlled study; cytotoxic T lymphocyte; dose response; double blind procedure; drug dose escalation; drug fatality; drug induced headache; drug safety; drug tolerability; drug withdrawal; enzyme linked immunosorbent assay; enzyme linked immunospot assay; fatigue; female; hepatitis A; hepatitis E; human; Human immunodeficiency virus 1 infection; immunogenicity; injection site pain; injection site reaction; intracellular cytokine staining; lymphocyte proliferation; male; multicenter study; normal human; phase 1 clinical trial; priority journal; randomized controlled trial; replicon; South Africa; staining; structural gene; United States; Venezuelan equine encephalitis; viremia; Adolescent; Adult; AIDS Vaccines; Alphavirus; Botswana; Cytokines; Double-Blind Method; Encephalomyelitis, Venezuelan Equine; Enzyme-Linked Immunosorbent Assay; Enzyme-Linked Immunospot Assay; Female; gag Gene Products, Human Immunodeficiency Virus; HIV Antibodies; HIV Infections; HIV-1; Humans; Interferon-gamma; Male; Middle Aged; South Africa; T-Lymphocytes, Cytotoxic; United States; Young Adult