Phase I safety and immunogenicity evaluations of an alphavirus replicon HIV-1 subtype C gag vaccine in healthy HIV-1-uninfected adults.
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.
Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. mwecker@fhcrc.org
M
M
Wecker
P
P
Gilbert
N
N
Russell
J
J
Hural
M
M
Allen
M
M
Pensiero
J
J
Chulay
Ya-Lin
YL
Chiu
S S
SS
Abdool Karim
D S
DS
Burke
D016915:AIDS Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D000293:Adolescent; D000328:Adult; D000524:Alphavirus / Q000235:genetics; D001902:Botswana; D016207:Cytokines / Q000032:analysis; D004311:Double-Blind Method; D004685:Encephalomyelitis, Venezuelan Equine / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D015483:HIV Antibodies / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control*; D015497:HIV-1 / Q000145:classification / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis; D008297:Male; D008875:Middle Aged; D013019:South Africa; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014481:United States; D055815:Young Adult; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
D016915:AIDS Vaccines; D016207:Cytokines; D015483:HIV Antibodies; D054301:gag Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma