A phase I double blind, placebo-controlled, randomized study of a multigenic HIV-1 adenovirus subtype 35 vector vaccine in healthy uninfected adults

PLoS One. 2012;7(8):e41936. doi: 10.1371/journal.pone.0041936. Epub 2012 Aug 3.

Abstract

Background: We conducted a phase I, randomized, double-blind, placebo-controlled trial to assess the safety and immunogenicity of escalating doses of two recombinant replication defective adenovirus serotype 35 (Ad35) vectors containing gag, reverse transcriptase, integrase and nef (Ad35-GRIN) and env (Ad35-ENV), both derived from HIV-1 subtype A isolates. The trial enrolled 56 healthy HIV-uninfected adults.

Methods: Ad35-GRIN/ENV (Ad35-GRIN and Ad35-ENV mixed in the same vial in equal proportions) or Ad35-GRIN was administered intramuscularly at 0 and 6 months. Participants were randomized to receive either vaccine or placebo (10/4 per group, respectively) within one of four dosage groups: Ad35-GRIN/ENV 2×10(9) (A), 2×10(10) (B), 2×10(11) (C), or Ad35-GRIN 1×10(10) (D) viral particles.

Results: No vaccine-related serious adverse event was reported. Reactogenicity events reported were dose-dependent, mostly mild or moderate, some severe in Group C volunteers, all transient and resolving spontaneously. IFN-γ ELISPOT responses to any vaccine antigen were detected in 50, 56, 70 and 90% after the first vaccination, and in 75, 100, 88 and 86% of Groups A-D vaccine recipients after the second vaccination, respectively. The median spot forming cells (SFC) per 10(6) PBMC to any antigen was 78-139 across Groups A-C and 158-174 in Group D, after each of the vaccinations with a maximum of 2991 SFC. Four to five HIV proteins were commonly recognized across all the groups and over multiple timepoints. CD4+ and CD8+ T-cell responses were polyfunctional. Env antibodies were detected in all Group A-C vaccinees and Gag antibodies in most vaccinees after the second immunization. Ad35 neutralizing titers remained low after the second vaccination.

Conclusion/significance: Ad35-GRIN/ENV reactogenicity was dose-related. HIV-specific cellular and humoral responses were seen in the majority of volunteers immunized with Ad35-GRIN/ENV or Ad35-GRIN and increased after the second vaccination. T-cell responses were broad and polyfunctional.

Trial registration: ClinicalTrials.gov NCT00851383.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • AIDS Vaccines / administration & dosage*
  • AIDS Vaccines / genetics
  • AIDS Vaccines / immunology
  • Adenoviruses, Human / genetics
  • Adenoviruses, Human / immunology*
  • Adolescent
  • Adult
  • Antibodies, Viral / blood
  • Antibodies, Viral / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Dose-Response Relationship, Immunologic
  • Double-Blind Method
  • Female
  • HIV Infections / blood
  • HIV Infections / genetics
  • HIV Infections / immunology
  • HIV Infections / prevention & control*
  • HIV-1 / genetics
  • HIV-1 / immunology*
  • Humans
  • Immunity, Cellular / drug effects
  • Immunity, Cellular / genetics
  • Immunity, Humoral / drug effects
  • Immunity, Humoral / genetics
  • Male
  • Middle Aged
  • Retroviridae Proteins / genetics
  • Retroviridae Proteins / immunology*
  • Vaccination*

Substances

  • AIDS Vaccines
  • Antibodies, Viral
  • Retroviridae Proteins

Associated data

  • ClinicalTrials.gov/NCT00851383

Grant support

This study was funded by the International AIDS Vaccine Initiative and its donors, including the generous support of the American people through the United States Agency for International Development (USAID; USAID Cooperative Agreement Number GPO-A-00-06-00006-00). The contents of this manuscript are the responsibility of IAVI and do not necessarily reflect the views of USAID or the US government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.