A Phase I Double Blind, Placebo-Controlled, Randomized Study of a Multigenic HIV-1 Adenovirus Subtype 35 Vector Vaccine in Healthy Uninfected Adults

• DOI: 10.1371/journal.pone.0041936
• Publication Date: 2012-08-03T22:58:24Z
• Authors: Michael C. Keefer; Jill Gilmour; Peter Hayes; Dilbinder Gill; Jakub Kopycinski; Hannah Cheeseman; Michelle Cashin-Cox; Marloes Naarding; Lorna Clark; Natalia Fernandez; Catherine A. Bunce; Christine M. Hay; Sabrina Welsh; Wendy Komaroff; Lottie Hachaambwa; Tony Tarragona-Fiol; Eddy Sayeed; Devika Zachariah; James Ackland; Kelley Loughran; Burc Barin; Emmanuel Cormier; Josephine H. Cox; Patricia Fast; Jean-Louis Excler
• Keywords: Adult; CD4-Positive T-Lymphocytes; Male; 0301 basic medicine; Adolescent; Science; Dose-Response Relationship, Immunologic; Retroviridae Proteins; 610; HIV Infections; CD8-Positive T-Lymphocytes; Antibodies, Viral; 03 medical and health sciences; Double-Blind Method; 616; Humans; AIDS Vaccines; Immunity, Cellular; Adenoviruses, Human; Q; Vaccination; R; Middle Aged; Immunity, Humoral; 3. Good health; HIV-1; Medicine; Female; Research Article

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.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.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.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.ClinicalTrials.gov NCT00851383.