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

作者：Keefer Michael C^*; Gilmour Jill; Hayes Peter; Gill Dilbinder; Kopycinski Jakub; Cheeseman Hannah; Cashin Cox Michelle; Naarding Marloes; Clark Lorna; Fernandez Natalia; Bunce Catherine A; Hay Christine M; Welsh Sabrina; Komaroff Wendy; Hachaambwa Lottie; Tarragona Fiol Tony; Sayeed Eddy; Zachariah Devika; Ackland James; Loughran Kelley; Barin Burc; Cormier Emmanuel; Cox Josephine H; Fast Patricia; Excler Jean Louis

来源：PLos One, 2012, 7(8): e41936.

DOI：10.1371/journal.pone.0041936

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 2x10(9) (A), 2x10(10) (B), 2x10(11) (C), or Ad35-GRIN 1610 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-gamma 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.

• 出版日期2012-8-3