title: A phase I double blind, placebo-controlled, randomized study of a multigenic HIV-1 adenovirus subtype 35 vector vaccine in healthy uninfected adults.
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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00851383.
authors.affiliation: University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America. Michael_Keefer@URMC.Rochester.edu
authors.forename: Michael C
authors.initials: MC
authors.lastname: Keefer
authors.forename: Jill
authors.initials: J
authors.lastname: Gilmour
authors.forename: Peter
authors.initials: P
authors.lastname: Hayes
authors.forename: Dilbinder
authors.initials: D
authors.lastname: Gill
authors.forename: Jakub
authors.initials: J
authors.lastname: Kopycinski
authors.forename: Hannah
authors.initials: H
authors.lastname: Cheeseman
authors.forename: Michelle
authors.initials: M
authors.lastname: Cashin-Cox
authors.forename: Marloes
authors.initials: M
authors.lastname: Naarding
authors.forename: Lorna
authors.initials: L
authors.lastname: Clark
authors.forename: Natalia
authors.initials: N
authors.lastname: Fernandez
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Bunce
authors.forename: Christine M
authors.initials: CM
authors.lastname: Hay
authors.forename: Sabrina
authors.initials: S
authors.lastname: Welsh
authors.forename: Wendy
authors.initials: W
authors.lastname: Komaroff
authors.forename: Lottie
authors.initials: L
authors.lastname: Hachaambwa
authors.forename: Tony
authors.initials: T
authors.lastname: Tarragona-Fiol
authors.forename: Eddy
authors.initials: E
authors.lastname: Sayeed
authors.forename: Devika
authors.initials: D
authors.lastname: Zachariah
authors.forename: James
authors.initials: J
authors.lastname: Ackland
authors.forename: Kelley
authors.initials: K
authors.lastname: Loughran
authors.forename: Burc
authors.initials: B
authors.lastname: Barin
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Cormier
authors.forename: Josephine H
authors.initials: JH
authors.lastname: Cox
authors.forename: Patricia
authors.initials: P
authors.lastname: Fast
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Excler
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology*; D000293:Adolescent; D000328:Adult; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D004311:Double-Blind Method; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000235:genetics; D056724:Immunity, Humoral / Q000187:drug effects / Q000235:genetics; D008297:Male; D008875:Middle Aged; D012191:Retroviridae Proteins / Q000235:genetics / Q000276:immunology*; D014611:Vaccination
chemical_list: D016915:AIDS Vaccines; D000914:Antibodies, Viral; D012191:Retroviridae Proteins