title: Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial.
abstract: BACKGROUND
  Observational data and non-human primate challenge studies suggest that cell-mediated immune responses might provide control of HIV replication. The Step Study directly assessed the efficacy of a cell-mediated immunity vaccine to protect against HIV-1 infection or change in early plasma HIV-1 levels.
  
  
  METHODS
  We undertook a double-blind, phase II, test-of-concept study at 34 sites in North America, the Caribbean, South America, and Australia. We randomly assigned 3000 HIV-1-seronegative participants by computer-generated assignments to receive three injections of MRKAd5 HIV-1 gag/pol/nef vaccine (n=1494) or placebo (n=1506). Randomisation was prestratified by sex, adenovirus type 5 (Ad5) antibody titre at baseline, and study site. Primary objective was a reduction in HIV-1 acquisition rates (tested every 6 months) or a decrease in HIV-1 viral-load setpoint (early plasma HIV-1 RNA measured 3 months after HIV-1 diagnosis). Analyses were per protocol and modified intention to treat. The study was stopped early because it unexpectedly met the prespecified futility boundaries at the first interim analysis. This study is registered with ClinicalTrials.gov, number NCT00095576.
  
  
  RESULTS
  In a prespecified interim analysis in participants with baseline Ad5 antibody titre 200 or less, 24 (3%) of 741 vaccine recipients became HIV-1 infected versus 21 (3%) of 762 placebo recipients (hazard ratio [HR] 1.2 [95% CI 0.6-2.2]). All but one infection occurred in men. The corresponding geometric mean plasma HIV-1 RNA was comparable in infected male vaccine and placebo recipients (4.61 vs 4.41 log(10) copies per mL, one tailed p value for potential benefit 0.66). The vaccine elicited interferon-gamma ELISPOT responses in 75% (267) of the 25% random sample of all vaccine recipients (including both low and high Ad5 antibody titres) on whose specimens this testing was done (n=354). In exploratory analyses of all study volunteers, irrespective of baseline Ad5 antibody titre, the HR of HIV-1 infection between vaccine and placebo recipients was higher in Ad5 seropositive men (HR 2.3 [95% CI 1.2-4.3]) and uncircumcised men (3.8 [1.5-9.3]), but was not increased in Ad5 seronegative (1.0 [0.5-1.9]) or circumcised (1.0 [0.6-1.7]) men.
  
  
  CONCLUSIONS
  This cell-mediated immunity vaccine did not prevent HIV-1 infection or reduce early viral level. Mechanisms for insufficient efficacy of the vaccine and the increased HIV-1 infection rates in subgroups of vaccine recipients are being explored.
authors.affiliation: HIV Research Section, San Francisco Department of Public Health, San Francisco, CA, USA. Electronic address: susan.buchbinder@sfdph.org.
authors.forename: Susan P
authors.initials: SP
authors.lastname: Buchbinder
authors.affiliation: Merck Research Laboratories, North Wales, PA, USA.
authors.forename: Devan V
authors.initials: DV
authors.lastname: Mehrotra
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Duerr
authors.affiliation: GHESKIO, Port-au-Prince, Haiti; Weill Medical College of Cornell University, New York, NY, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Fitzgerald
authors.affiliation: Merck Research Laboratories, North Wales, PA, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Mogg
authors.affiliation: Merck Research Laboratories, North Wales, PA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Li
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Gilbert
authors.affiliation: Asociacion Civil IMPACTA Salud y Educacion, Miraflores, Lima, Peru.
authors.forename: Javier R
authors.initials: JR
authors.lastname: Lama
authors.affiliation: NYU Langone Medical Center, New York, NY, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Marmor
authors.affiliation: Hope Clinic at Emory University, Atlanta, GA, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Del Rio
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: M Juliana
authors.initials: MJ
authors.lastname: McElrath
authors.affiliation: Merck Research Laboratories, North Wales, PA, USA.
authors.forename: Danilo R
authors.initials: DR
authors.lastname: Casimiro
authors.affiliation: Merck Research Laboratories, North Wales, PA, USA.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Gottesdiener
authors.affiliation: Merck Research Laboratories, North Wales, PA, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Chodakewitz
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Corey
authors.affiliation: Merck Research Laboratories, North Wales, PA, USA.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Robertson
mesh_terms: D016915:AIDS Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D000293:Adolescent; D000328:Adult; D004311:Double-Blind Method; D005260:Female; D015488:HIV Antigens / Q000145:classification / Q000187:drug effects / Q000302:isolation & purification; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012307:Risk Factors; D012725:Sexual Behavior; D055815:Young Adult
chemical_list: D016915:AIDS Vaccines; D015488:HIV Antigens