title: Safety and efficacy of the HVTN 503/Phambili study of a clade-B-based HIV-1 vaccine in South Africa: a double-blind, randomised, placebo-controlled test-of-concept phase 2b study.
abstract: BACKGROUND
  The MRKAd5 HIV-1 gag/pol/nef subtype B vaccine was designed to elicit T-cell-mediated immune responses capable of providing complete or partial protection from HIV-1 infection or a decrease in viral load after acquisition. We aim to assess the safety and efficacy of the vaccine in South Africa, where the major circulating clade is subtype C.
  
  
  METHODS
  We did a phase 2b double-blind, randomised test-of-concept study in sexually active HIV-1 seronegative participants at five sites in South Africa. Randomisation was by a computer-generated random number sequence. The vaccine and placebo were given by intramuscular injection on a 0, 1, 6 month schedule. Our coprimary endpoints were a vaccine-induced reduction in HIV-1 acquisition and viral-load setpoint. These endpoints were assessed independently in the modified intention-to-treat (MITT) cohort with two-tailed significance tests stratified by sex. We assessed immunogenicity by interferon-γ ELISPOT in peripheral-blood mononuclear cells. After the lack of efficacy of the MRKAd5 HIV-1 vaccine in the Step study, enrolment and vaccination in our study was halted, treatment allocations were unmasked, and follow-up continued. This study is registered with the South Africa National Health Research Database, number DOH-27-0207-1539, and ClinicalTrials.gov, number NCT00413725.
  
  
  RESULTS
  801 of a scheduled 3000 participants, of whom 360 (45%) were women, were randomly assigned to receive either vaccine or placebo. 445 participants (56%) had adenovirus serotype 5 (Ad5) titres greater than 200, and 129 men (29%) were circumcised. 34 MITT participants in the vaccine group were diagnosed with HIV-1 (incidence rate 4·54 per 100 person-years) and 28 in the placebo group (3·70 per 100 person-years). There was no evidence of vaccine efficacy; the hazard ratio adjusted for sex was 1·25 (95% CI 0·76-2·05). Vaccine efficacy did not differ by Ad5 titre, sex, age, herpes simplex virus type 2 status, or circumcision. The geometric mean viral-load setpoint was 20,483 copies per mL (n=33) in the vaccine group and 34,032 copies per mL (n=28) in the placebo group (p=0·39). The vaccine elicited interferon-γ-secreting T cells that recognised both clade B (89%) and C (77%) antigens.
  
  
  CONCLUSIONS
  The MRKAd5 HIV-1 vaccine did not prevent HIV-1 infection or lower viral-load setpoint; however, stopping our trial early probably compromised our ability to draw conclusions. The high incidence rates noted in South Africa highlight the crucial need for intensified efforts to develop an efficacious vaccine.
  
  
  BACKGROUND
  The US National Institute of Allergy and Infectious Disease and Merck and Co Inc.
authors.affiliation: Perinatal HIV Research Unit, University of Witwatersrand, Johannesburg, South Africa. gray@pixie.co.za
authors.forename: Glenda E
authors.initials: GE
authors.lastname: Gray
authors.forename: Mary
authors.initials: M
authors.lastname: Allen
authors.forename: Zoe
authors.initials: Z
authors.lastname: Moodie
authors.forename: Gavin
authors.initials: G
authors.lastname: Churchyard
authors.forename: Linda-Gail
authors.initials: LG
authors.lastname: Bekker
authors.forename: Maphoshane
authors.initials: M
authors.lastname: Nchabeleng
authors.forename: Koleka
authors.initials: K
authors.lastname: Mlisana
authors.forename: Barbara
authors.initials: B
authors.lastname: Metch
authors.forename: Guy
authors.initials: G
authors.lastname: de Bruyn
authors.forename: Mary H
authors.initials: MH
authors.lastname: Latka
authors.forename: Surita
authors.initials: S
authors.lastname: Roux
authors.forename: Matsontso
authors.initials: M
authors.lastname: Mathebula
authors.forename: Nivashnee
authors.initials: N
authors.lastname: Naicker
authors.forename: Constance
authors.initials: C
authors.lastname: Ducar
authors.forename: Donald K
authors.initials: DK
authors.lastname: Carter
authors.forename: Adrien
authors.initials: A
authors.lastname: Puren
authors.forename: Niles
authors.initials: N
authors.lastname: Eaton
authors.forename: M Julie
authors.initials: MJ
authors.lastname: McElrath
authors.forename: Michael
authors.initials: M
authors.lastname: Robertson
authors.forename: Lawrence
authors.initials: L
authors.lastname: Corey
authors.forename: James G
authors.initials: JG
authors.lastname: Kublin
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D000293:Adolescent; D000328:Adult; D015331:Cohort Studies; D004311:Double-Blind Method; D005260:Female; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D007371:Interferon-gamma / Q000097:blood; D008297:Male; D016016:Proportional Hazards Models; D012367:RNA, Viral / Q000097:blood; D013019:South Africa; D055815:Young Adult
chemical_list: D016915:AIDS Vaccines; D012367:RNA, Viral; D007371:Interferon-gamma