title: Recombinant adenovirus type 5 HIV gag/pol/nef vaccine in South Africa: unblinded, long-term follow-up of the phase 2b HVTN 503/Phambili study.
abstract: BACKGROUND
  The HVTN 503/Phambili study, which assessed the efficacy of the Merck Ad5 gag/pol/nef subtype B HIV-1 preventive vaccine in South Africa, was stopped when futility criteria in the Step study (assessing the same vaccine in the Americas, Caribbean, and Australia) were met. Here we report long-term follow-up data.
  
  
  METHODS
  HVTN 503/Phambili was a double-blind, placebo-controlled, randomised trial that recruited HIV-1 uninfected, sexually active adults aged 18-35 years from five sites in South Africa. Eligible participants were randomly assigned (1:1) by computer-generated random numbers to either vaccine or placebo, stratified by site and sex. Cox proportional hazards models were used to estimate HIV-1 infection in the modified intention-to-treat cohort, all of whom were unmasked early in follow-up. The trial is registered with ClinicalTrials.gov, number NCT00413725 and the South African National Health Research Database, number DOH-27-0207-1539.
  
  
  RESULTS
  Between Jan 24, 2007, and Sept 19, 2007, 801 participants (26·7%) of a planned 3000 were randomly assigned (400 to vaccine, 401 to placebo); 216 (27%) received only one injection, 529 (66%) received only two injections, and 56 (7%) received three injections. At a median follow-up of 42 months (IQR 31-42), 63 vaccine recipients (16%) had HIV-1 infection compared with 37 placebo recipients (9%; adjusted HR 1·70, 95% CI 1·13-2·55; p=0·01). Risk for HIV-1 infection did not differ according to the number of vaccinations received, sex, circumcision, or adenovirus type 5 (Ad5) serostatus. Differences in risk behaviour at baseline or during the study, or annualised dropout rate (7·7% [95% CI 6·2-9·5] for vaccine recipients vs 8·8% [7·1-10·7] for placebo recipients; p=0·40) are unlikely explanations for the increased rate of HIV-1 infections seen in vaccine recipients.
  
  
  CONCLUSIONS
  The increased risk of HIV-1 acquisition in vaccine recipients, irrespective of number of doses received, warrants further investigation to understand the biological mechanism. We caution against further use of the Ad5 vector for HIV vaccines.
  
  
  BACKGROUND
  National Institute of Allergy and Infectious Diseases, Merck, and South African Medical Research Council.
authors.affiliation: Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa; South African Medical Research Council, Cape Town, South Africa. Electronic address: gray@pixie.co.za.
authors.forename: Glenda E
authors.initials: GE
authors.lastname: Gray
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Moodie
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Metch
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Gilbert
authors.affiliation: Desmond Tutu HIV Foundation, University of Cape Town, Cape Town, South Africa.
authors.forename: Linda-Gail
authors.initials: LG
authors.lastname: Bekker
authors.affiliation: Aurum Institute for Health Research, Johannesburg, South Africa.
authors.forename: Gavin
authors.initials: G
authors.lastname: Churchyard
authors.affiliation: MEDUNSA HIV Clinical Research Unit, University of Limpopo, Mankweng-E, South Africa.
authors.forename: Maphoshane
authors.initials: M
authors.lastname: Nchabeleng
authors.affiliation: Centre for AIDS Programme for Research in South Africa, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Koleka
authors.initials: K
authors.lastname: Mlisana
authors.affiliation: Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Fatima
authors.initials: F
authors.lastname: Laher
authors.affiliation: Desmond Tutu HIV Foundation, University of Cape Town, Cape Town, South Africa.
authors.forename: Surita
authors.initials: S
authors.lastname: Roux
authors.affiliation: Centre for AIDS Programme for Research in South Africa, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Mngadi
authors.affiliation: Aurum Institute for Health Research, Johannesburg, South Africa.
authors.forename: Craig
authors.initials: C
authors.lastname: Innes
authors.affiliation: MEDUNSA HIV Clinical Research Unit, University of Limpopo, Mankweng-E, South Africa.
authors.forename: Matsontso
authors.initials: M
authors.lastname: Mathebula
authors.affiliation: Vaccine Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Allen
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: M Julie
authors.initials: MJ
authors.lastname: McElrath
authors.affiliation: Infectious Diseases and Vaccines Clinical Research, Merck and Company, North Wales, PA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Robertson
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Kublin
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Corey
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage*; D000256:Adenoviridae / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D005822:Genetic Vectors; D015658:HIV Infections / Q000453:epidemiology / Q000517:prevention & control*; D006801:Humans; D015994:Incidence; D008297:Male; D016016:Proportional Hazards Models; D011498:Protein Precursors / Q000276:immunology*; D018570:Risk Assessment; D013019:South Africa; D014614:Vaccines, Synthetic / Q000276:immunology; D055815:Young Adult; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000276:immunology*; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000276:immunology*; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D011498:Protein Precursors; D014614:Vaccines, Synthetic; D054301:gag Gene Products, Human Immunodeficiency Virus; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; D054302:pol Gene Products, Human Immunodeficiency Virus; C091950:pr160 gag-pol precursor protein, Human immunodeficiency virus 1