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

• Published in: The Lancet infectious diseases Vol. 14; no. 5; pp. 388 - 396
• Main Authors: Gray, Glenda E, Prof, Moodie, Zoe, PhD, Metch, Barbara, MS, Gilbert, Peter B, PhD, Bekker, Linda-Gail, Prof, Churchyard, Gavin, PhD, Nchabeleng, Maphoshane, MBChB, Mlisana, Koleka, MBChB, Laher, Fatima, MBBCH, Roux, Surita, MBChB, Mngadi, Kathryn, MPhil, Innes, Craig, MBChB, Mathebula, Matsontso, MBChB, Allen, Mary, MS, McElrath, M Julie, Prof, Robertson, Michael, MD, Kublin, James, MD, Corey, Lawrence, Prof
• Format: Journal Article
• Language: English
• Published: London Elsevier Ltd 01-05-2014; Lancet Publishing Group; Elsevier Limited
• Subjects: Acquired immune deficiency syndrome; Adenoviridae - genetics; Adenovirus; Adolescent; Adult; AIDS; AIDS Vaccines - administration & dosage; Allergies; Biological and medical sciences; Double-Blind Method; Female; Follow-Up Studies; gag Gene Products, Human Immunodeficiency Virus - immunology; Genetic Vectors; HIV; HIV Infections - epidemiology; HIV Infections - prevention & control; Human immunodeficiency virus; Human immunodeficiency virus 1; Human viral diseases; Humans; Immunization; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Incidence; Infectious Disease; Infectious diseases; Male; Medical research; Medical sciences; Men; nef Gene Products, Human Immunodeficiency Virus - immunology; pol Gene Products, Human Immunodeficiency Virus - immunology; Proportional Hazards Models; Protein Precursors - immunology; Public health; Risk Assessment; Risk taking; Sexually transmitted diseases; South Africa; STD; Vaccines; Vaccines, Synthetic - immunology; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Young Adult; South Africa; Africa; Immunopathology; Adenoviridae; Retroviridae; AIDS; Vaccine; Immune deficiency; Lentivirus; Long term; Infection; Virus; Prevention; Adenovirus 5; Immunoprophylaxis; Human adenovirus; Viral disease; Mastadenovirus; Human immunodeficiency virus
• ISSN: 1473-3099; 1474-4457
• DOI: 10.1016/S1473-3099(14)70020-9

Summary 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. Findings 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. Interpretation 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. Funding National Institute of Allergy and Infectious Diseases, Merck, and South African Medical Research Council.