“A phase I/II clinical trial to evaluate the safety and immunogenicity of a multiclade HIV-1 DNA plasmid vaccine boosted by a multiclade HIV-1 recombinant adenovirus-5 vector vaccine in HIV uninfected adult volunteers in East Africa”
Purpose
The objectives of the study were to evaluate the safety and immunogenicity of a multiclade A, B and C HIV DNA prime (VRC-HIVDNA016-00-VP) boosted with a multiclade A, B and C recombinant Adenovirus type 5 vector (VRC-HIVADV014-00-VP). The vaccine was provided by the NIH Vaccine Research Center (VRC) consisting of a multiclade A, B and C HIV DNA prime (VRC-HIVDNA016-00-VP) boosted with a multiclade A, B and C recombinant Adenovirus type 5 vector (VRC-HIVADV014-00-VP).
Team: Leonard Maboko (Principal Investigator), Mirjam Schunk, Arne Kroidl (Clinical Research Coordinator)
TREATMENT (Vaccine/Placebo) IMMUNIZATION SCHEDULE
Approach
Overall 324 HIV uninfected, low risk adult volunteers were enrolled from three East African study sites (Uganda, Kenya, Tanzania). Study participants attended 14 scheduled study visits over a period of 12 months. The DNA vaccine was administered by Biojector® 2000 needle-free injection device at weeks 0, 4 and 8, with Ad5 boosting at week 24 in a 1:1 ratio of placebo to vaccine.
MMRC participated in the phase II part of the study enrolling 60 participants. This was the first HIV vaccine trial conducted in Tanzania introducing high levels of community engagement and outreach activities as well as quality control, monitoring and reporting requirements according to international standards for IND trials at the MMRC study site.
Results
Enrollment in Mbeya started in June 2006 and was closed with 60 participants (60% females) in October 2006. During the screening period 491 persons attended briefing session and 280 volunteers were screened leading to a briefing/screening/enrolment ratio of 8:5:1. The last study visit at MMRC took place in September 2007 with 56/60 participants (93%) completing all study visits.
Overall the vaccine was safe and well tolerated. HIV-specific T cell responses were detected in 63% of vaccine recipients. Titres of pre-existing Ad5 neutralizing antibody did not affect the frequency and magnitude of T cell responses in prime-boost recipients but did affect the response rates in participants that received rAd5 alone (P = .037).
Implications from results and other HIV Vaccine Trials
Based on results from the RV172 trial as well as the IAVI 001 and HVTN 204 phase I/II trials investigating the same HIV vaccine candidates (TRIAD Trials) further evaluation was planned for a phase IIb efficacy trial (PAVE 100). Mbeya was involved to recruit 700 HIV negative, high risk volunteers and study preparations were advanced. However, the Adenovirus type 5 vector containing PAVE 100 concept was stopped after results from the phase IIb STEP Study and the South African Phambili Trial were announced in September 2007. The STEP study which used a recombinant non-replicating adenovirus serotype 5 vector Merck HIV candidate vaccine (MRK Ad5) was discontinued early, because the MRK Ad5 vaccine was ineffective both at preventing HIV infection and at reducing viral loads in study participants who became infected with HIV during the trial. Of concern, more HIV infections were seen in people who received the MRK Ad5 vaccine than in people who got the placebo. Additional post hoc analyses demonstrated a trend toward a higher rate of infection for male vaccinees with prior immunity to rAd5 from natural as well as for uncircumcised men (www.stepstudies.com).
RV172 Amendment
Following the STEP and Phambili trial results the RV172 Trial was amended for a 2 years long term HIV safety and immunogenicity 4-monthly follow-up period. The RV172 Amendment started in Mbeya in June 2009 and will be completed in April 2011.
Sponsor
U.S. Division of AIDS (DAIDS), National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Health (NIH).
Partners
The trial is lead by the Walter Reed Army Institute of Research (WRAIR) and the U.S. Military HIV Research Program (MHRP). The study site partners are the:
• U.S. Army Medical Research Unit-Kenya and Kenya Medical Research Institute in Kericho, Kenya
• Makerere University-Walter Reed Project in Kampala,Uganda,
• NIMR-Mbeya Medical Research Center (MMRC) in Mbeya,Tanzania
The LMU Department of Infectious Diseases and Tropical Medicine participate in this trial providing study coordination and management of the laboratory and immunology services. Logistical support is provided through the Munich office within the NIMR-MMRC collaboration.
Publications
Kibuuka H, Kimutai R, Maboko L, Sawe F, Schunk MS, Kroidl A, Shaffer D, Eller LA, Kibaya R, Eller MA, Schindler KB, Schuetz A, Millard M, Kroll J, Dally L, Hoelscher M, Bailer R, Cox JH, Marovich M, Birx DL, Graham BS, Michael NL, de Souza MS, Robb ML. A phase 1/2 study of a multiclade HIV-1 DNA plasmid prime and recombinant adenovirus serotype 5 boost vaccine in HIV-Uninfected East Africans (RV 172). J Infect Dis. 2010 Feb 15; 201(4):600-7
