IAVI B001 Clinical trial of Ad35-GRIN/ENV (USA): This Phase I trial, done in collaboration with the University of Rochester Medical Center, evaluates the safety and immunogenicity of an AIDS vaccine candidate built into a vector that is based on serotype 35 of the adenovirus (Ad35).

Key facts:

• The vaccine candidate is being tested in 56 adult, HIV-uninfected, healthy, low-risk volunteers in a randomized, placebo-controlled, double-blind study.  Volunteers received either a candidate vaccine or the placebo intramuscularly at months 0 and 6. The vaccine candidate was given at three dosage levels: 2 billion, 20 billion and 200 billion virus particles. An Ad35-GRIN candidate (i.e. lacking the ENV A insert) has also been also assessed for safety and immunogenicity at 0 and 6 months, at a dosage level of 10 billion virus particles.

• The vaccine candidate was designed and assessed by IAVI in preclinical studies. It incorporates into the Ad35 genome portions of several synthetic genes for proteins from clade A of HIV-1, the predominant type of HIV circulating in East Africa. 

• The underlying technology for the Ad35 vector was licensed from Crucell, NV, a Dutch biotech company, and the vaccine candidate was manufactured by Transgene, SA, a French biotech.

• Initial analyses of the data gathered in this trial suggest the vaccine is both safe and immunogenic.
  

IAVI B002: Prime-boost trial of adjuvanted GSK investigational AIDS vaccine with Ad35-GRIN (Kenya, Uganda, Zambia): This Phase I trial is the first to evaluate the safety and immunogenicity of a candidate of two components – a protein-based vaccine component developed and manufactured by GlaxoSmithKline (GSK) and a viral vector vaccine component manufactured by Transgene made from a version of Adenovirus serotype 35 (Ad35) that has been stripped of its ability to replicate inside cells. The trial is sponsored by IAVI and will be conducted in partnership with GlaxoSmithKline (GSK), the Kenya AIDS Vaccine Initiative (KAVI) in Nairobi, the Uganda Virus Research Institute-IAVI (UVRI-IAVI) in Entebbe, Uganda, the Medical Research Council-Uganda Virus Research Institute (MRC-Masaka) in Masaka, Uganda, and the Zambia Emory HIV Research Project in Lusaka (ZEHRP-Lusaka), Zambia. Enrollment in the trial has begun at KAVI in Nairobi and screening has begun at MRC-Masaka, UVRI-IAVI, and ZEHRP-Lusaka. Previous preclinical and Phase I studies suggest that both vaccine components have potential for use as components in an AIDS vaccine. This study will evaluate whether these two components used in combination will produce broader and stronger immune responses than can be achieved with either component alone.

Key facts:

• The trial will enroll approximately 140 HIV-uninfected volunteers between the ages of 18 and 40.

• The trial is expected to take approximately two years to complete.

• In a Phase I study conducted in Ghent, Belgium, the adjuvanted HIV protein vaccine component exhibited an acceptable safety profile, was generally well-tolerated and elicited good CD4+ T-cell immune responses in humans.

• Preliminary data from an IAVI-sponsored Phase I study being conducted at the University of Rochester in Rochester, New York, of Ad35-based vaccine candidates known as Ad35-GRIN/ENV and Ad35-GRIN indicate the candidates were generally safe and well-tolerated and elicited good CD8+ T-cell immune responses in the majority of volunteers.

IAVI B003/IPCAVD-004: Prime-boost trial of Ad26.ENVA.01 and Ad35.ENV (US, Kenya, Rwanda, South Africa): This Phase I trial will evaluate the safety and immunogenicity of two adenovirus vector-based vaccines. It is a joint effort of the Beth Israel Deaconess Medical Center (BIDMC), the HIV Vaccine Trials Network (HVTN), the National Institute of Allergy and Infectious Diseases’ Division of AIDS (NIAID DAIDS), the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, the biopharmaceutical company Crucell, and a number of clinical trial centers. Six clinical research centers are participating in B003/IPCAVD-004: Brigham and Women’s Hospital in Boston, the Kenya AIDS Vaccine Initiative (KAVI) in Nairobi, the Projet San Francisco clinical research center in Kigali, Rwanda, and three HVTN research centers in South Africa: Desmond Tutu HIV Foundation in Cape Town, the Perinatal HIV Research Unit in Soweto, and the Aurum Institute for Health Research in Klerksdorp. The trial is testing whether delivering these vaccines in sequential prime-boost combination will induce different types of immune responses or enhance those responses. Specifically, the strategy might induce both antibody and T-cell responses, and thus elicit a response of greater magnitude, broader potency and longer duration than would either vaccine candidate alone.

Key facts:

• The trial will enroll 212 healthy volunteers between the ages of 18 and 50, will assess the two candidate vaccines delivered in six different prime-boost regimens, and will take approximately two years to complete.

• Both vectors bear synthetic versions of the env gene of HIV.

• The Ad26.ENVA.01 vaccine candidate was developed by researchers at the Beth Israel Deaconess Medical Center and is manufactured by the Dutch biopharmaceutical company Crucell. The Ad35-ENV vaccine candidate was developed by IAVI and is manufactured by the French biotechnology firm Transgene.

• In previous studies in the US in which BIDMC and IAVI have been involved, preliminary data showed that candidate vaccines based on adenovirus serotypes 26 and 35 had a good safety profile and elicited immune responses in humans. 
  

Completed Trials

Prime-boost trial of ADVAX and TBC-M4 (India): In collaboration with The Indian Council of Medical Research (ICMR), IAVI supported a Phase I clinical trial to evaluate the safety and immunogenicity of a prime-boost regimen of two AIDS vaccine candidates, ADVAX and TBC-M4.

Key facts:

• This Phase I, randomized, double-blind, placebo-controlled trial enrolled a total of 32 volunteers at two ICMR institutions, the National AIDS Research Institute (NARI) in Pune, India, and the Tuberculosis Research Centre (TRC) in Chennai, India. YRG CARE, a nongovernmental organization in Chennai, collaborated with TRC to mobilize local communities for the trial.

• ADVAX, a DNA AIDS vaccine candidate, was used to prime the immune system to respond to the HIV antigens it carries. TBC M4—an AIDS vaccine candidate based on a vector built from recombinant Modified Vaccinia Ankara (MVA), a weakened version of the smallpox vaccine—was then be used to boost that response.

• An initial IAVI-supported Phase I trial of the TBC-M4 vaccine candidate at the TRC in Chennai previously established that the vaccine candidate is safe, well-tolerated and capable of generating an immune response—albeit modest—at the higher dose assessed.

• TBC-M4 was designed by a biotech firm in the U.S. in collaboration with Dr. Sekhar Chakrabarty from the National Institute of Cholera and Enteric Diseases in Kolkata, India. It targets HIV-1 subtype C, the predominant HIV subtype in India, and contains synthetic copies of 6 HIV genes known as env, gag, reverse transcriptase, rev, tat and nef.

• The AIDS vaccine candidate ADVAX is a DNA vaccine containing synthetic copies of HIV-1 subtype C genes env, gag, pol, nef and tat. It was designed by the Aaron Diamond Research Centre in New York City, through collaboration with Rockefeller University in New York City and the International AIDS Vaccine Initiative. This trial was the third AIDS vaccine trial to be conducted successfully in India and enrolled 41% female volunteers.

• Initial analyses of the data gathered in this trial suggest the vaccine regimens are both safe and immunogenic.

Prime-boost trial of ADVAX and TBC-M4 (UK): This Phase I trial, conducted in collaboration with Imperial College London and the St. Stephen’s AIDS Trust at the Chelsea and Westminster Hospital is another randomized, double blind, placebo-controlled trial of ADVAX and TBC-M4

Key facts:

• The ADVAX and TBC M4 candidate vaccines were evaluated for safety and immunogenicity in a prime-boost regimen. The study enrolled 32 healthy, HIV-negative men and women volunteers at low risk for HIV infection.
  
• This study differed from the India trial in the mode of administration of the ADVAX candidate and the dosages and vaccination regimens.
  
• The results of the trials from both countries are currently under analysis.
  

Intermittent pre-exposure prophylaxis (PrEP) (Kenya, Uganda): These small Phase I/II studies were launched in October 2009 at the Kenya AIDS Vaccine Initiative, in Nairobi, the Centre for Geographic Medical Research – Coast, in Kilifi, Kenya, and the Medical Research Council Centre unit in Entebbe, Uganda. The PrEP studies were designed to determine whether tenofovir plus emtricitabine (TDF/FTC) tablet administered on an intermittent or daily basis is safe and acceptable. The studies also compare adherence and drug levels between the intermittent and daily regimens. The studies were too small to evaluate whether intermittent or daily PrEP is effective in preventing HIV transmission.

Key facts:

• Each of the two studies enrolled approximately 72 volunteers, who were assigned to take either one placebo tablet or one tablet of FTC/TDF, also known as Truvada, either daily or intermittently. Those on the intermittent regimen were also asked to take a dose Mondays and Fridays, and post-coital doses within two hours after sex, but not to exceed one dose per day.
  
• Initial results, presented at the International AIDS Conference in July 2010, reveal that:
  
  · Fixed doses of PrEP, either daily dosing or fixed Monday and Friday dosing (intermittent), had similar and relatively high adherence rates among the study populations.
  
  · Regimens of one tablet of FTC/TDF, administered daily or intermittently, have similarly good safety profiles.
  
  · Intermittent dosing is feasible in at-risk populations in Africa. However, post-coital adherence was low.
  
• The IAVI trials were the first  clinical studies to test whether intermittent oral PrEP is safe and feasible, and to evaluate what drug levels can be achieved when oral PrEP is taken intermittently by at-risk populations.
  

The data from these trials are being analyzed now. Depending on the results of the trial, intermittent PrEP regimens might need to be tested further to gather more information on adherence and drug levels in populations for which the regimen is thought to be useful. 

Currently, we know that one large study of daily PrEP in MSM reported significant efficacy (iPrEX) whereas one trial in women has been stopped because it was unlikely to show efficacy (FEM-PrEP).  Learn more.