Phase II Prime-Boost Trial Begins in the US

By Regina McEnery

A Phase II trial testing the safety and efficacy of a combination of two AIDS vaccine candidates developed by the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases (NIAID), part of the US National Institutes of Health (NIH), recently began enrolling volunteers in the US. The trial, which is sponsored by NIAID and is being conducted by the HIV Vaccine Trials Network (HVTN), is referred to as HVTN 505. Researchers aim to enroll 1,350 men who have sex with men (MSM) at 15 clinical research centers in 12 US cities.

The two vaccine candidates being evaluated in HVTN 505 will be administered sequentially in a prime-boost regimen. Volunteers will first receive three vaccinations with a DNA-based candidate that contains non-infectious HIV fragments or immunogens, followed by a second vaccine candidate that employs an inactivated strain of the common cold virus, known as adenovirus serotype 5 (Ad5), to ferry HIV immunogens into the body to provoke an immune response against HIV. Neither vaccine candidate can cause HIV infection.

The HVTN 505 trial will evaluate the safety of the vaccine candidates as well as their efficacy; however the trial is not designed to determine whether the candidates can block HIV infection entirely. The efficacy of the prime-boost regimen will instead be determined by measuring whether individuals who receive the vaccine candidates and become HIV infected through natural exposure have lower viral loads (the quantity of HIV circulating in blood) than those who receive an inactive placebo.

Soon after a person becomes infected with HIV, their viral load is typically very high. Once a person’s immune system responds specifically to HIV, the viral load usually drops to a much lower level, referred to as the set point viral load. Generally, the lower the set point viral load, the longer it takes for a person to develop AIDS. In HVTN 505, researchers will assess if volunteers who received the DNA/Ad5 prime-boost regimen have lower set point viral loads than those who receive an inactive placebo.

The prime-boost regimen being evaluated in HVTN 505 was originally slated for a much larger trial, known as PAVE 100, a Phase IIb test-of-concept trial of 8,500 HIV-uninfected men and women from North and South America and Africa. But the start of PAVE 100 was postponed in 2007, after another Ad5-based candidate, known as MRKAd5, which was developed by Merck, failed to prevent HIV infection or lower viral load in vaccinated volunteers who subsequently became HIV infected in a Phase IIb trial known as the STEP study. The PAVE 100 protocol then went through numerous revisions before NIAID settled on the current HVTN 505 trial.

Based on the STEP trial results, which showed that uncircumcised male vaccine recipients who had pre-existing antibody immunity to Ad5 from being exposed to the naturally circulating cold virus were at increased risk of HIV infection compared to placebo recipients with the same characteristics, trial investigators for HVTN 505 decided to only enroll circumcised MSM who also have no pre-existing Ad5 immunity (see Primer, this issue.) “We are deeply committed to the population that we are hoping to recruit for this trial,” says Scott Hammer, study chair of HVTN 505. “We will do our part to provide them with counseling and education and make sure that they are fully aware of the STEP trial results.”

Alan Fix, chief of the Vaccine Clinical Research Branch at the NIH, says there are a number of differences between the regimen being assessed in HVTN 505 and MRKAd5. In the STEP trial, volunteers received three doses of MRKAd5, whereas in HVTN 505 they will receive only one dose of a different Ad5 candidate, as part of a prime-boost regimen. The HIV immunogens in the DNA/Ad5 candidates being tested in HVTN 505 also differ from those in MRKAd5. “We don’t know if this vaccine, with its similarities and differences from the Merck vaccine, will behave the same way,” says Fix, who added that the DNA/Ad5 candidates being tested in HVTN 505 are not intended for future licensure.

The Fenway Community Health Center in Boston is one of the research centers now screening volunteers for the HVTN 505 trial. “While we hope to be vaccinating people very soon, it’s been an intense screening process,” says Ken Mayer, principal investigator at this research center. Community forums are being held at many clinical research centers to help potential participants understand the trial and put the STEP results in their proper context.