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.

What are come of the eligibility requirements for volunteers to participate in AIDS vaccine clinical trials?

Before an AIDS vaccine candidate can be tested in clinical trials, various committees comprised of scientists, ethicists, government regulatory bodies, and community members review the plans for the trial, which are known as the trial protocol. The trial protocol details such things as what vaccine candidate will be tested, the goals and design of the study, the number of visits that volunteers will be asked to make to the clinical research center where the trial takes place, when and how data will be collected, as well as many other specifics about how the trial will be conducted and how data will be analyzed once the trial is complete (see VAX November 2003 Primer on Understanding Trial Approval).

Another important detail outlined in the trial protocol is the eligibility criteria for volunteers interested in enrolling in the study. These guidelines for participation are referred to as the inclusion/exclusion criteria for a trial and may include many characteristics about potential volunteers, such as their age range, sex, and overall level of health. Before a volunteer is eligible to enroll in an AIDS vaccine clinical trial, nurses or counselors will collect baseline information about the volunteer from a physical examination, as well as laboratory tests such as collecting a blood sample, to determine whether the individual is healthy. For clinical trials of preventive AIDS vaccine candidates, already being infected with HIV is an exclusion criterion that prohibits someone from participation. Many vaccine trials also exclude volunteers who have a history of adverse reactions to vaccines or a psychiatric condition that could preclude compliance with the trial protocol to ensure the safety of the volunteers.

Individuals who are being treated for other health problems may also be excluded. For instance, AIDS vaccine trials may exclude volunteers who are taking immunosuppressant medications or those who are being treated for tuberculosis. Women who are pregnant or planning to become pregnant are also often excluded from participating in AIDS vaccine trials for safety reasons.

Specifying sexual risk

Some trials may also have specific inclusion criteria pertaining to the level of sexual risk activity of the volunteers. To evaluate the efficacy of preventive AIDS vaccine candidates, researchers must study the candidates in individuals who are potentially at risk of becoming infected with HIV (see VAX May 2008 Primer on Understanding the Recruitment of Volunteers at Risk of HIV Infection). These individuals would also benefit most from a preventive AIDS vaccine, so it is essential they participate in clinical trials. Inclusion criteria specifically related to sexual behavior helps ensure that at-risk individuals are enrolled in the trial. For example, if an AIDS vaccine candidate is being tested in men who have sex with men (MSM), the trial protocol may specify that to be eligible to enroll in the trial, men must report having had unprotected anal intercourse with at least one partner who they knew was HIV infected in the last six months.

Specific exclusion criteria

Exclusion criteria for trials can also be informed by results of previous vaccine trials. Such is the case with HVTN 505, a Phase II trial launched recently to evaluate the safety and efficacy of two vaccine candidates administered sequentially in what is known as a prime-boost regimen (see Global News, this issue, for more details).

One of the candidates being tested in HVTN 505 uses an inactivated cold virus called adenovirus serotype 5 (Ad5), which is manipulated by researchers to carry non-infectious fragments of HIV into the body in the hope of generating an immune response against HIV (see VAX September 2004 Primer on Understanding Viral Vectors). This viral vector-based candidate cannot cause infection or disease either with HIV or with the common cold.

Other Ad5 vectors have been tested in previous trials, including one developed by Merck, known as MRKAd5, which was tested in the Phase IIb trial known as the STEP study (see VAX September 2007 Special Report). MRKAd5 was found to be ineffective. Subsequent findings also indicated that the vaccine candidate may have increased susceptibility to HIV among a certain subset of volunteers. Because Ad5 is a naturally circulating form of a virus that causes the common cold, many individuals have previously been exposed to Ad5, and therefore have developed antibodies against it. In the STEP trial, uncircumcised MSM with high levels of Ad5 antibodies who received MRKAd5 were found to be at an increased risk of HIV infection compared to individuals who received the inactive placebo. Although this result is not fully understood yet, and may have been an anomaly that occurred by chance, researchers who were involved in drafting the protocol for HVTN 505 ultimately decided to exclude uncircumcised men, as well as any volunteers who have pre-existing Ad5 immunity, from this trial. Researchers can determine through a blood test whether an individual has Ad5 antibodies and thereby exclude these individuals from enrolling.

Researchers decided to conduct HVTN 505 only in the US, where prevalence of naturally circulating Ad5 is lower, so that potential volunteers would be less likely to have pre-existing Ad5 immunity and therefore fewer potential volunteers would have to be excluded from participating based on the criteria for enrollment.