Understanding Inclusion/Exclusion Criteria

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.