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While scientists may come up with approaches to HIV/AIDS vaccines which seem promising in laboratory experiments and animal studies, the only way to truly determine a vaccine's safety, effectiveness in stimulating an immune response and ability to prevent HIV infection or delay progression of HIV disease, is to test it in people.
This testing process occurs through a series of clinical trials. HIV/AIDS vaccine clinical trials have taken place in a range of populations and locations around the world.
Clinical trials are used to test experimental drugs, behavioral interventions and other strategies to prevent or treat HIV and many other diseases. The clinical trials sequence described below is the one used to evaluate HIV/AIDS vaccine candidates. All candidates go through a version of this sequence, which includes at least three types of trials:
- Phase I trials generally involve less than a hundred volunteers. This phase is used to determine the safety of the candidate vaccine. Volunteers are closely monitored to see if the candidate causes illnesses or any severe side effects. Phase I trials also measure the types and strength of the immune responses caused by the vaccines. This is called measuring immunogenicity. The same candidate may be tested in several Phase I trials in different populations to gather information about the safety and immunogenicity of different dosages or immunization schedules.
- Phase II trials involve several hundred volunteers from low- and high-risk populations. These trials gather additional information on safety and immunogenicity in a larger population of people. Since these trials involve more people, researchers can learn more about the types of immune responses caused by the vaccine.
- Efficacy Trials: These are studies in which a candidate is evaluated to determine whether it prevents HIV infection or delays disease progression in people who receive the vaccine and later become HIV-infected through exposure during unprotected sex or other high-risk activities. There are two different types of efficacy trials:
- Test-of-Concept trials are smaller than traditional Phase III efficacy studies. They can provide preliminary evidence of efficacy and can help vaccine developers make more informed decisions about whether or not to move the product into a full Phase III trial. The size of test-of-concept studies depends on various factors including the rates of new HIV infections (incidence) in the community where the trial is taking place.
- Phase III trials are large-scale studies designed to provide definitive information about the efficacy of the vaccine. One or more Phase III trials can be used as the basis for gaining regulatory approval of an experimental candidate. These trials usually involve thousands, or tens of thousands, of volunteers from high-risk populations. These trials generally take several years. For more information on how Phase IIb and Phase III trials are designed to measure efficacy, see below.
Every HIV/AIDS vaccine trial has a slightly different design or protocol. However in general these trials are randomized, placebo-controlled and double-blind. Randomized means that the volunteers are randomly assigned to a group, or study "arm". Placebo-controlled means that some of the participants receive an inactive substance, called a placebo, which is indistinguishable from the candidate vaccine but does not have any immune effects. Double-blind means that neither the volunteers nor the trial staff know whether the volunteers are receiving the experimental candidate or the placebo.
When a vaccine candidate has completed Phase I and Phase II trials and has been proven safe and immunogenic, it moves to efficacy trials. These studies take place in communities that have been studied, generally for two to three years, prior to the launch of the efficacy trials. The two to three years of "preparedness" studies provide information about rates of new HIV infection (incidence) in the community. This information is critical for Phase III trials.
Volunteers in efficacy trials are randomized to the vaccine or placebo arm. Volunteers in both arms receive extensive counseling about HIV/AIDS prevention. They are reminded at enrollment and at all study visits that there is no way of knowing whether or not the vaccine is effective, or of knowing whether they have received the vaccine or the placebo. They are given condoms and behavior change information; IV drug users should receive clean needles.
These volunteers are then followed for several years. At the end of the trial, the study team compares rates of HIV infection in the two study "arms." If the vaccine is effective, then the incidence rate in the group of volunteers will be lower than the incidence rate in the placebo group. Alternatively, the volunteers who received the vaccine and became HIV infected could show less severe or slower HIV disease progression than volunteers in the placebo group who became HIV infected. This would also be a sign of vaccine efficacy, and it is one of the reasons why all trial volunteers are followed for the duration of the trial, whether they remain HIV-uninfected or not.
HIV/AIDS VACCINE TRIALS TO DATE
A range of products have entered the HIV vaccine "pipeline" but few have made it to efficacy trials.
Since 1983-84, when HIV was identified as the cause of AIDS-an important precursor to HIV/AIDS vaccine research-there have been three Phase III efficacy trials: one in North American men who have sex with men and heterosexual women; one in Thailand involving intravenous drug users; and a second one in Thailand involving a large community where heterosexual contact is the primary risk factor.
The first two trials involved a candidate called AIDSVAX. They were completed in 2003 and did not find any efficacy. The third efficacy trial in Thailand is ongoing. It is evaluating a prime-boost combination of AIDSVAX and a candidate called ALVAC.
While there have only been a few HIV/AIDS efficacy trials to date, more are planned and the field is expanding every year.
For more information on where trials are happening click here for more information on how to volunteer for a trial and what's involved see Participation in a Trial.
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