Understanding Vaccine Trials

How are AIDS vaccines tested?

Contrary to some people’s fears, AIDS vaccines are not tested by vaccinating people and then deliberately exposing them to HIV. This strategy is rarely used for tests of any experimental vaccine, and never for a vaccine against a disease as serious as HIV. Rather, vaccines are evaluated through a series of trials, called Phase I, Phase II and Phase III. While these trials serve different purposes, all of them involve volunteers who have been counseled about the vaccine being studied and the risks and benefits of trial participation. This is called the informed consent process, and it is designed to ensure that trial volunteers are well-informed of their rights and responsibilities.

Phase I trials enroll small numbers of people who are at low risk for HIV. The primary goal of these first trials is to determine the safety of these products for human use. Vaccines in Phase I trials have already been through extensive testing in animals, which give a good indication of the products’ overall safety and possible toxicities. Once vaccinated, the volunteers are monitored to determine whether or not the vaccine causes any side effects. They also periodically have their blood drawn, and scientists analyze these blood samples to see whether the vaccine has induced immune responses to HIV. It’s important to remember that these responses may or may not protect against HIV—only later, larger trials can determine this.

Phase II trials enroll larger numbers of people and may include some individuals who are at higher risk for HIV. They yield further data on safety and side effects, and on immune responses to the vaccine in this larger population. Phase I and Phase II trials also gather information on vaccine doses and the best schedule for a series of immunizations (most AIDS vaccines in development will require a sequence of immunizations delivered over several months or longer).

Phase III trials are the true test of whether a vaccine provides any protection against infection or disease. These trials generally evaluate an experimental vaccine by comparing the rate of infection in individuals given the experimental vaccine with the rate of infection in a group given an inactive substance, called a placebo. Neither the trial staff nor the volunteers know who has been assigned to receive the vaccine or the placebo until the study is over. This is called a blinded study.

The trials make the assumption that some of them will be exposed to HIV, i.e., through unprotected sex, over the course of the study period. Prior to starting a Phase III trial, vaccine developers gather information on rates of infection, or incidence, in different regions and communities, since this is what determines how many volunteers will be needed and for how long they will have to be followed. The higher the incidence, the fewer volunteers and/or shorter the follow-up period required.

For HIV vaccine trials, these volunteers are usually followed for a period of 2-3 years. Throughout the entire trial, volunteers receive regular HIV/AIDS tests and risk reduction counseling, which reinforces the message that they should not consider themselves to be protected. Those who never theless become infected will be monitored to see whether the vaccine has an impact on viral load or CD4 cell counts, which are markers of the stage of HIV disease. Once completed, the study is "unblinded" and scientists look for differences in infection rates between the vaccine and placebo groups and, in infected participants, in viral load and CD4 counts. If differences are detected, statistical tests are performed to determine whether they are due to the vaccine, or whether they are coincidental. A "statistically significant" result is one which is very unlikely to arise by coincidence, and—if the trial was well designed and carried out—gives a solid scientific answer on whether, and how well, the vaccine works.

In an ideal scenario, a Phase III trial will yield clear answers. But in the real world, there may still be open questions—as with VaxGen’s Phase III study, or the Phase III herpes vaccine trial, both described above. So in practice, there are sometimes multiple Phase III trials of the same product.

Once efficacy is proven, vaccines must then go through an approvals process before they are licensed for use. Even then, countries may need time to develop sites and strategies for delivering the vaccine. These steps can take as long as the trial itself! This is one reason why it is important to design and build these systems in advance in the countries where they are not already in place.