Vaccines that protect against infection are typically developed through a series of studies and trials. After basic biologic research and animal studies have been completed, progressive clinical trials in humans are conducted. Advancement from one phase of a clinical trial to the next depends on the successful completion of the preceding phase.

In phase I trial, the vaccine is tested in a small number (20–80) of healthy, low-risk, noninfected volunteers to determine the safety of the candidate vaccine and the optimal dosage and immunization schedule.

If the vaccine produces the desired immune response and is well tolerated, a phase II trial is conducted with larger numbers (up to a few hundred) of healthy, noninfected volunteers to further establish safety and to refine the dosage and immunization schedules. Larger phase II HIV vaccine trials can help in determining whether significant efficacy is likely; this type of trial has been termed phase IIb HIV vaccine trials (see “Spotlight: Measuring AIDS Vaccine Efficacy: Intermediate versus Full-Scale Trials,” in the International AIDS Vaccine Initiative Newsletter, May 2004, available at http://www.iavireport.org/VAX/VAXMay2004.asp).

Promising vaccine candidates then advance to a phase III trial, which is a much larger-scale trial involving thousands of noninfected, high-risk persons to determine the protective efficacy of the vaccine. This is the last and most important step in evaluation before a vaccine is considered for licensing. Phase III efficacy trials usually require the use of a placebo, which is an inactive substance given to some participants. Researchers compare the data from the placebo with data from the vaccine to determine the efficacy and the safety of the vaccine.

During the past 15 years, several dozen HIV candidate vaccines have entered phase I clinical trials. The candidate vaccines developed and tested to date have been safe and well tolerated, and nearly all, with varying degrees of success, have produced HIV-specific immune responses; several candidates have undergone, or are undergoing, phase II evaluation. As of July 2005, two phase III vaccine trials of first-generation rgp120 vaccine candidates have been completed; these trials failed to show efficacy but demonstrated that HIV vaccine efficacy trials can be successfully conducted in developed and developing countries. Currently, two second-generation vaccine candidates are in efficacy trials. More information on ongoing and completed clinical trials of HIV vaccine candidates can be found at the National Institutes of Health HIV vaccine clinical trials Web site, http://www.aidsinfo.nih.gov/vaccines.

It is anticipated that multiple phase III efficacy trials will be necessary both in developed and developing countries. Similar to the first vaccines for other diseases, the first HIV vaccine(s) may provide limited protection. It is hoped that the early HIV vaccines, like other early vaccines, will quickly lead to improved vaccines with greater safety and efficacy.

Any vaccine trial can fail to show efficacy, in that some candidate vaccines may not provide sufficient, or indeed any, protection. Such failures are sometimes part of the development of an effective vaccine. Researchers must prepare the community, the government, and the medical and public health communities for the possibility of such outcomes. Nonetheless, such trials can be an important step if they are well designed and conducted to lead to clear conclusions, if the population is well informed about the potential risks and benefits, and if the information gathered advances vaccine development.