Scientists have identified important immunologic targets on HIV and on infected cells. For example, they know that the glycoprotein 120 (gp120) on the outer coat of the virus contains the region that attaches to cells of the host, the CD4 binding site. Scientists also know that most neutralizing antibodies (proteins that block a virus from infecting cells) in HIV-infected people are directed against gp120. For these reasons, vaccines based on genetically engineered HIV envelope proteins -- gp160 and one of its cleavage products, gp120 -- have been the most well-studied to date.
More than 40 experimental HIV vaccines have been tested in humans worldwide. Vaccine approaches in development or in clinical trials include the following:
After an experimental vaccine performs well in preclinical safety and immunogenicity tests, it must successfully complete three stages of testing in people before development into a licensed product.
A Phase I trial is the first setting in which an experimental HIV vaccine is given to people. Such a trial enrolls about 20 to 80 non-HIV-infected volunteers at apparent low risk of HIV infection. A Phase I trial primarily seeks information on safety, usually assessing any vaccine-related side effects by comparing the vaccine with an inactive placebo or control that looks like the test product. A Phase I trial also can provide data on the vaccine's immunogenicity, including the dose and administration schedule required to achieve optimal immune responses. If the vaccine elicits neutralizing antibodies, scientists can study how these react against HIV strains from the same or other clades to determine the potential breadth of protection. A Phase I trial may last one to two years.
Once Phase I trials show that the experimental HIV vaccine is well-tolerated, it can advance into Phase II trials. These trials enroll more people, up to a few hundred, and often include some volunteers at higher risk for acquiring HIV. Researchers gather data about safety and immune responses, asking more sophisticated questions that such larger trials allow. Optimally, the trials are randomized and double-blind, meaning that volunteers are assigned at random to a study group and that neither the health care workers nor the patients know what preparations the patients receive. Phase II trials usually last one to two years.
The most promising candidate vaccines move into Phase III or efficacy trials, enrolling large numbers of non-HIV-infected people at high risk for exposure to the virus. A Phase III trial usually is designed to ensure the collection of enough data on safety and effectiveness to support a license application, if warranted. The vaccine may be tested against a placebo or a vaccine such as hepatitis B of known potential benefit to the study population. An efficacy trial can involve thousands of volunteers and therefore takes much longer, at least four years, to complete.
In August 1987, NIAID opened the first clinical trial of an experimental HIV vaccine at the NIH Clinical Center in Bethesda, Md. This safety trial eventually enrolled 138 non-infected healthy volunteers. The gp160 subunit candidate vaccine tested caused no serious adverse effects.
Since the first trial, more than 40 preventive HIV vaccine trials have been initiated worldwide. These Phase I/II trials examine the vaccine's safety and provide preliminary information on its ability to stimulate immune responses.
The NIAID AIDS Vaccine Evaluation Group (AVEG) is the largest U.S. cooperative HIV vaccine clinical trials group. The AVEG, which began enrolling volunteers in February 1988, includes the following:
As of January 1997, more than 2,000 men and women have participated in preventive HIV vaccine trials conducted at six medical center AVEU sites located in Baltimore, Nashville, Seattle, St. Louis, Birmingham and Rochester, N.Y.
To date, all the vaccine candidates tested have been well-tolerated, generally producing only mild side effects typical of most vaccines. The first candidates tested stimulated production of antibodies, although levels decreased within a relatively short period of time. Initial formulations and dosages of these vaccines produced few or low levels of neutralizing antibodies and rarely elicited cytotoxic T cells, which are invoked through cell-mediated immunity to kill HIV-infected cells.
With newer protocols, using increased vaccine dosages, different immunization schedules, experimental adjuvants and new recombinant proteins, more promising data regarding the induction of neutralizing antibodies and cytotoxic T cells have emerged.
In December 1992, NIAID launched the first Phase II HIV vaccine clinical trial. Earlier trials enrolled non-infected people at low risk of HIV infection and primarily sought data on safety. This trial includes non-infected volunteers with a history of high-risk behavior--injection drug use, multiple sex partners or sexually transmitted diseases. Participants are counseled repeatedly to avoid any behavior that puts them at risk of HIV infection. Follow-up for this trial has been extended to four years.
The trial will help determine if these distinct populations, representative of people likely to be enrolled in large-scale efficacy trials, respond differently to vaccines. The trial also will provide more detailed data on the safety and ability of vaccines to stimulate immune responses.
A second Phase II HIV vaccine clinical trial is now under way at AVEU sites and in the HIV Network for Prevention Trials (HIVNET).
Experimental HIV vaccines are growing in number and kind. Clinical trials will yield valuable information about the relative effects on immune response of different formulations and delivery methods.
Although the challenges are daunting, scientists remain optimistic that safe and effective HIV vaccines can be developed. Novel ways to present HIV proteins to the immune system continue to be designed and tested, as do new antigen/adjuvant vaccine formulations. A growing number and variety of experimental vaccines are entering clinical tests in primates and humans, and more trials are exploring whether changing immunization schedules, increasing booster doses or using a combination vaccine strategy can stimulate stronger, more durable immune responses. Together, progress in basic and clinical research is moving scientists closer toward identifying products suitable for large-scale HIV vaccine efficacy trials.