Clinical Research on HIV/AIDS Vaccines

The National Institute of Allergy and Infectious Diseases (NIAID) conducts clinical trials of candidate vaccines to discover which might most successfully protect people from human immunodeficiency virus (HIV) infection (preventive vaccine) or from becoming ill after they acquire the virus (therapeutic vaccine). (Throughout this fact sheet scientific terms common to vaccine research have been printed in bold-faced type and defined.)

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:

  • subunit vaccine: a piece of the outer surface of HIV, such as gp160 or gp120, produced by genetic engineering.
  • recombinant vector vaccine: a live bacterium or virus such as vaccinia (used in the smallpox vaccine) modified to transport into the body a gene that makes one or more HIV proteins.
  • vaccine combination: for example, use of a recombinant vector vaccine to induce cellular immune responses followed by booster shots of a subunit vaccine to stimulate antibody production, referred to as a prime-boost strategy.
  • peptide vaccine: chemically synthesized pieces of HIV proteins (peptides) known to stimulate HIV-specific immunity.
  • virus-like particle vaccine (pseudovirion vaccine): a non-infectious HIV look-alike that has one or more, but not all, HIV proteins.
  • anti-idiotype vaccine: antibodies generated against antibodies to the virus.
  • plasmid DNA vaccine (nucleic acid vaccine): direct injection of genes coding for HIV proteins.
  • whole-inactivated virus vaccine: HIV that has been inactivated by chemicals, irradiation or other means so it is not infectious.
  • live-attenuated virus vaccine: live HIV from which one or more apparent disease-promoting genes of the virus have been deleted.

Clinical Trials Background

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.

Clinical Trials of Preventive Vaccines

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:

  • The AIDS Vaccine Evaluation Units (AVEUs), located at six U.S. research centers, conduct Phase I and II clinical trials of candidate HIV vaccines in low-risk and high-risk HIV-seronegative volunteers.
  • The Central Immunology Laboratory provides state-of-the-art evaluation of humoral and cellular immune responses of vaccinees in AVEG trials. The evaluations use standardized tests, permitting comparison of responses in different individuals and to different candidate vaccines.
  • The Data Coordinating and Analysis Center provides a central facility for collecting and analyzing data from the trials conducted by the AVEUs.
  • The Immunology Laboratory Support for Assessment of Mucosal Immune Responses Induced by AIDS Vaccines evaluates human mucosal immune responses to candidate vaccines in standardized tests, permitting the comparison of responses in volunteers at different AVEUs and in volunteers who receive different candidate vaccines.
  • The Specimen Repository collects and maintains blood samples and other specimens from volunteers in AVEG trials for use in current and future studies.
  • A Data and Safety Monitoring Board periodically reviews data from AVEG studies.

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.

Future Directions

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.

NIAID, a component of the National Institutes of Health, supports research on AIDS, tuberculosis and other infectious diseases as well as allergies and immunology.

Prepared by:
Office of Communications
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, MD 20892

Public Health Service
U.S. Department of Health and Human Services
May 1997

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