May 2007

Clinical Trials of HIV Vaccines

OVERVIEW

Experimental vaccines are first tested in laboratory and animal studies for safety and immunogenicity. If the results are favorable, a vaccine must successfully complete several phases of testing in people before it can gain Food and Drug Administration (FDA) approval for licensing and marketing to the public. All the phases conduct randomized, controlled, and double-blinded studies. These studies compare the safety and effectiveness of the vaccine to an inactive placebo or a control that may be another licensed vaccine of potential benefit to the study population, such as hepatitis B vaccine.

PHASES OF CLINICAL TRIALS

A Phase I trial is the first setting in which an experimental HIV vaccine is given to people. The trial, which can last up to 2 years, may enroll between 20 to 100 HIV-uninfected volunteers at low risk for HIV infection. A Phase I trial primarily seeks information on safety, particularly looking for any vaccine-related side effects. The trial can also provide data on the dose and administration schedule needed to achieve the optimal immune responses. If the vaccine elicits neutralizing antibodies or cytotoxic T lymphocytes (CTLs), scientists can study whether these responses are broadly protective against a wide variety of HIV strains that scientists refer to as subtypes or clades.

Once Phase I trials show the experimental HIV vaccine is safe, well tolerated, and appears promising, it can advance into Phase II. These trials, which can last longer than 2 years, enroll between 100 to 300 volunteers at high and low risk for acquiring HIV. In these trials researchers gather more data on safety and immunogenicity.

Investigators supported by the National Institute of Allergy and Infectious Diseases (NIAID) investigators are also developing designs for intermediate trials that can provide preliminary answers about a candidate vaccine's efficacy, and determine if the vaccine candidate should move forward into large Phase III, or efficacy, trials. A Phase IIb trial, also known as a "proof-of-concept" trial, is smaller, requiring 2,000 to 5,000 volunteers, is less expensive than Phase III trials, and may provide clues about the immune responses that can protect against disease.

The most promising vaccine candidates move into Phase III, enrolling 10,000 or more HIV-uninfected people at high risk for exposure to the virus. A Phase III trial, which can last up to 4 years, is typically designed to ensure enough data are collected on safety and effectiveness to support a license application to FDA.

CLINICAL TRIALS OF PREVENTIVE HIV VACCINES

Currently, there are no approved preventive vaccines for HIV infection. Since the first HIV vaccine trial opened in 1987, researchers have studied more than 50 different preventive vaccine candidates in more than 100 NIAID-funded clinical trials.

The first HIV vaccine clinical trial opened in August 1987 at the National Institutes of Health Clinical Center in Bethesda, Maryland. This Phase I trial enrolled 138 healthy, uninfected volunteers. The gp160 subunit candidate vaccine tested caused no serious adverse effects. Six months later, the NIAID AIDS Vaccine Evaluation Group (AVEG), the first U.S. cooperative HIV vaccine clinical trials group, began enrolling volunteers in its first trial.

In December 1992, NIAID launched its first Phase II HIV vaccine clinical trial. This trial included uninfected volunteers with a history of high-risk behavior-injection drug use, multiple sex partners, or sexually transmitted infections. Participants were counseled repeatedly to avoid any behaviors that put them at risk of HIV infection.

Created in May 2000, the NIAID-funded HIV Vaccine Trials Network (HVTN) is a network of clinical sites in the United States and abroad dedicated to developing a preventive HIV vaccine by testing and evaluating candidate vaccines in all phases of clinical trials. The network includes more than 25 sites in the United States, Africa, Asia, South America, and the Caribbean.

HVTN's global capacity allows for rapid expansion as more vaccine candidates enter the pipeline for testing and development, and for carrying out large-scale studies of suitable vaccines. HVTN built upon the many accomplishments of the HIV Prevention Trials Network and AVEG, two former NIAID networks that conducted preparedness and HIV vaccine studies. Scientific creativity, along with collaboration among private industry, academia, and government, are key aspects of HVTN's design.

In addition, NIAID's Dale and Betty Bumpers Vaccine Research Center (VRC) conducts research that facilitates the development of effective vaccines for human disease, with the primary focus of research being the development of vaccines for AIDS. Established in 1997 by former President Bill Clinton as part of an initiative to develop an AIDS vaccine and located in Bethesda, VRC develops and tests vaccine candidates in all phases of clinical testing.

VRC works with scientists in academic, clinical, and industrial laboratories through a program of national and international collaborations. The center actively seeks industrial partners for the development, efficacy testing, and marketing of vaccines, and focuses on the development of new methodologies and training opportunities that will benefit all HIV vaccine researchers.

CLINICAL TRIALS OF THERAPEUTIC AIDS VACCINES

Currently, there are no approved therapeutic vaccines for people infected with HIV. To date, scientists have conducted more than 30 NIAID-funded therapeutic vaccine clinical trials. Additionally, new vaccine candidates are being tested as both potential therapeutic and preventive vaccines.

Therapeutic vaccine research started in the early 1990s with several trials in the United States and Europe in volunteers on antiretroviral therapy (ART). In June 1992, AVEG began its first therapeutic vaccine trial, enrolling 55 HIV-infected men and women. The experimental gp160 vaccine was found to be safe. The first therapeutic vaccine trial enrolling asymptomatic HIV-infected children and HIV-infected pregnant women began in 1993.

The current NIAID-funded network conducting therapeutic vaccine studies is the AIDS Clinical Trials Group (ACTG). The group was created in 1987 as a network of domestic clinical sites to develop therapeutic agents to treat HIV and opportunistic infections and malignancies. By 1991, ACTG was divided to create the Adult ACTG (AACTG) and the Pediatric ACTG (PACTG). As the largest network of its kind in the world, ACTG carries out a broad scientific, therapeutic, and pathogenesis-based research agenda.

FUTURE DIRECTIONS

Progress in the basic sciences and clinical research is moving scientists closer to identifying vaccine candidates suitable for large-scale HIV vaccine trials. Researchers continue to design and test novel ways to present HIV proteins to the immune system, as well as develop new antigen-adjuvant vaccine formulations. Although the challenges are daunting, scientists remain hopeful that they can develop safe and effective HIV vaccines.

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. Currently, about 30 NIAID-sponsored preventive HIV vaccine clinical trials are underway or planned for various stages of testing in the United States and internationally. More vaccines will be studied in the next 2 years than in the last 5 years combined, and thousands of additional healthy volunteers from all populations will be needed in the coming years.

MORE INFORMATION

AIDSinfo is a comprehensive resource for up-to-date information on government and industry sponsored HIV/AIDS treatment and prevention clinical trials. AIDSinfo also maintains the most current, federally approved guidelines for treating and preventing HIV/AIDS in adults and children, for AIDS-related illnesses, for managing occupational exposure to HIV, and for preventing HIV transmission from mother-to-child during pregnancy. AIDSinfo is sponsored by the NIH Office of AIDS Research, NIAID, National Library of Medicine, Centers for Disease Control and Prevention, Health Resources and Service Administration, and Centers for Medicare and Medicaid Services.

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