The National Institute of Allergy and Infectious Diseases (NIAID) supports all phases of clinical research, worldwide, to develop vaccines that protect people from infection with the human immunodeficiency virus (HIV), the cause of AIDS. (Scientific terms printed in bold-faced type are defined in the NIAID HIV Vaccine Glossary.)
To help design these vaccines, scientists have identified important targets on HIV and on infected human cells. For example, glycoprotein 120 (gp120) on the outer coat or envelope of the virus contains the CD4 binding site, the region that attaches to human cells. Scientists also know that most neutralizing antibodies in HIV-infected people are directed against gp120. For these reasons, vaccines based on genetically engineered HIV envelope proteins gp120 and a larger molecule, gp160, have been the best studied to date.
Since the first HIV vaccine trial opened in 1987, researchers have studied 31 different preventive vaccine candidates in NIAID-funded clinical trials and nearly 60 worldwide. HIV vaccine research has progressed from its early focus on HIV envelope proteins and the role of antibodies to increased attention on the importance of cytotoxic T cells (CTLs). Many novel vaccine strategies that result in production of both anti-HIV antibodies and CTLs are now being pursued.
Types of experimental AIDS vaccines:
1. Subunit vaccine: a structural piece of HIV, such as the outer surface components, gp160 or gp120, produced by genetic engineering
2. Live vector vaccine: a live bacterium or virus such as vaccinia (used in the smallpox vaccine) modified so it cannot cause disease but can transport into the body a gene or genes that makes one or more HIV proteins
3. 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
4. Peptide vaccine: chemically synthesized pieces of HIV proteins (peptides) known to stimulate HIV-specific immunity
5. Virus-like particle vaccine (pseudovirion vaccine): a non-infectious HIV look-alike that has one or more, but not all, HIV proteins
6. DNA vaccine: direct injection of genes coding for HIV proteins
7. Whole-killed virus vaccine: HIV that has been inactivated by chemicals, irradiation, or other means so it is not infectious
8. Live-attenuated virus vaccine: live HIV from which one or more disease-promoting genes of the virus have been deleted
After an experimental vaccine has been tested in laboratory and animal studies to determine its safety and immunogenicity, it must successfully complete three stages of testing in people before it can be licensed and marketed to the public.
A Phase I trial is the first setting where an experimental HIV vaccine is given to people. Such a trial usually enrolls anywhere from 20 to 100 HIV-uninfected volunteers at apparent low risk of HIV infection. A Phase I trial primarily seeks information on safety, looking for 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 needed to achieve the optimal immune responses. If the vaccine elicits neutralizing antibodies or CTLs, scientists can study how these react against HIV strains from the same or different HIV subtypes or clades to determine if it is likely to be broadly protective. A Phase I trial may last one to two years.
Once Phase I trials show the experimental HIV vaccine is well tolerated and appears promising, 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 additional questions that such larger trials allow. Ideally, the trials are randomized and double-blind. Phase II trials usually last one to two years.
The most promising candidate vaccines then move into Phase III or efficacy trials, enrolling large numbers of HIV-uninfected people whose behavior places them at high risk for exposure to the virus. A Phase III trial usually is designed to ensure enough data is collected on safety and effectiveness to support a license application to the U.S. Food and Drug Administration. 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 take at least four years to complete.
NIAID-supported investigators also are developing creative designs for intermediate studies that can provide preliminary answers about which products to move forward into efficacy trials. An intermediate trial design may help quickly sort out potentially useful vaccines before starting Phase III trials.
Clinical Trials of Preventive HIV Vaccines
In August 1987, NIAID opened the first clinical trial of an experimental HIV vaccine at the National Institutes of Health Clinical Center in Bethesda, Maryland. This Phase I trial eventually enrolled 138 uninfected, healthy volunteers. The gp160 subunit candidate vaccine tested caused no serious adverse effects.
Six months later, the NIAID AIDS Vaccine Evaluation Group (AVEG), the largest U.S. cooperative HIV vaccine clinical trials group at the time, began enrolling volunteers in its first trial.
In December 1992, NIAID launched the first Phase II HIV vaccine clinical trial. Earlier trials enrolled uninfected people at low risk of HIV infection and primarily sought data on safety. That trial includes uninfected volunteers with a history of high-risk behavior - injection drug use, multiple sex partners, or sexually transmitted diseases. Participants were counseled repeatedly to avoid any behavior that puts them at risk of HIV infection. Follow-up for this trial is almost completed.
Since 1987, more than 3,900 HIV-uninfected volunteers in the United States have enrolled in 59 NIAID-supported preventive HIV vaccine studies (55 Phase I and four Phase II studies) involving 31 vaccines. Previous trials were conducted through two former NIAID networks, AVEG and the HIV Network for Prevention Trials (HIVNET). Current vaccine studies are conducted through the HIV Vaccine Trials Network (HVTN).
The HVTN, which was created in May 2000, is a network of clinical sites in the United States and abroad that is dedicated to the development of a preventive HIV vaccine through testing and evaluating candidate vaccines in all phases of clinical trials. The network includes 18 sites in the United States and 11 international sites, including sites in Africa, Asia, South America, and the Caribbean. The HVTN's global capacity will allow for rapid expansion as more vaccine candidates enter the pipeline for testing and development, and for carrying out larger scale studies of suitable vaccines. The HVTN builds upon the many accomplishments of AVEG and HIVNET. Scientific creativity, along with collaboration among private industry, academia, and government, are key aspects of HVTN's design.
Although the challenges are daunting, scientists remain hopeful that they can develop safe and effective HIV vaccines. 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 to identifying products suitable for large-scale HIV vaccine trials.
For information about Food and Drug Administration-approved HIV-related clinical trials being conducted throughout the United States, contact the AIDS Clinical Trials Information Service.
1-800-TRIALS-A (1-800-874-2572) 1-888-480-3739 (TTY/Deaf Access) 301-519-0459 (International) http://www.actis.org
For federally approved treatment guidelines on HIV/AIDS, contact the HIV/AIDS Treatment Information Service.
1-800-HIV-0440 (1-800-448-0440) 1-301-519-6616 1-800-480-3739 (TTY/Deaf Access) 301-519-0459 (International) http://www.hivatis.org
Both services operate from 12 p.m. to 5 p.m. Eastern Time, Monday through Friday. Spanish-speaking specialists are available.
To get information specifically about clinical trials conducted by the NIAID Intramural AIDS Research Program, call 1-800-243-7644 (http://www.clinicaltrials.gov).
NIAID is a component of the National Institutes of Health (NIH). NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, tuberculosis, malaria, autoimmune disorders, asthma and allergies.
Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.
Prepared by: Office of Communications and Public Liaison National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, MD 20892
US Department of Health and Human Services