August 2003

Clinical Research on HIV Vaccines

Overview

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 antibodiesin 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 38 different preventive vaccine candidates in 67 NIAID-funded clinical trials. 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

• Component (or Subunit) vaccine: a structural piece of HIV, such as the outer surface components, gp160 or gp120, produced by genetic engineering, or a regulatory protein
• 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
• Vaccine combination: for example, use of a recombinant vector vaccine to induce cellular immune responses followed by booster shots of a component 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
• DNA vaccine: direct injection of genes coding for HIV proteins
• Whole-killed 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 disease-promoting genes of the virus have been deleted

No HIV preventative vaccine candidate can cause infection with HIV.

Clinical Trials

A Phase I trial is the first setting where an experimental HIV vaccine is given to people. Such a trial may enroll anywhere from 20 to 100 HIV-uninfected volunteers usually at 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 it reacts 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 1 to 2 years. Ideally, these trials are randomized, controlled, and double-blinded.

Once Phase I trials show the experimental HIV vaccine is safe, well tolerated, and appears promising, it can advance into Phase II trials. These trials enroll more people, up to a few hundred, and include both volunteers at high and low 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, controlled, and double-blinded. Phase II trials usually last 1 to 2 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 are collected on safety and effectiveness to support a license application to the 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 4 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

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 behaviors that put them at risk of HIV infection. Follow-up for this trial is almost completed.

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 dedicated to developing a preventive HIV vaccine through testing and evaluating candidate vaccines in all phases of clinical trials. The network includes 13 sites in the United States and 12 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 the HIV Network of Prevention Trials 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.

Future Directions

More Information

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