Although the current anti-retroviral drug therapy has proven successful at reducing patient viral loads, most HIV infected individuals will never benefit from these therapeutic agents. Ninety percent of all new HIV infections occur in developing countries where adequate financial resources are not available to allow for drug access. Even in wealthy, industrialized nations, where antiviral drugs are available, poor drug tolerance and emerging drug-resistant viral strains make long-term responsiveness to antiviral therapy far from common. Tragically, once patients are removed from drug therapy, their viral loads increase to levels equivalent to those detected prior to treatment. This is likely a result of latent virus reactivation. Successful containment of the AIDS pandemic will ultimately require an effective vaccination strategy designed to prevent HIV infection.

Major impediments to developing a successful vaccine include constant variability of the virus (within the individual) through mutation and recombination, multiple virus subtypes, the inability of most known specificities of anti-HIV antibodies to consistently neutralize primary HIV isolates and the lack of full understanding of the correlates of immunity. The majority of vaccine efforts to date have been focused on the envelope glycoprotein, gp160 or its cleavage product gp120 which forms the outer spike projection of the virion. In 1987, the NIAID initiated the first clinical trial of an HIV vaccine, a gp160 subunit vaccine candidate, and since then over 40 clinical trials of various vaccine strategies have been implemented worldwide in the hope of finding an effective vaccine.

It is believed that for a preventative HIV vaccine to be effective it would be required to induce certain events:

1. neutralizing antibodies that block entry of HIV into cells (humoral)
2. cytotoxic T lymphocytes (CTL’s) to eliminate or control infected cells (cell-mediated)
3. memory cells to ensure long-term protection (cell-mediated)

There are several categories of vaccine strategies outlined below. They are mostly being developed as single-approach vaccines, but it may ultimately be determined that the most effective immunization strategy will be to combine approaches.

• Live-attenuated vaccines: These vaccines consist of live viruses whose virulence has been weakened. The attenuated virus is able to infect cells and replicate but does not cause significant disease. It so closely resembles intact virus that viral components can be presented to the immune system in the same cells and in the same manner as a natural infection. This process can stimulate a vigorous immune response to protect against future infection by the pathogen. As a result of the ideal combination of good antibody and cell-mediated immunity that develop, these vaccines often require only a single immunization, eliminating the need for repeated boosters. This is an advantage particularly in Third World countries where many individuals fail to get follow-up boosters. Existing live-attenuated vaccines are in use against polio, measles and rubella.

• Whole inactivated vaccines: This vaccine approach consists of inactivating the whole pathogen by chemical modification so that it is no longer capable of replicating in the host. The advantage to this type of vaccine is that all potential antibody-inducing determinants on the surface of the virus are present without danger of infection. There are several disadvantages to inactivated vaccines; primarily, without being infectious, these viral particles predominantly evoke an antibody response; they are less effective than attenuated vaccines at inducing cell-mediated or mucosal immunity. Repeated boosters are often required to maintain the immune status of the individual. Lastly, the risk associated with this type of vaccine is that without careful surveillance, the pathogen may not be properly killed. The Salk polio vaccine and pertussis vaccine are two therapies currently produced by formaldehyde inactivation.

• Recombinant subunit vaccines: Some of the risks associated with attenuated or killed whole organism vaccines can be avoided by using specific, macromolecules derived from the pathogen. Theoretically, the gene encoding any immunogenic protein can be isolated and cloned into bacterial, yeast or mammalian cells using recombinant DNA technology. The expressed protein is purified and used in combination with immune enhancers as the vaccine. Such subunit vaccine was first for the hepatitis B vaccine. One disadvantage of subunit vaccines, like whole-killed pathogen, is that the primary response is antibody mediated with very little induction of cell-mediated activity.

• Vector vaccines: It is possible to introduce HIV genes into attenuated viruses or bacteria. The attenuated organism serves as a vector, replicating within host cells and expressing the proteins that are capable of inducing HIV-specific immune responses without causing disease. Several organisms that have being examined for vector vaccines include vaccinia virus, canarypox virus, adenovirus and Salmonella. Clinical trials have shown that this type of vaccine is capable of inducing cell-mediated as well as antibody-mediated immunity.

• DNA vaccines: This is a recently developed strategy where plasmid DNA encoding a viral antigen is injected directly into the muscle of the recipient, where it is used to produce HIV proteins. The encoded protein that is expressed has been shown to elicit a CTL response but only a weak antibody response to the viral antigen. This type of vaccine may be suited for world-wide use as it has the potential to be inexpensive, stable, and easy to transport relative to other vaccines.

For a complete list of HIV vaccines in clinical trials, please see the List of Clinical Trials page on this website

 You may email the author of this portion of the website at: Liz_Lavigne@brown.edu

During these trials, laboratory and animal studies are performed with the candidate vaccine to determine if the compound can eventually be tested in humans. Usually, preclinical testing takes about 2 to 3 years to complete. The company then submits an application to the FDA to initiate clinical trials to test the vaccine in humans (FDA, 1997).

Phase I studies involve a small cohort of healthy volunteers who are at low risk of contracting HIV. These studies are performed mainly to determine the safety of the experimental vaccine in humans. Usually, Phase I studies take about 1 to 2 years to complete. Data from these studies are evaluated to determine if further investigation of the experimental vaccine is appropriate. If it is decided that further studies should be performed, Phase II studies can begin before the Phase I studies are completed (FDA, 1997).

Phase II studies involve larger groups of volunteers. These studies are performed to determine how effective the vaccine is against the disease and to identify an appropriate dosage schedule. These studies usually take about 1 to 2 years to complete (FDA, 1997).

Phase III studies involve large groups of volunteers (approximately 1,000 to 3,000) who are at high risk of contracting HIV. These studies are performed to determine the effectiveness and safety of the vaccine. The use of additional subjects helps to identify side effects that may rarely occur. Phase III studies usually take about 2 to 3 years to complete. In a few cases, all three trials or two of the three trials can be ongoing at the same time (FDA, 1997).

After the Phase III studies are completed, data regarding the new vaccine is submitted to the FDA. The FDA reviews and analyzes this information to determine the safety and effectiveness of the vaccine in humans. Depending on the medical priority of the vaccine, the approval process takes approximately 6 to 18 months to complete. However, the FDA's fast track programs are designed to speed up the development and review of new vaccines that are intended for the treatment of serious or life-threatening conditions, such as HIV/AIDS. (FDA, 1997).

Once the FDA approves the vaccine, it can be administered. The pharmaceutical company then continues to collect information on the vaccine to monitor its long-term effects.

obtained from http://www.unaids.org

 HIV Phase III trials in North America and Thailand

Specifically, phase III trials are taking place in North America and Thailand to test the different forms of the controversial vaccine, AIDSVAX. The AIDSVAX B/B vaccine, which is being tested on residents in North America, is a genetically engineered subunit investigational vaccine. Consequently, the vaccine is not made from a live virus, but rather a protein from the surface of the virus copied through genetic engineering. AIDSVAX does not have HIV DNA, but 300 mg of each recombinant gp120 envelope antigens from two clade B viruses and aluminum adjuvant to enhance an immune response. The clade B virus represents the specific virus circulating in North America, Western Europe, Australia, the Carribean, parts of Thailand, and South America. The two viruses used to develop AIDSVAX have complementary neutralization sites. The first strain is HIV-1 MN, a T-cell tropic virus. The other strain is HIV-1 GNE8, a macrophage tropic virus. Researchers hope that the injection of the recombinant protein would stimulate the production of the antibodies that would attack any invading HIV in the future. This would prevent the virus from infecting healthy T-cells (VaxGen, 1999).

The primary objective of this trial is to determine whether immunization with the AIDSVAX B/B' vaccine can protect persons-at-risk from acquiring the HIV-1 infection. In addition, the studies will determine if prior immunization with AIDSVAX B/B can prevent persistent virus in the blood and reduce the viral load of HIV-1 infected individuals. The trials will also assess the safety of the vaccine and evaluate the possible immunologic markers that correlate with protection from HIV-1 infections (VaxGen, 1999).

This trial in the United States and Canada has already enrolled 5,000 male and female volunteers between the ages of 18 to 60 who do not have the HIV-1 infection, but who are at risk of acquiring HIV-1 infection by sexual contact. Two out of the three participants will receive the investigational vaccine while the other third will receive a placebo. All volunteers will receive a total of seven vaccinations over a three year period. After the first vaccination, a subsequent vaccination will be given 1, 6 , 12, 18, 24, and 30 months later (VaxGen, 1999).

On February 9, 1999, VaxGen announced that Thailand's Ministry of Public Health approved the start of large-scale clinical trial of the company's AIDS B/E preventive vaccine against the HIV strains that cause AIDS in Asia. This announcement is significant because it marked the first efficacy trial of a preventive vaccine against HIB to take place outside of North America. The phase III trial in Bangkok began in February for 2,500 HIV-negative volunteers who are at high-risk of contracting HIV infection because of injection drug use. The vaccine being tested in Thailand has the same structure as AIDSVAX B/B, except that its gp120 envelope has antigens from clade B and clade E. Clade E is an HIV subtype which is especially prevalent in Thailand and the rest of the pacific rim (VaxGen, 1999).

However, there has been disagreement over the vaccine's potential in both North America and Thailand. The AIDSVAX is a subunit vaccine that does not contain the live virus and will not cause HIV-1 infection. AIDSVAX does not induce the cellular response because it is presented by MHC II. This response is critical for the body to fight the infection. In addition, there is debate about the immune "correlates of protection" or the type of immune response that should be induced by the vaccine. Many in the scientific community believe that additional research is needed to determine the most effective immune response and ensure the safety of the vaccine (AIDS Alert, 1998). Furthermore, if the phase II trial is unsuccessful in Thailand, other nations will be hesitant to allow their citizens to participate in future clinical trials.

For more information about AIDSVAX, visit VaxGen's homepage at http://www.vaxgen.com/

 Uganda HIV Vaccine Trial

In February of 1999, the National Institute of Health (NIH) announced the first HIV vaccine trial to be held in Africa. It is a small phase I trial , known as HIVNET 007, conducted in Uganda by the Joint Clinical Research Center and the Ugandan Virus Research Institute under the direction of professor Roy Mugeria of Maskere University and Dr. Jerrold Ellner of Case Western Reserve University. The vaccine, referred to as ALVAC vCP205, is manufactured by Pasteur Merieux Connaught and consists of a weakened canary pox virus carrying 3 HIV genes derived from clade B virus. Because the HIV genes will be presented to the immune system by the live canary pox virus, both humoral and cell-mediated responses are expected to be elicited. The vaccine has already been tested on 800 volunteers in the U.S. and in France with no reports of serious side-effects. The Ugandan trial will involve 40 healthy volunteers aged 18-40 that are at low risk of contracting HIV. Volunteers will receive 4 injections over a period of six months. Twenty volunteers will receive HIV vaccine, ten will serve as controls receiving a similar experimental canary pox vaccine for rabies virus, and ten will receive placebo injections that do not contain vaccine. The recipients’ immune responses to HIV will be monitored over a two year period by invitro analysis, no volunteers will be intentionally exposed to HIV.

Ugandan Funeral for AIDS victim. (Scientific American 1988. Vol.259)

The HIV vaccine trial in Uganda has been met with some skepticism. The vaccine is composed of HIV genes derived from clade B, which is predominantly found in the U.S. and in Europe. Since clades A and D are predominantly found in Uganda, critics are asking why genes from these clades are not incorporated in the HIV vaccine being tested in Uganda. Researchers defend the Ugandan trial, explaining it as a way to determine if cross-clade immunogenicity will be achieved with this vaccine. Recent evidence revealed that cytotoxic T cells, derived from individuals naturally infected with clades A and D, can recognize clade B isolates in the laboratory. However, lab isolates tested in vitro often behave very differently than primary isolates do within a human host. Global eradication of HIV will require researchers to focus on developing a vaccine which will elicit effective immune responses against all known clades of HIV.

For more information regarding the Ugandan trial visit http://www.iavi.org/newpage/sdemand.html

Questions or comments about this portion of the website should be directed to Erin_Kil@brown.edu

"CMC Section of INDs for Phase I, Phase 2, and Phase 3/Pivotal Clinical Trials", Food and Drug Administration (1997)http://www.fda.gov/cder/guidance/cmcsprds.pdf#xml=http://www.verity.fda.gov/search97cgi/s97is.dll?action=View&VdkVgwKey=http%3A%2F%2Fwww%2Efda%2Egov%2Fcder%2Fguidance%2Fcmcsprds%2Epdf&doctype=xml&Collection=all&QueryZip=Clinical+trials&hlnavigate=ALL

International AIDS Vaccine Initiative website on HIV vaccine concepts. http://www.iavi.org/science_basics_new.html#retro

NIAID Fact Sheet. Challenges in designing HIV vaccines. http://www.niaid.nih.gov/factheets/challvacc.htm

"Phase II Clinical Trials of AIDSVAX", AIDSVAX. (1999) http://www.vaxgen.com/vaccine.htm

"Thai Authorities Approve Large-Scale Testing of VaxGen's HIV Vaccine; Trial Focused on HIV Epidemic in Asia and Pacific Rim", AIDSVAX. (1999) http://www.gaxgen.com/newsrelease/thai_author_approves.htm

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