Despite education and treatment advances, experts project a worsening of the human immunodeficiency virus (HIV) crisis through the year 2000. HIV infection and AIDS death rates will continue to mount worldwide. In the United States, the tally of AIDS cases will escalate, particularly among women and minorities. If present trends continue, numbers of new infections will remain relatively stable in Europe and North America but will increase in parts of Latin America, Africa and, most markedly, in Asia.
Developing a safe and effective vaccine to curb the human and economic costs of the HIV/AIDS pandemic has become an international health priority. To help reach this goal, the National Institute of Allergy and Infectious Diseases (NIAID), which spearheads federal funding for biomedical research on HIV/AIDS for the National Institutes of Health (NIH), has intensified its HIV vaccine research program.
This fact sheet summarizes NIAID's approach to developing an HIV/AIDS vaccine. It describes the challenges facing vaccine researchers and the Institute's response, including basic and clinical research initiatives and advance planning for efficacy trials of the most promising candidate vaccines. Throughout the fact sheet scientific terms common to vaccine research have been printed in boldface type and defined.
NIAID"S HIV VACCINE PROGRAM -- A BALANCED STRATEGY
NIAID's Division of AIDS (DAIDS) directs the HIV vaccine research program. Institute staff meet regularly with scientific, public health and community advisors to review the priorities and operation of the program.
The program has two main thrusts:
* to foster basic research on the structure and function of HIV, vaccine formulations, vaccine delivery systems and laboratory studies of vaccine performance; and
* to promptly evaluate promising candidate vaccines in animal models and, if warranted, in humans.
Although traditional investigator-initiated research forms the foundation for HIV/AIDS vaccine research, NIAID supports several special initiatives to accomplish specific research objectives.
These include the following:
* National Cooperative Vaccine Development Groups (NCVDGs) represent the core HIV vaccine discovery and development effort sponsored by NIAID. Teams of scientists from industry, academia and government collaborate to develop and test novel experimental HIV vaccine concepts in the laboratory and in animal models.
* AIDS Cooperative Adjuvant Groups conduct multidisciplinary research on the mechanisms of action of adjuvants, substances that can be combined with a vaccine to enhance immune responses.
The groups also develop new adjuvant formulations and evaluate vaccine-adjuvant combinations in relevant animal models.
* The NIAID AIDS Vaccine Clinical Trials Network conducts trials in humans to determine the safety of and immune responses stimulated by experimental HIV vaccines (Phase I and Phase II trials). The network includes a specimen bank, immunology laboratories and a data analysis center.
* Primate research laboratories answer HIV vaccine-related questions by testing HIV and HIV-like vaccines in chimpanzees and monkeys.
* Master Contracts for Preclinical HIV Vaccine Development provide flexible resources for the preclinical development of the most promising HIV vaccine candidates. These resources include vaccine production, preclinical evaluation of vaccines in nonhuman primates and the development of biological and chemical substances called reagents for use in comparative vaccine studies.
* The HIV Variation Project examines the rates and magnitudes of genetic and immunologic changes in HIV and related retroviruses and their consequences for vaccine design.
In addition, NIAID's nationwide university-based and community-based clinical trials programs conduct clinical studies of candidate therapeutic HIV vaccines.
Planning for Efficacy Trials
Inevitably, promising candidate HIV vaccines suitable for testing of their effectiveness will be identified. The Institute is laying the groundwork for such large-scale Phase III efficacy trials in the United States and abroad to ensure that no delay in starting them occurs.
To determine the feasibility of and develop the infrastructure for conducting such trials abroad, NIAID has awarded eight Preparation for AIDS/HIV Vaccine Evaluations (PAVE) grants to U.S. researchers and their international collaborators.
To prepare for efficacy trials, PAVE investigators as well as domestic contractors are collecting baseline data on virus strains being transmitted, rates of new infections and the prevalence of sexually transmitted diseases and other potential co-factors of HIV transmission from various populations at high risk for HIV infection who live in the United States and abroad.
Institute staff assist public health and government officials, community members, scientists and others affiliated with potential trial sites to resolve legal, practical and ethical issues that attend planning for efficacy trials. These concerns include vaccine cost and delivery, liability issues and training of medical personnel and conduct of trials at potential overseas sites.
To further prepare for such trials, NIAID has established the HIV Vaccine Efficacy Trials Network (HIVNET), which will operate as follows:
* A domestic HIV/AIDS vaccine efficacy trials master contractor will subcontract with sites to evaluate the efficacy of candidate HIV vaccines in U.S. populations.
* An international HIV/AIDS vaccine efficacy trials master contractor will subcontract with sites to support trials in international populations.
* A statistical and data coordinating center contract will provide statistical and data management support for the domestic and international trials.
* A laboratory contract will provide specialized testing for the domestic and international trials.
* A specimen repository contract serves the domestic and international trials.
CHALLENGES IN DESIGNING HIV VACCINES
The ideal HIV vaccine would be inexpensive, easy to store and to administer and would elicit strong, appropriate immune responses that confer long-lasting protection against both bloodborne and mucosal (sexual) exposure to many HIV subtypes. However, the following describes why this ideal has not been easy to achieve.
What Constitutes Immune Protection?
Researchers face unprecedented scientific obstacles in trying to develop effective vaccines for HIV. The easiest way to design an effective vaccine is to know what immune responses protect against the specific infection and construct a vaccine that stimulates those responses. Although scientists have found clues about these so-called correlates of immunity or correlates of protection for HIV, they have not been able to precisely identify them.
Unlike other viral diseases for which successful vaccines have been made, recovery from HIV infection has not been documented. Therefore, researchers have no human model of protection to guide them when constructing candidate HIV vaccines. Indeed, whether a natural protective state against HIV can exist remains unknown.
However, now that the pandemic has matured, long-term HIV survivors and others provide ample evidence that some people appear better able than others to resist HIV infection or the development of AIDS. Much of this information has come from extended studies of people at high-risk for HIV. The "resisters" can be grouped as: 1) those who maintain healthy levels of CD4+ T cells, a crucial immune cell and HIV's main target, for seven to 10 years or more after becoming infected; 2) individuals who lose a significant proportion of CD4+ T cells but apparently remain healthy; and 3) people who appear to escape infection despite repeated exposure to the virus.
To determine if genetic or biologic factors affect the body's response to HIV exposure and infection, NIAID-funded investigators and others are comparing long-term HIV survivors with people who quickly became infected or sick. Leading areas of research include genetics, individual variations in the immune response and exposure to or infection by less deadly variants of HIV. Any patterns found in the data may help decode what contributes to protective immunity against HIV.
The ability to stimulate immune responses is called immunogenicity.
Two main types of immunity exist: humoral immunity and cellular immunity. Humoral (antibody-mediated) immunity refers to protection provided by the products of one type of white blood cell called a lymphocyte. These products, custom-made proteins known as antibodies, circulate in body fluids, primarily blood and lymph. B lymphocytes (B cells) produce antibodies in response to a specific foreign invader like HIV or a vaccine.
Several different antibodies can be generated. So-called binding antibodies simply attach to part of HIV and may or may not have antiviral effects. Functional antibodies are binding antibodies that actually do something. For example, one type--neutralizing antibodies--inactivates HIV or prevents it from infecting other cells.
Scientists have identified HIV's V3 loop as important for stimulating neutralizing antibodies. The V3 loop is part of gp120 (glycoprotein 120), a major protein found on the surface or envelope of HIV. Together with its parent protein gp160, gp120 forms the basis of many recombinant subunit vaccines, so-called because they are genetically engineered and contain only pieces of the virus.
The second type of immunity, cellular (cell-mediated) immunity, refers to activities of T lymphocytes. Cytotoxic T lymphocytes (CTLs), nicknamed killer T cells, directly destroy HIV-infected cells. A subset called CD8+ CTLs (CD8+ T cells) bear CD8 receptors on their surfaces and kill cells that are producing HIV. CD8+ T cells most likely are critical to protection against HIV.
Regulatory T cells, another component of cellular immunity, direct antibody- and cell-mediated immune responses, like a conductor leading a symphony orchestra. The chief regulatory T cell, the helper T cell, also is HIV's main target. The virus attaches to the cell through a receptor on the cell's surface called CD4. Hence, helper T cells are called CD4+ T cells.
A subset of helper T cells, memory T cells, are evoked on first exposure to an invading organism. The name "memory" reflects their function, which is to create a criminal record file on that virus or microorganism. If the virus enters the body again, memory T cells will quickly stir the immune system into action. The most common way to measure memory T cells is by a test called the T lymphocyte proliferation assay, which indicates the strength of such cell responses to HIV.
To be effective, an HIV vaccine may have to stimulate a third type of immunity, mucosal immunity. Immune cells lining the mucous membranes of the genital tract and other HIV portals into the body produce special immune responses.
NIAID's Correlates of HIV Immune Protection project will characterize immune responses in selected HIV vaccines enrolled in Phase III efficacy trials and compare those immune responses that are protective with those that are not.
HIV Strain Variation
HIV continually evolves as a result of genetic mutation and recombination. Thus, researchers must estimate the significance of strain variation within individuals and among populations when developing AIDS vaccines. Usually a person is not infected with more than one HIV strain. But once HIV infection becomes established, the virus undergoes changes, and many variants of one HIV strain may arise within an infected person.
Whenever a drug or immune response destroys one variant, a distinct but related one can emerge. Also, certain variants may thrive in specific tissues or become dominant in an individual because they replicate faster than others. Any of these changes may yield a virus that can escape immune detection.
The envelope regions of many HIV isolates, the viruses taken from patients, have been genetically analyzed and compared. Based on this information, scientists have grouped HIV isolates into at least six subtypes or clades, each about 30 percent different from any of the others. Successful vaccines for other viruses have had to protect against only one or a limited number of virus strains.
The first AIDS vaccines made were based on the LAI strain (also known as IIIB and LAV). Subsequently, LAI has been shown to be unlike most strains found in infected people. Newer vaccines have been based on the SF-2 and MN isolates, which are the same subtype as LAI but better represent HIV strains isolated from North Americans and Europeans.
A preventive vaccine will need to generate immune responses that protect noninfected individuals from all the different HIV clades to which they may be exposed. Scientists are looking for conserved regions of HIV genes that exist in more than one clade. A cocktail vaccine of several proteins or peptides from different HIV strains may be the most effective way to invoke broad-based immunity.
NIAID's HIV Variation Project comprises several collaborative research studies aimed at solving vaccine development problems related to HIV's genetic diversity. Part of the project is conducted in collaboration with the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO).
These studies investigate the rate and magnitude of genetic variation in HIV and related retroviruses and how this variation impacts strategies for developing HIV vaccines. The project includes a laboratory that uses state-of-the-art technology to determine the genetic sequences of many HIV specimens. A separate laboratory is being established to assess the immunologic significance of genetic variation.
Another component of the HIV Variation Project is the HIV Sequence Database and Analysis Unit at New Mexico's Los Alamos National Laboratory, which compiles and analyzes genetic sequences of different HIVs contributed by various laboratories. So far it has received about 170 sequences from around the world.
HIV Transmission Complex
Unlike most other viruses, HIV can be transmitted and can exist in the body not only as free virus but also in infected cells. Thus, a vaccine against HIV may be required to stimulate the two main types of immunity. Humoral immunity uses antibodies to defend against free virus. Cellular immunity directly or indirectly results in the killing of infected cells by immune cells. A major unanswered question is how important each type of immunity is to protection from HIV. Data on long-term HIV survivors and those generated from animal model and human clinical trials of experimental HIV vaccines may offer clues to the answer.
Another factor complicates the attempt to define HIV protection. According to WHO, 80 percent of all HIV transmission worldwide occurs sexually. Thus, to be effective, an HIV vaccine also may need to stimulate mucosal immunity. Mucosal immune cells lining the respiratory, digestive and reproductive tracts and found in nearby lymph nodes are the first line of defense against HIV and other infectious organisms. Unfortunately, relatively little is known about how the mucosal immune system works.
NIAID has increased its commitment to research that enables scientists to learn how HIV and other pathogens elude the defenses of mucosal cells and the immune-modulating proteins, called cytokines, that they stimulate.
Specifically, the Cooperative Mucosal Immunology Group for Investigations on AIDS Vaccines supports research on methods to stimulate and evaluate mucosal immune responses to HIV and its counterpart that infects monkeys, simian immunodeficiency virus (SIV), and uses this information to design new vaccines that will protect from mucosal exposure to HIV. Animal models are being developed to explore novel strategies for vaccination and for mucosal challenge with HIV. The investigators also are developing tests, reagents and technology to evaluate specific, protective immune responses induced by HIV vaccines in animal and human volunteers.
Immune System Breakdown
Perhaps the most difficult challenge for vaccine researchers is that the major target organ of HIV is the immune system itself. HIV infects the key CD4+ T cells that regulate the immune response, modifying or destroying their ability to function. After infection, HIV incorporates its genetic material into that of the host cell. There the virus can hide indefinitely until the cell receives an activation signal and makes new viruses. Other cells act as HIV reservoirs, harboring intact viruses that may remain undetected by the immune system.
Understanding how HIV disease evolves, especially during early infection, is a high priority for the Institute. Scientists at NIAID and elsewhere have shown that no true period of biological latency exists in HIV infection. After entering the body, the virus rapidly disseminates, homing to the lymph nodes and related organs where it replicates and accumulates in large quantities. Paradoxically, the filtering system in these lymphoid organs, so effective at trapping pathogens and initiating an immune response, may help destroy the immune system by infecting the steady stream of CD4+ T cells that travel there in response to HIV infection.
The study of early HIV infection is an area where basic research in immunology, epidemiology studies of long-term survivors and animal model and human clinical trials all can contribute to a greater understanding of the immune system breakdown and ways vaccines may be designed to prevent or slow down the progress of HIV disease.
NIAID's AIDS Vaccine Reagent Project is a contract effort to provide large quantities of reagents for comparative immunologic studies. These reagents also will be used in preclinical vaccine development, adjuvant development and standardized immunologic assessments of clinical samples from volunteers in vaccine trials.
In addition, the Institute's Antibody Serologic Project identifies and standardizes panels of monoclonal antibodies to characterize specific components of HIV and SIV. This project, a collaborative effort between NIAID and WHO, involves investigators from around the world.
Adjuvants, Other Immune Enhancers
Because of safety concerns, most candidate HIV/AIDS vaccines are made from one or more pieces of HIV rather than the whole virus. These new-generation vaccines contain no intact live virus and thus stimulate less potent immune responses than traditional vaccines made from whole viruses that have been inactivated or attenuated (weakened).
To augment the immune responses elicited by these and other vaccines, scientists use immunologic adjuvants. Currently, only one adjuvant -- alum, first discovered in 1926 -- is incorporated into vaccines licensed for human use by the U.S. Food and Drug Administration (FDA). An adjuvant may work well with one experimental vaccine and not another. Therefore, the FDA licenses the vaccine formulation, or the antigen-adjuvant combination, rather than the adjuvant alone. Experimental adjuvants can increase the type, strength and durability of immune responses evoked by an experimental vaccine. For example, some vaccine antigen/adjuvant combinations can induce cell-mediated immune responses, even if the vaccine antigen by itself does not. Some adjuvants also stimulate mucosal immunity. Alum primarily increases the strength of antibody responses generated by the vaccine antigen. Because of its limited activity, other adjuvants may be better suited for the newer candidate HIV vaccines.
NIAID-funded scientists are evaluating a panel of promising adjuvants in monkeys to help identify the suitable candidates to incorporate in experimental human HIV vaccines. In 1993, NIAID began the first Phase I HIV vaccine adjuvant trials in humans. Various adjuvants paired with two different vaccine candidates are being compared to determine the best vaccine formulations to pursue.
A different way to enhance immune responses to HIV is the prime-boost vaccine strategy. Researchers first ready or prime the immune systems of volunteers with a live vector vaccine, a bacterium or virus that has been genetically engineered to contain a gene for an HIV protein such as gp160 but that cannot infect the person with HIV or cause disease.
The best studied vector is vaccinia virus, formerly used to immunize against smallpox. Vaccinia transports the foreign HIV gene into the body. There, the HIV gene makes a protein that the body perceives as foreign, stimulating production of protective antibodies. Later, the volunteers receive booster shots of a recombinant vaccine made from the same HIV protein.
By itself, a gp160-containing vaccinia virus vaccine stimulates memory T cells but few antibodies. The prime-boost combination, however, can stimulate a strong cellular immune response -- including persistent killer CD8+ T cells -- as well as antibodies that neutralize the virus or inhibit formation of syncytia, giant cells formed when HIV-infected cells fuse with cells that are not infected.
Because of concerns that a vaccinia-based vaccine might cause serious vaccinia infection in some people who have compromised immune systems, such as people with HIV who have not been exposed to either smallpox or the vaccine, other vector vaccines also are being developed and evaluated.
One candidate made from a canarypox virus that closely resembles vaccinia is in clinical trials. Canarypox virus does not grow in human cells and therefore should be much safer. Another example of a vector under development for HIV vaccines is Salmonella, bacteria that infect the human gut.
Animal Model Studies
Animal model studies can answer critical questions that may pose undue risk to humans or cannot be answered using computer modeling or laboratory tests. For example, animals can be inoculated with an experimental vaccine and then challenged with HIV to test the vaccine's effectiveness -- a study that would be unethical to conduct in humans.
Although chimpanzees can be infected with HIV, they have not yet been observed to develop disease. Moreover, they are expensive to maintain.
Most large-animal AIDS research is conducted with macaque monkeys. They can be infected with SIV, a retrovirus similar to HIV that causes an AIDS-like disease. The genetic and physical structures of SIV differ enough from those of HIV, however, that extrapolating the results of SIV experiments to humans must be done carefully.
Despite the lack of an ideal animal model, important information has been obtained from both monkeys and chimpanzees. Experiments in both primates have demonstrated the feasibility of developing a protective vaccine. Moreover, two new animal models -- infection of pigtail macaques with HIV and of rhesus macaques with a chimeric SIV-HIV virus -- may become valuable alternatives to chimpanzees for evaluating candidate HIV vaccines.
In late 1992, NIAID-funded investigators first reported results from their experiments with a live-attenuated SIV vaccine made by deleting the SIV nef gene. The vaccine demonstrated durable protection against high intravenous doses of a lethal SIV different from that used in the vaccine. These findings provide hope that safe and effective human HIV vaccines can be developed.
NIAID's SIV Vaccine Evaluation Units (SIV VEUs) evaluate vaccine concepts in the SIV model. The units permit standardized and directly comparable evaluations of various SIV vaccine candidates. NIAID's Chimpanzee Unit, operated through an interagency agreement with the National Cancer Institute, prepares chimpanzee stocks and to evaluate candidate vaccine concepts and products in chimpanzees. In addition, NIAID's Immunology Laboratory Support for Assessment of AIDS Vaccines in Primates develops and standardizes cellular and serologic immunology tests to assess responses to SIV and HIV vaccines in the SIV VEUs, the Chimpanzee Unit and NCVDG laboratories.
This standardization permits the direct comparison of candidate vaccines evaluated in independent laboratories and facilitates selection of the most promising vaccine designs.
Important immunologic targets on HIV and on infected cells have been identified. For example, scientists now know that gp120 contains the cell attachment site called CD4. 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. Approximately 25 experimental HIV vaccines are currently in various stages of human testing around the world. Vaccine approaches in development or in clinical trials include the following:
* subunit vaccine -- a piece of HIV, such as the envelope protein gp160 or gp120, produced by genetic engineering.
* recombinant vector vaccine -- a live bacterium or virus such as vaccinia (used in the smallpox vaccine) modified so that it can transport into the body a gene that makes an HIV protein.
* 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.
* peptide vaccine -- chemically synthesized portions of HIV proteins (peptides) known to stimulate immunity.
* virus-like particle vaccine -- a non-infectious HIV look-alike that retains all or part of the HIV envelope but only some of the interior components.
* anti-idiotype vaccine -- antibodies generated against antibodies to the virus.
* naked DNA 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 has performed well in preclinical safety 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 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. At this stage, researchers try to determine the maximum useful dose that can be tolerated without compromising safety. A Phase I trial also can provide preliminary data on the vaccine's immunogenicity. 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 an experimental HIV vaccine to be well-tolerated, it then 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 acquiring 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 noninfected healthy volunteers. The gp160 subunit candidate vaccine tested caused no serious adverse effects.
From the first trial until May 1993, about two dozen preventive HIV vaccine trials have been initiated worldwide. These Phase I trials examine the vaccine's safety and preliminary information on its ability to stimulate immune responses.
The NIAID AIDS Vaccine Clinical Trials Network is the largest cooperative HIV vaccine clinical trials group in the United States.
Between 1988 and December 1993, more than 1,300 men and women have participated in preventive HIV vaccine trials conducted at its five medical center sites located in Seattle, Baltimore, St. Louis, Nashville 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 most thoroughly tested candidates stimulate production of antibodies, although levels decrease 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 the newer protocols that have increased vaccine dosages, changed immunization schedules, tested experimental adjuvants and used recombinant proteins shaped more like those of native HIV, more promising data have begun to emerge.
In December 1992, NIAID launched the first Phase II preventive HIV trial worldwide. Earlier trials enrolled noninfected people at low risk of HIV infection and primarily sought data on safety. The Phase II trial includes noninfected 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. The trial will help determine if these distinct populations, representative of people likely to be enrolled in large-scale efficacy trials, respond differently to the vaccines. The trial also will gather more detailed data on the safety and ability of the vaccines to stimulate immune responses.
As experimental HIV vaccines continue to grow in number and kind, clinical trials are expected to yield valuable information about the relative effects of different vaccine formulations and different methods of delivery on the immune response.
The NIAID AIDS Vaccine Clinical Trials Network includes the following:
* The AIDS Vaccine Evaluation Units (AVEUs) [known collectively as the AIDS Vaccine Evaluation Group (AVEG)], located at five research centers across the United States, 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 vaccines in AVEG trials. Samples from the AVEUs are evaluated using standardized tests, permitting the 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 Data and Safety Monitoring Board periodically reviews data from AVEG studies.
* 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.
Therapeutic Vaccines -- A New Strategy
Traditionally, vaccines are used prophylactically, that is, to prevent infection. Experimental HIV vaccines also are being tested as possible treatments. The goal of therapeutic vaccination is to boost the immunity of an HIV-infected person to prevent or slow further development of disease.
As of early 1993, NIAID and other sponsors had initiated more than a dozen therapeutic HIV vaccine trials worldwide, including some larger, more advanced trials. So far, the vaccine candidates being tested seem to be well tolerated, but longer follow-up is needed to generate more data for interpretation.
Most therapeutic HIV vaccine trials have enrolled people who are HIV-infected but otherwise healthy and free of AIDS symptoms. In the first half of 1993, NIAID launched the first trials in the world to test therapeutic HIV vaccines in three additional populations:
* pregnant HIV-infected women and infants born to them, * asymptomatic HIV-infected infants and * asymptomatic children.
Early 1993 also marked the opening of the first NIAID therapeutic HIV vaccine trial to include people with more advanced HIV disease.
Although the challenges are daunting, scientists remain optimistic that safe and effective HIV vaccines can be developed. Basic researchers have made tremendous strides in understanding how HIV causes disease, recently describing how throughout the long symptomless period of HIV infection, the virus gradually ravages the lymph nodes and related organs, a process imperceptible by the patient who generally feels well during this time.
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 NIH, supports research on AIDS, tuberculosis and other infectious diseases as well as allergies and immunology. NIH is an agency of the U.S. Public Health Service, U.S. Department of Health and Human Services.
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