Developing safe and effective prevention strategies to curb the human and economic costs of the HIV/AIDS pandemic has become an international health priority. Toward this end, NIAID, which spearheads federal funding for biomedical research on HIV/AIDS for the National Institutes of Health (NIH), supports a broad-based HIV vaccine and prevention research program.
NIAID's Division of AIDS (DAIDS) directs this 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, laboratory studies of vaccine performance and microbicides, and
* to promptly evaluate promising candidate vaccines, microbicides and other intervention strategies in animal models and, if warranted, in humans.
Traditional investigator-initiated research forms the foundation for HIV/AIDS vaccine research. NIAID supports several special collaborative and interdisciplinary initiatives to accomplish specific research objectives.
National Cooperative Vaccine Development Groups (NCVDGs) constitute the core of preclinical HIV vaccine design and evaluation efforts 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.
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 monkey counterpart, simian immunodeficiency virus (SIV). Investigators use this information to design new vaccines that will protect against mucosal exposure to HIV.
The Antibody Serologic Project identifies and standardizes panels of monoclonal antibodies to characterize the antigenic components of HIV and SIV. This collaborative project involves investigators from around the world.
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. The project includes a laboratory that determines the genetic sequences of large numbers of viral isolates (Genetic Variation Contract), a laboratory to assess the immunologic significance of genetic variation (Antigenic Variation Contract), and the HIV Sequence Database and Analysis Unit at the Los Alamos National Laboratory, which compiles and analyzes genomic sequences contributed by sequence laboratories. The HIV Variation Project is carried out in collaboration with the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO).
Primate Research Laboratories answer HIV-vaccine-related questions by testing HIV and HIV-like vaccines in chimpanzees and monkeys. The Simian Vaccine Evaluation Units (S-VEUs) evaluate vaccine concepts in the macaque model and compare immunologic and protection data, permitting standardized and directly comparable evaluations of various vaccine candidates. Substantial effort is being made to develop the chimeric SIV-HIV (SHIV) model for use in challenge studies. The Chimpanzee Unit, operated through an interagency agreement with the National Cancer Institute, has been used to prepare chimpanzee stocks and to evaluate candidate vaccine concepts and products in chimpanzees. The Immunology Laboratory Support for Assessment of AIDS Vaccines in Primates (which includes several contracts) develops, standardizes and performs cellular and serologic immune assays to assess responses to SIV and HIV vaccines in the S-VEUs, and is also available to NCVDG laboratories. This permits the direct comparison of candidate vaccines evaluated in independent laboratories and facilitates selection of the most promising vaccine designs.
The Reagent/Resource AIDS Vaccine Project acquires or produces biological and chemical substances for comparative immunologic analyses, preclinical vaccine development, adjuvant development and standardized immunologic assessments of clinical samples from volunteers in vaccine trials.
The Master Agreement for Preclinical HIV Vaccine Development provides flexible resources for the preclinical evaluation of the most promising HIV vaccine candidates. These resources include preclinical evaluation of vaccines in nonhuman primates, vaccine production and the development of reagents for preclinical and clinical vaccine studies.
The AIDS Vaccine Evaluation Group (AVEG) conducts Phase I and Phase II trials in humans to evaluate the safety of and immune responses stimulated by experimental HIV vaccines. AVEG includes the following:
*A Vaccine Selection Group independently evaluates the rationale and preclinical safety and immunogenicity data of candidate vaccines prior to their study in AVEG trials.
*Six AIDS Vaccine Evaluation Units (AVEUs), located at research centers throughout the United States, conduct Phase I and II clinical trials of candidate HIV vaccines in volunteers who are not infected with HIV.
* A Central Immunology Laboratory provides state-of-the-art evaluation of antibody and cellular immune responses of vaccinated volunteers in AVEG trials. Laboratory scientists evaluate samples from the AVEUs using standardized assays, permitting the comparison of responses in volunteers who receive different candidate vaccines at different AVEUs.
* A Mucosal Immunology Laboratory evaluates human mucosal immune responses to candidate vaccines in standardized assays, permitting the comparison of responses in volunteers who receive different candidate vaccines at different AVEUs.
* A Data Coordinating and Analysis Center provides a central facility for collecting and analyzing data from the trials conducted by the AVEUs.
*A Data and Safety Monitoring Board periodically reviews data from AVEG studies.
Planning for Efficacy Trials
NIAID is laying the groundwork for large-scale Phase III efficacy trials of candidate HIV vaccines and other prevention strategies to ensure that such trials begin promptly once suitable candidates are identified.
To assess the feasibility of conducting vaccine trials in the United States, NIAID initially provided supplemental funds to help support ongoing studies sponsored by the Centers for Disease Control and Prevention and the National Institute on Drug Abuse, and to other investigators working with populations at high risk of HIV infection.
To determine the feasibility of and develop the capability for conducting such trials abroad, NIAID in 1992 awarded eight two-year Preparation for AIDS/HIV Vaccine Evaluations (PAVE) grants to U.S. researchers and their international collaborators.
In 1993 the NIAID unified and extended these efforts by establishing the HIV Network for Prevention Trials (HIVNET). HIVNET is charged with preparing for and conducting large-scale, randomized, controlled trials to evaluate the efficacy of vaccines and other strategies to prevent sexual, parenteral and perinatal transmission of HIV. In addition, HIVNET provides a unique opportunity to study the epidemiology of HIV transmission in different populations, and to examine the natural history and pathogenesis of early HIV infection and disease. HIVNET consists of five contracts:
* A domestic master contractor subcontracts with clinical sites to conduct activities in preparation for efficacy trials. These sites will evaluate the efficacy of HIV vaccines and other prevention strategies in U.S. populations once suitable candidates are identified.
* An international master contractor subcontracts with clinical sites to prepare for efficacy trials and to evaluate prevention strategies in international populations.
* A statistical and data coordinating center provides statistical and data management support for the domestic and international trials.
* A central laboratory provides quality assurance and specialized testing for the domestic and international trials, and preparatory research trials.
* A specimen repository collects, stores and distributes samples from the domestic and international clinical sites.
HIVNET investigators are collecting baseline data on virus strains being transmitted, rates of new HIV infections and the prevalence of other sexually transmitted diseases and other potential cofactors of HIV transmission from various populations at high risk for HIV infection. They also are collecting data on the willingness of high-risk individuals to enroll in vaccine trials.
Several of the HIVNET sites are conducting randomized controlled trials of various methods to prevent sexual and perinatal HIV infection. These interventions include microbicides to prevent sexual transmission, and antiretroviral drugs and HIV immune globulin to prevent perinatal transmission. Behavioral interventions also are being evaluated.
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 involved in planning for vaccine efficacy trials. These concerns include vaccine cost and delivery, liability issues, training of medical personnel and conduct of trials at potential overseas sites.
NIAID, a component of the National Institutes of Health, supports research on AIDS, tuberculosis and other infectious diseases as well as allergies and immunology.
Prepared by: Office of Communications National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, MD 20892
Public Health Service U.S. Department of Health and Human Services January 1997