NIH 1999 Almanac/The Organization/NIAID/
National Institute of Allergy & Infectious Diseases: Research Programs
Investigators at universities, hospitals, and private research institutions throughout
the country receive support through grants and contracts administered by the Division of
Microbiology and Infectious Diseases; Division of Allergy, Immunology, and
Transplantation; and Division of Acquired Immunodeficiency Syndrome.
Division of Microbiology and Infectious Diseases
The Division of Microbiology and Infectious Diseases supports extramural research to control and prevent diseases caused by virtually all infectious agents except HIV. DMID supports projects spanning basic biomedical research--such as studies of microbial physiology--to applied research, including the development of diagnostic tests and the conduct of clinical trials to evaluate experimental drugs and vaccines. Current areas of emphasis include emerging infectious diseases, hepatitis C, malaria, and foodborne diseases.
In addition, the NIAID supports the large-scale sequencing of the genomes of several pathogens. The sequence information provides the genetic information that defines an organism. Access to this information will help accelerate the development of new diagnostics, the discovery of targets for drugs and vaccines, and the identification of pathogen factors that are essential for infection and disease.
Viral Diseases. Viruses are the major cause of infectious diseases requiring medical care in the United States. The cost in dollars or in days lost from work is estimated to be in the billions each year. Following an initial infection, which may occur without symptoms, many viruses persist in the body for life and may lead to serious medical problems, including immune complex diseases, degenerative diseases, cancer, heart disease, and liver disease.
NIAID supports basic studies of virus structure, replication, gene regulation and evolution as well as studies in animals and humans that investigate the viral epidemiology, pathogenesis, and host immune response. This research program provides the foundation for the development of vaccines and antiviral therapies.
Respiratory infections are the major cause of acute illness in the U.S. NIAID supports development and testing of vaccines against viral respiratory diseases such as influenza, and respiratory syncytial and parainfluenza viruses, which cause the majority of croup, bronchitis, and pneumonia in infants and children.
Viral hepatitis caused by hepatitis A, B, C, D, and E, and as yet unidentified viruses, is another group of diseases that exact a heavy burden on health worldwide. In some parts of the world, hepatitis is the primary cause of liver cancer. Each year in the U.S., more than 600,000 new viral hepatitis infections occur which, when acute, can be debilitating and costly. Chronic disease resulting from infection with hepatitis B, C, and D is an even greater problem. Medical costs for chronic hepatitis are between $1 and $2 billion a year.
The Centers for Disease Control and Prevention (CDC) predicts that the death reate from hepatitis-C complications will triple in the next 15 years unless new interventions become available. NIAID-sponsored research focuses on virology, molecular biology, immunology, pathogenesis, development of antivirals, animal model development and studies, natural history, vaccine development, and clinical trials. Vaccines for hepatitis A and B are available in the U.S.
Diarrheal diseases caused by viruses are particularly a problem for infants in developing countries. Experimental vaccines against rotaviruses and calciviruses--major causes of infant diarrhea worldwide--are in various stages of research and devlopment. One vaccine, against rotavirus, developed in NIAID intramural laboratories, was expected licensed for use in the U.S.
Although there have been reports of possible viral associations in chronic fatigue syndrome (CFS), no specific causative role for any virus has been demonstrated. To explore possible causes of CFS, the institute has funded CFS Cooperative Research Centers to provide a multidisciplinary approach to CFS research by conducting basic science and clinical investigations. NIAID also supports scientists who are studying the possible immune system dysfunction, exercise-induced fatigue in CFS patients, as well as other aspects of CFS pathophysiology, and its epidemiology.
Development of Antiviral Drugs. Because many drug sponsors do not have access to comprehensive antiviral screening facilities, NIAID established screening facilities for the in vitro evaluation of an experimental compound's activity against hepatitis B virus, human herpes viruses--herpes simplex virus (HSV) 1 and 2, varicella zoster virus, cytomegalovirus (CMV), and Epstein-Barr virus--and the respiratory viruses--influenza types A and B, respiratory syncytial virus, parainfluenza, measles, and adenovirus.
This service is available to any scientist with a potential antiviral compound that needs testing. NIAID supports drug evaluation studies, preclinically in animal models of human viral infections and in human clinical trials. Institute-supported investigators participating in the Collaborative Antiviral Study Group test drugs for treating herpes encephalitis, neonatal herpes, hantavirus pulmonary syndrome, symptomatic congenital CMV infection, chronic hepatitis B and C virus infection, flu, and respiratory syncytial virus infection.
Bacterial Diseases. In the last decade, several bacterial diseases have emerged as new or recurring threats to the health of people in the U.S. and elsewhere, including Lyme disease, ehrlichiosis and tuberculosis (TB). Widespread resistance of microbes to drugs led to the reemergence of TB in America and threatens to cause disease outbreaks of other pathogens, including Staphylococcus aureus.
Lyme disease, first recognized in the early 1980's in this country, is caused by a bacterium transmitted to humans by certain ticks. It has emerged as a significant problem in the northeast coastal areas, among others. NIAID spearheads NIH studies on Lyme disease, supporting research focused on pathogenesis, improved therapies, better diagnostic tests, and vaccines.
NIAID also supports research on ehrlichiosis, a life-threatening tick-borne infection transmitted by the same Ixodes ticks that carry Lyme disease. NIAID-supported investigators are trying to determine whether coinfection with ehrlichiosis interferes with the diagnosis and pathology of Lyme disease.
Tuberculosis, a serious disease once thought to have been conquered in the U.S., recently reemerged in certain American cities. TB has a staggering impact worldwide, since one-third of the world's population is infected with the TB bacterium. Although most people who are infected never develop active TB, those with weakened immune systems--especially those with HIV--are particularly vulnerable to active TB disease. Each year 8 million people worldwide develop active TB, and 3 million die.
With appropriate antibiotic therapy, TB usually can be cured. In recent years, however, drug-resistant cases of TB have increased dramatically. Particularly alarming is the increase in the number of persons with multidrug-resistant TB caused by bacterial strains resistant to two or more drugs. Even with treatment, the death rate for multidrug-resistant TB patients is 40 to 60 percent.
As the lead institute for studies on tuberculosis, NIAID supports basic research into its biology; development of new tools to diagnose, treat, and prevent TB.
NIAID also funds research on leprosy, or Hansen's disease, which is caused by a mycobacterium. Although treatable today, there are about 1.3 million leprosy patients requiring treatment worldwide, largely in subtropical climates. Approximately 800,000 new cases were diagnosed in 1998. Research on atypical mycobacteria--which constitute a diverse and heterogeneous group of acid-fast bacilli that are widespread throughout the environment--is of increasing importance in light of the AIDS epidemic. These organisms rarely cause disease in healthy adults; however, they can cause serious opportunistic infections in people with impaired immune systems.
Cholera is a disease caused by the bacterium Vibrio cholerae. Infection results in severe, dehydrating diarrhea that is particularly dangerous to infants and small children. In 1991 cholera reappeared in the Western hemisphere for the first time in 100 years. The organism is now endemic in Central and South America, causing periodic disease outbreaks. In 1992, a new strain of V. cholerae appeared in Asia. NIAID supports research aimed at understanding the pathogenesis of the disease and developing effective vaccines. NIAID supports research aimed at understanding the pathogenesis of the disease, what constitutes protective immunity, and the development of effective vaccines.
Although their usefulness is limited by increasing bacterial resistance to antibiotics, effective antimicrobial agents have significantly reduced the burden of bacterial infections. NIAID supports the development and testing of bacterial vaccines for Hemophilus influenzae type b, Streptococcus pneumoniae and all causes of meningitis; pertussis (whooping cough); cholera; shigella; typhoid fever; and foodborne salmonella and campylobacter.
Hospital-associated, or nosocomial, infections have emerged in recent years as a significant health problem and cause of increased morbidity and mortality. They directly contribute to rising health care costs. An estimated 2 million hospital-associated infections occur in the U.S. each year, at a cost of more than $3 billion.
Gram-negative sepsis following surgery or trauma remains a serious threat to patients, with mortality rates ranging from 25 to 40 percent if sepsis occurs. NIAID supports studies on immune mechanisms--cellular and humoral--that protect healthy people against normal microbial flora commonly encountered every day.
Hospital acquisition and transmission of methicillin-resistant staphylococci, Candida, enterococci, Clostridium difficile, and antibiotic-resistant gram-negative bacteria are important areas of investigation.
The recent emergence of S. aureus exhibiting intermediate levels of resistance to vancomycin (the antibiotic reserved for treating infections due to multidrug resistant strains) has prompted NIAID to initiate an integrated research plan to address this important problem.
Fungal Diseases. Severe, sometimes life-threatening systemic infections caused by fungal organisms have long been recognized in all age groups and in all parts of the U.S. Treatment requires prolonged administration of relatively toxic drugs and is sometimes ineffective, even in the otherwise healthy patient. Fungal infections are increasingly recognized as a major cause of morbidity and mortality in patients with impaired immune defenses. NIAID supports research on medically important fungi such as Coccidioides immitis, Histoplasma capsulatum, Blastomyces dermatitidis, Cryptococcus neoformans, Candida albicans, and Aspergillus fumigatus.
Antimicrobial Drug Development. As promising new antibacterial and antifungal agents are developed, they must be critically evaluated for safety and efficacy in humans. NIAID supports the testing of licensed and unlicensed drugs that the pharmaceutical industry is unlikely to test further in humans, even though the drugs may show considerable clinical promise. Controlled, prospective, and multicentered studies are designed to compare efficacy, safety, duration, and costs with standard chemotherapeutic agents. Currently, the institute supports trials of new systemic antifungal agents and, together with NICHD, an antibiotic trial for vaginal infections in pregnant women.
Sexually Transmitted Diseases (STD). A dramatic increase in the number of new cases of STDs has occurred over the past 50 years in the United States. Gonorrhea, syphilis, genital herpes, genital warts, chlamydial infections, and pelvic inflammatory disease (PID) take an increasingly large toll emotionally, physically, and economically. Each year in the U.S. there are approximately 4 million new cases of chlamydia, one-half million new cases of gonorrhea and 1 million new cases of PID. Thirty million Americans are estimated to have genital herpes, and 24-40 million are thought to be infected with human papillomavirus (HPV), several types of which can cause cervical cancer.
STDs often have long-term, devastating consequences--particularly for women and children. Infertility, ectopic pregnancy, cervical cancer, increased risk of infection with HIV, and adverse outcomes of pregnacy, including fetal death, low birth weight, and congenital infections resulting in permanent physical and mental damage to infants, can result from STDs. In 1995 economic costs associated with PID alone were estimated to exceed $6 billion.
Current research priorities and initiatives focus on vaccine development, the sequelae of STDs in women, behavioral research, HPV, genital ulcer disease, the development of rapid, inexpensive diagnostics, and the development of topical microbicides.
NIAID conducts and supports basic research necessary to develop vaccines against all STDs including gonorrhea, chlamydial infections, syphilis, herpes, HPV infection, and chancroid.
Because of the severe and disproportionate impact of STDs on health of women and infants, NIAID seeks to develop and evaluate interventions to reduce the incidence and severity of complications of PID, such as infertility, ectopic (tubal) pregnancy, and chronic pelvic pain syndromes.
In recognition of the critical interplay between behavioral and biomedical risk factors for STDs, NIAID developed a program in integrated, intervention-oriented behavioral research for the prevention and control of STDs.
Studies of the pathogenesis and natural history of HPV are important areas of research. NIAID-supported research on HPV includes studies on the role of HPV in development of cervical dysplasia and malignancy, the development of animal models of genital HPV infection, as well as improved methods for detection and management of HPV infection.
The expansion of research on the pathogenesis and natural history of genital ulcer disease and on the interrelationship between these diseases and HIV is a priority. Research on chancroid, syphilis, and genital herpes is being emphasized.
Parasitic Diseases. Parasitic diseases, a world health problem, affect billions of people and are responsible for millions of deaths annually. While their principal health and economic impact is felt primarily in poor and developing countries, many parasitic infections remain endemic within the United States and can present a threat to individuals with immature or compromised immune systems or in situations where normal sanitation procedures fail. In addition, increased foreign travel by U.S. citizens as well as immigration to the United States allows importation of so-called "exotic" parasites from other countries.
Several unicellular protozoa and multicellular helminths cause parasitic disease. Goals of NIAID-sponsored studies on the immunology of parasitic diseases include development of effective vaccines against malaria, schistosomiasis, leishmaniasis, and others; the intervention in the host response to prevent immunologically mediated disease processes; and the development or improvement of immunodiagnostic procedures. NIAID also supports basic research on the biochemistry and molecular biology of parasites to develop chemotherapeutic agents or improve the efficacy of existing drugs. Antimicrobial resistance is a rapidly increasing problem, particularly by parasites that cause malaria. Application of modern biochemical and molecular techniques may help determine how resistance develops and reveal ways to reverse the phenomenon.
In recognition of the burgeoning problem of malaria, especially in Africa, the NIAID has significantly increased its support of malaria research. Specifically, NIAID implemented a plan to develop malaria vaccines and established a malaria research and reference reagent repository. This latter resource provides well-characterized reagents and information to malaria investigators throughout the world. NIAID's activities are coordinated with other agencies involved in the Multilateral Initiative on Malaria, which was launched at an international conference in Dakar, Senegal in January 1997.
NIAID supports Tropical Disease Research Units at domestic institutions to provide a stable environment for research on parasitic diseases. These programs apply relevant and innovative biomedical technology to develop new approaches to control parasitic diseases.
The NIAID also supports research in tropical countries where parasitic and other diseases, including TB, enteric and arboviral diseases are endemic. The International Collaborations in Infectious Diseases Research and the Tropical Medicine Research Centers programs provide opportunities for studies of natural history, pathogenesis, host immunity, and vector biology and for field and clinical testing of intervention strategies.
Vaccine Development. Vaccines have virtually eliminated once common killers such as diphtheria, tetanus, and polio in the U.S. Nearly 25 major human diseases caused by infectious agents are preventable or controllable through vaccine use. Despite this success, both new and old infectious diseases continue to threaten the health of people around the world.
The aim of the NIAID vaccine program is to capitalize on the extraordinary advances in molecular biology and immunology in order to improve the safety, effectiveness, and efficiency of existing vaccines and enhance the development of new vaccines.
As the lead PHS agency for vaccine research, NIAID coordinates a comprehensive program among scientists in government, industry, and academic settings. Vaccine research is conducted by NIAID scientists as well as by institute-supported investigators at research institutions, including six Vaccine Treatment and Evaluation Units. The units conduct clinical trials of candidate vaccines to determine whether they are safe, immunogenic (capable of stimulating an immune response), and effective.
Research on HIV vaccines is supported by NIAID's Division of AIDS.
The institute's international research activities involve grants, contracts and intramural projects to promote scientific research on tropical and other diseases of great importance to the health of people in developing and developed countries of the world.
Immediate aims are to improve means for diagnosing, treating, and controlling these diseases with the ultimate goal of disease prevention. For example, the U.S.-Japan Cooperative Medical Science Program, organized in 1965, provides an opportunity for American and Japanese scientists to cooperate in studying 10 disease-related areas of importance to the health of Asian people.
In September 1979, the International Collaboration in Infectious Diseases Research Program replaced the International Centers for Medical Research and Training which had been operational since 1960. Under the program, research centers are established in tropical countries through multidisciplinary program project grants awarded to U.S. institutions. The program is designed to promote true collaboration and scientific exchange between U.S. scientists and their overseas counterparts. The program addresses infectious diseases of health importance to the host country. In 1991 NIAID established Tropical Medicine Research Centers to provide overseas facilities for the study of tropical diseases within endemic areas.
Established in 1994, the Tuberculosis Research Unit (TBRU) is an international, multidisciplinary research group focused on translating basic research findings into human clinical trials with the goal of developing tools for TB control. The TBRU brings together investigators with expertise in TB pathogenesis and microbiology, immunology, diagnostics development, epidemiology, and the conduct of clinical trials at domestic and international multiple research centers.
Following emergence of the HIV/AIDS pandemic, NIAID set up special international award mechanisms to support international research in this area. The emphasis and structure of these programs have evolved over time. NIAID presently supports an international HIV Vaccine Evaluation Network (HIVNET) in Africa, Asia, Latin America, and the Caribbean.
Division of Allergy, Immunology and Transplantation
This division supports research, including basic and clinical studies, on the immune system as it functions in the maintenance of health and as it malfunctions in the production of disease.
Basic research is supported in 1) immuno-biology and immunochemistry and 2) immunogenetics and transplantation immunology. Clinical research is supported in asthma and allergic diseases, and immunologic diseases and immunopathology. NIAID's approach integrates the basic science disciplines with relevant clinical specialties.
Basic Immunology. DAIT supports a spectrum of research to better understand the structure and function of the immune system. Such studies focus on the origin, maturation, and interactions of the immune system's major cells and the production and regulation of biochemical modulators that are produced by these cells during an immune response. Studies include mechanisms responsible for induction and regulation of the immune response.
Immunochemical research encompasses the delineation of the chemical structure and function of antigens and antibodies; chemical basis of immunologic specificity; regulation of immunoglobulin synthesis; and mechanisms of antigen-antibody reaction.
Research projects are designed to:
- Elucidate the critical immunologic functions of T cell receptors, cell-adhesion molecules, and cytokines and their receptors in various systems in the human body and in laboratory animals;
- Isolate and characterize human stem cells;
- Participate in the formulation of a repository of cell lines and gene probes for use in the study of mucosal immunity and digestive diseases; and
- Elucidate the chemical nature and structure of small organic molecules that generate allergic and hypersensitive responses.
Genetics and Transplantation. Primary goals of genetics and transplantation research are to:
- Clarify the organization and mechanisms of expression of the genes on which immune function depends;
- Characterize protein products of genes;
- Determine how these gene products condition the response to foreign antigens, for example, transplanted organs; and
- Develop therapies to modulate the immune response and prevent rejection of transplanted organs and tissues.
By supporting the acquisition, characterization and distribution of tissue typing reagents and the evaluation and improvement of tissue typing methodologies, the program facilitates the matching of donors and recipients for transplants.
Research projects in this area are designed to:
- Investigate the mechanisms and innovative use of immunosuppressive drugs;
- Develop new monoclonal antibodies directed against specific cells to prevent graft rejection;
- Further develop reagents for precise typing of major histocamptibility antigens for tissue typing; and
- Delineate the development of the fetal and adult immune response, using in vitro systems.
Identification and Acquisition of Reagents. NIAID contracts serve as sources of standard reagents to identify cell surface molecules that play a role in immune response.
Some of these reagents are available for use in workshops or similar large-scale studies.
The institute also is a primary source of standard reagents for distribution and analyses for basic immunogenetic studies of murine transplantation antigens.
Transplantation. Program projects in transplantation immunology, located at major transplant centers, are funded by NIAID to facilitate rapid translation of basic immunologic discoveries into clinical use. The centers carry out basic and clinical research pertinent to mechanisms of rejection, organ availability and preservation, and management of rejection.
National Cooperative Clinical Trial in Transplantation. NIAID established this trial to expedite the evaluation of new treatment modalities to prevent kidney graft rejection. Multicenter clinical trials to assess the potential efficacy of various therapies are conducted at eight kidney transplant units throughout the U.S.
Asthma, Allergy and Inflammation. More than 50 million Americans suffer from allergic diseases including asthma. NIAID supports studies encompassing the cause, pathogenesis, diagnosis, prevention, and treatment of allergic diseases. The institutes supports studies on various types of allergic problems including asthma, allergic reactions and disorders caused by insect bites and stings, foods, airborne allergens, and infectious agents. Studies also include structure of antibodies, particularly IgE, and chemical mediators released by cells responsible for allergic reactions; isolation and chemical characterization of the active components of allergenic agents; and therapy and prevention of allergic disorders.
Asthma, Allergic and Immunologic Disease Cooperative Research Centers. A network of cooperative research centers represents an effort to integrate the basic concepts of immunology, genetics, biochemistry, and pharmacology into clinical investigations of patients with asthma, allergic and immunologic diseases. The program encourages collaboration between basic and clinical scientists, provides a research environment for such interactions, and implements clinical application of adequately tested research findings and procedures.
National Cooperative Inner-City Asthma Study. NIAID established this study to assess factors contributing to the increased morbidity and mortality from asthma among children residing in urban areas, and to develop and evaluate a comprehensive therapeutic, educational, and environmental intervention program designed around those contributing factors. Seven sites in six cities nationwide are participating in this cooperative study.
Clinical Immunology. Investigations of underlying mechanisms of disease and applications of basic knowledge to the cause, prevention, and management of immunologic disorders are approached from either of two disciplines--clinical immunology or immunopathology. Studies of clinical immunology involve acquired and inherited diseases associated with dysfunctions of the immune system, whereas immunopathology studies encompass genetics, cytology, biochemistry, pathology, and pharmacology of the immune system.
Areas under investigation include:
- Immune deficiency diseases arising from primary defects in development or maturation of the immune responses;
- acquired immune deficiency disorders excluding AIDS;
- clinical manifestations mediated by products of lymphocytes;
- diseases associated with immune complexes and autoimmune phenomena; and
- immunotherapy of disease process, including the use of immunopotentiating and immunoregulatory substances.
DAIT supports program projects in mechanisms of immunologic diseases and autoimmunity aimed at increasing the understanding of pathophysiologic processes of immune-mediated diseases and the development of improved methods of diagnosis, treatment and prevention of immune system disorders.
Division of AIDS
The Division of AIDS (DAIDS) was formed in 1986 to address national research needs created by the advent and spread of the HIV/AIDS epidemic. DAIDS ensures that federally supported scientific investigation of HIV infection is focused and appropriately balanced on the most critical biomedical research issues.
Specifically, the mission of DAIDS is to increase basic knowledge of the pathogenesis, natural history, and transmission of HIV disease and to promote progress in its detection, treatment, and prevention. DAIDS accomplishes this through planning, implementing, and evaluating programs in: 1) fundamental basic and clinical research; 2) discovery and development of therapies for HIV infection and its complications; 3) discovery and development of vaccines and other preventive interventions; and 4) training of researchers in these activities. An extramural portfolio of grants and contracts addresses research in these areas.
HIV Pathogenesis. Research on the patho-genesis of HIV infection will advance under-standing of the biological causes of HIV-related disease and serve as a foundation for advancing treatment and prevention.
Investigator-initiated research and the traditional research grant are the foundation of division activity in this area. Important research gaps are identified by division staff in concert with investigators and advisory committees.
Other key NIAID resources for the study of pathogenesis include:
- longitudinal epidemiological studies of cohorts of individuals infected with, or at risk of infection with, HIV, and serially collected specimens stored in an DAIDS-supported repository;
- animal model research and development projects;
- the NIAID AIDS Reference and Reagent Repository, through which DAIDS acquires and distributes essential research reagents to scientists around the world; and
- the Centers for AIDS Research (CFAR), designed to support coordinated scientific and administrative activities that enhance the capacity for collaboration between basic and clinical research.
Epidemiology and Natural History. The division's goals in epidemiology and natural history are to foster population-based research that will advance understanding of the biology and clinical course of HIV infection and serve as a foundation for advancing treatment and prevention.
The division oversees several longitudinal cohort studies that conduct multidisciplinary research involving specific populations of individuals infected with or at significant risk of infection with HIV. These include:
- Multicenter AIDS Cohort Study,
- San Francisco Men's Health Study, and
- Women's Inter-Agency HIV Study.
In addition to collecting clinical data obtained at serial examinations and interviews, all these studies are linked to a DAIDS-supported repository that stores a variety of serially collected biological specimens from participants and subsequently retrieves them for use in experiments conducted by investigators around the world. These studies therefore represent a powerful investigative tool for basic and applied research in pathogenesis, diagnosis, behavior, treatment, and prevention.
Vaccine and Prevention Research and Development. Development and testing of vaccines and other biomedical interventions such as drugs and microbicides to prevent HIV disease is a key role of DAIDS-funded research.
NIAID supports vaccine research from early concepts through clinical trials. This comprehensive approach to vaccine development includes fundamental and vaccine evaluation research.
Institute efforts in vaccine research and development are built on a strong foundation of investigator-initiated research in basic virology, immunology, and microbiology. In addition, DAIDS uses a number of specific resources to stimulate development of new vaccine concepts and to ensure that this infrastructure emphasizes a rational, deliberate process for moving concepts through to clinical trials.
- The Innovation Grant Program for Approaches in HIV Vaccine Research encourages novel and innovative concepts in vaccine discovery and development. Little preliminary date are required. NIAID funds research in the following areas: 1) structure and function of the HIV envelope protein (Env), 2) improved animal models for vaccine and pathogenesis studies, and 3) mechanisms of directing antigen processing in vivo to maximize the immune response.
- The HIV Vaccine Research and Design Program (HIVRAD) supports concepts that have evolved beyond early testing and "matured" innovation grants. Other general vaccine research that does not involve a clinical component, such as animal model development and work on correlates of immunity, is also supported by HIVRAD.
- The Integrated Preclinical/Clinical AIDS Vaccine Development Program (IPCAVD) supports the iterative processes of vaccine concept refinement and testing. Through the program, research groups investigate promising vaccine concepts that are amenable to product development and are likely to lead to preliminary studies in humans.
- The HIV Vaccine Design and Development Teams Program will help transition vaccine concepts from the lab to human trials. This infrastructure will allow companies and researchers from academia, with development experience and a promising vaccine concept that is amenable to targeted development, to further develop their product through a focused, development-based, milestone-oriented approach.
- The HIV Vaccine Production Contract will offer a menu of resources in several applied, developmental areas (e.g., quality control testing, scale-up activities, IND assembly, small animal toxicity testing, and GMP manufacturing).
Other areas include:
- the AIDS Vaccine Evaluation Group (AVEG), which conducts phase I and II clinical trials of candidate HIV vaccines;
- central immunology laboratory facilities in support of activities of the IPCAVD, SIV Vaccine Evaluation Units, the chimpanzee unit, and the AVEG;
- HIV Variation Project, which investigates the rate and magnitude of genetic variation in HIV and related retroviruses and explores the impact of this variation on strategies to develop HIV vaccines;
- Cooperative Group for Investigations of AIDS Vaccine Adjuvants, which supports investigator-initiated research into mechanisms of adjuvant action, develops new adjuvant formulations to stimulate immune responses and generate long-lasting immunity and immunological memory, and evaluates vaccine-adjuvant combinations in relevant animal models;
- and HIV Network for Prevention Trials (HIVNET), which consists of both domestic and international sites that conduct trials of HIV vaccines and other prevention strategies. Researchers at HIVNET sites also study cohorts of individuals at high risk for HIV infection to prepare for conducting vaccine efficacy trials within these populations.
Therapeutics Research and Development. The division's goal in therapeutics is to foster the discovery and development of interventions that will improve the quality and duration of life of HIV-infected individuals.
NIAID devotes substantial resources to the discovery stage of therapeutics research, attempting to focus resources on areas of promise that are receiving insufficient attention from the private sector. The effort begins with a strong commitment to basic research in microbiology and pathogenesis. In addition, NIAID supports targeted drug discovery for HIV through the Integrated Preclinical/Clinical AIDS Therapeutic Development Program. The consortia of academia, industry, and government investigators work collaboratively on focused "gap" areas of targeted drug discovery. Small portfolios of highly applied traditional investigator-initiated research round out this effort.
NIAID's preclinical development resources are limited in scope to those necessary to ensure that the national effort has the capability to carry out specific rate-limiting developmental steps involving selected highly promising candidate agents that lack a private sponsor with sufficient resources or commitment. These "gap-filling" resources include capabilities for 1) chemical resynthesis; 2) analytical chemistry and quality control; 3) dosage form development and manufacturing; 4) small and large animal toxicology; and 5) in vitro screening and animal model efficacy studies.
In addition, the Strategic Program for Innovative Research on AIDS Treatment (SPIRAT) fosters coordinated and interdependent basic and clinical research between current HIV pathobiology and clinical evaluation of novel therapeutic strategies.
NIAID conducts clinical trials of new therapeutics in adults in two networks:
- Adult AIDS Clinical Trials Group--a large, multicenter clinical trials network; and
- Terry Beirn Community Programs for Clinical Research on AIDS--designed to address questions of importance to primary care clinicians and extend opportunity for participation in trials to persons under-represented in HIV research.
The Pediatric AIDS Clinical Trials Group supports resources specifically for children and adolescents.
Division of Intramural Research
The institute's Division of Intramural Research (DIR) consists of 16 laboratories,13 of which are on the Bethesda campus and at off-campus sites in Frederick and Rockville, Md., and 3 are located at the Rocky Mountain Laboratories in Hamilton, Mont. Scientists in these laboratories conduct basic and applied research in immunologic, allergic, and infectious diseases and related clinical disorders. Considerable effort is devoted toward vaccine development and the understanding of the immune system's ability to react to certain foreign molecules, or antigens.
The scope of laboratory investigations includes the disciplines of virology, parasitology, mycology, microbiology, biochemistry, immunology, immunopathology and immunogenetics. Additionally, DIR supports a 52-bed inpatient service and an outpatient facility located in the Clinical Center on the NIH campus. CC physician-scientists treat patients with a variety of diseases, including AIDS, vasculitis, immunodeficiencies, host defense defects, unusual fungal infections, asthma, allergies, various parasitic diseases and disorders of inflammation. Frequently patients participate in new and exciting treatment or diagnostic procedures derived from ongoing laboratory research efforts.
Successful vaccines or therapies for infectious diseases derive from a myriad of research activities on the disease agent as well as interactions of the agent with the host. HIV/AIDS is a major challenge to DIR scientists and physicians. The creation of suitable laboratory animal models is critical to developing therapeutic strategies and vaccines for AIDS.
DIR scientists study the pathogenesis of HIV infection as well as immune responses to the virus. Immunomodulators called cytokines that are secreted by immune cells have been shown to induce the expression of HIV in latently or chronically infected cell lines, thus providing tools for understanding mechanisms of the progression of immunosuppression in HIV-infected individuals.
In addition, NIAID researchers explore the many components of HIV disease, including phases of immune system activation and suppression. In studying dissemination of HIV to lymphoid tissues in the body such as the lymph nodes and spleen, investigators have found that HIV is active within these tissues from the earliest stages of HIV infection. This finding provides a scientific rationale for early treatment when safer and more effective antiretroviral drugs become available. DIR investigators have conducted intensive studies of antiretroviral and immunomodulator therapies. Clinical trials of a number of therapies, including use of IL-2 to maintain CD4 levels, are ongoing.
NIAID intramural scientists are working to develop and test vaccines against a number of infectious agents such as viruses causing AIDS, dengue fever, diarrhea in infants, and pneumonia and croup in infants and young children. NIAID intramural laboratories also study bacterial agents that cause sexually transmitted diseases such as chlamydia and gonorrhea, and Lyme disease.
Basic immunologic studies are aimed at defining components and mechanisms of action of humoral and cellular responses. Scientists are working to characterize receptor molecules on the surface of immune cells. Information derived from these studies may allow design of therapies that inhibit specific immune responses by blocking receptor binding to its natural ligand and may have great importance in controlling rejection associated with transplantation.
DIR scientists also study the structure and function of B lymphocytes, critical components of the immune response and responsible for antibody responses. These studies are important in the design of future vaccines that can enhance production of certain forms of antibody.
Inflammation is an important aspect of immunity. A series of proteins collectively called the complement system are important mediators of inflammation. NIAID scientists identified a new protein present in large concentrations in humans. The new protein binds to the fourth protein of the complement cascade where it acts as an inhibitor of this important inflammation-producing system. Certain patients with unusual swelling disorders have an abnormality in the degradation of this protein, and thus the protein may be very important in certain swelling disorders.
The scavenger blood cells of the immune system known as phagocytic cells (e.g., neutrophils and monocytes) are particularly important for host defense against disease causing bacteria and fungi. Phagocytic cells kill microorganisms by engulfing them and producing antimicrobial substances such as hydrogen peroxide or enzymes which damage the pathogen.
Chronic granulomatous disease (CGD) of childhood is an inherited disease in which severe infections result from a deficiency of hydrogen peroxide production by phagocytes. DIR scientists showed that treatment with interferon gamma, an immune system stimulating hormone, will reduce the frequency of infections in CGD, though this is not a cure for CGD.
In other studies, DIR scientists have demonstrated that inherited abnormalities in either of the two subunits of the receptor for gamma interferon results in an inability of the patient's monocytes to fight off infections with atypical mycobacteria (a pathogen related to tuberculosis, but which does not usually infect normal people). DIR physicians have successfully developed a novel method of blood stem cell transplantation which they have used to treat patients with CGD and interferon gamma receptor deficiency. Similar to conventional bone marrow transplantation, blood stem cells (precursors of the phagocytic cells) obtained from an unaffected sibling are transplanted in the patient to cure the disorder. However, the transplant method differs from a conventional bone marrow transplant in that the patient receives only a level of chemotherapy to provide some room in the marrow for the newly transplanted stem cells and does not completely eliminate the patient's own bone marrow, resulting in less dangerous side effects from the preparative medications. In addition, the transplanted cells are partially depleted of lymphocytes to reduce graft versus host disease, another complication that can occur following transplantation. This may allow the use of transplantation to cure inherited immune deficiencies where the risks of conventional transplantation would be unacceptable.
Studies on parasitic infections have revealed that the type of immune response induced can be very important in determining disease outcome. In the case of leishmaniasis, DIR scientists have shown that the induction of IL-12 dependent Th1 responses protects mice against infection, while Th2 responses generally result in enhanced, uncontrolled growth of the protozoan. They have utilized this concept in developing an experimental DNA vaccine against leishmania parasites which incorporates IL-12 promoting elements.
In schistosomiasis, the fibrotic diseases induced by the response to this parasite's eggs was shown by DIR researchers to be mediated by cytokines (IL-13, IL-4) produced by Th2 cells. When IL-12 was used to shift the immune response to the eggs toward the production of Th1 rather than Th2 cells, disease was prevented. Such studies support the concept that manipulation of Th1/Th2 T cell subsets may represent a powerful approach for vaccination as well as immunotherapy.
Studies of allergy are carried out by investigators working in basic immunology laboratories as well as by clinical investigators in the Clinical Center. The clinical allergy program has focused on the pathogenesis of asthma and the role of different immune cells in allergic disease. Clinical studies on disorders related to important mediators of allergies called mast cells have not only led to insight into the biologic characteristic of human mast cells, but have permitted studies which have furthered the diagnosis, classification, and treatment of these diseases.
The basic research program for allergic diseases has focused on immunomodulatory molecules called cytokines, signal transduction, and mast cell biology. The cytokine IL-4, produced by T cells, has been shown essential for the production of IgE, the primary molecule involved in allergic reactions, and strategies to block the production of IgE by interfering with the action of IL-4 have resulted in down-regulation of normal immune responses to certain antigens. The intracellular events following activation of the surface receptor for IL-4, as well as receptors for additional immunomodulatory molecules, have contributed to the elucidation of signaling pathways within inflammatory cells that may one day offer new targets for therapeutic intervention.
Studies of mast cells are ongoing to identify their cell-of-origin, growth factors that regulate their differentiation and survival, and surface receptors which when aggregated lead to the release of potent inflammatory chemicals from mast cells. Among critical observations arising from this research have been the identification of the cell-of-origin for the human mast cell, the recognition that interferon gamma limits mast cell numbers, and the realization that other immunoglobulin receptors, in addition to the IgE receptor, may regulate mast cell activation.