NIH 1998 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 a wide spectrum of 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
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 virus-caused 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 is another group of diseases with
a major impact 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. NIAID-sponsored studies
focus on virology, molecular biology, immunology, pathogenesis, development of antivirals,
animal model development, natural history, vaccine development and clinical trials.
Vaccines have now been licensed for hepatitis A and B.
Diarrheal diseases caused by viruses are particularly a problem among infants in
developing countries. Experimental vaccines against rotaviruses--a major cause of infant
diarrhea worldwide--have been extensively tested in children and infants. One vaccine
developed in NIAID intramural laboratories is expected to be 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 on CFS. 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 has established screening facilities
for the in vitro evaluation of an experimental compounds 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 and an inability
to test it. 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. Other investigators have evaluated interferons for human papilloma infections
such as genital warts.
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).
Lyme disease, first recognized in the early 1980s 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 focusing 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., is
reemerging in certain American cities. TB has a staggering impact worldwide, since
one-third of the worlds population is infected with the TB bacterium. Although most
people who are infected never develop active TB, those with weakened immune
systems--especially those infected with HIV--are particularly vulnerable to active TB
disease. Each year 8 million people world-wide 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 TB, NIAID supports basic research into its
biology; development of: new tools to diagnose TB; drugs or ways to deliver them; clinical
trials of anti-TB therapies; and vaccines to prevent it.
NIAID also funds research on leprosy, or Hansens 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. More than half a million
cases are diagnosed each year. 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 epidemic has spread as far north as Mexico and is a threat to travelers to
Central and South America.
In 1992 a new strain of V. cholerae appeared in Asia and an area of the Bay of
Bengal. NIAID supports research aimed at understanding the pathogenesis of the disease,
what constitutes protective immunity, and the development of effective vaccines.
Effective antimicrobial agents have significantly reduced the burden of bacterial
infections, even though their usefulness is limited by increasing bacterial resistance to
antibiotics and in those diseases with an onset and progression so rapid that effective
treatment is difficult. 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; and typhoid fever.
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 the most 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. Another focus is the study
of disturbances in resistance mechanisms in hospitalized or immunocompromised patients.
Gram-negative bacteria from the gastrointestinal tract are the primary etiologic agents
and many have become resistant to antibiotics.
Hospital acquisition and transmission of methicillin-resistant staphylococci, Candida,
enterococci, and antibiotic-resistant gram-negative bacteria are important areas of
The recent emergence of Staphylococcus 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.
The interplay of bacterial toxins such as lipopolysaccharide and staphylococcal toxic
shock toxin with host serum and cell components can result in fever, shock, and death.
NIAID is investigating the underlying mechanisms of shock and its control and prevention.
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 selects for trial 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, 0.5
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 are causally associated with
development of 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
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. Furthermore, because STDs are preventable causes of adverse
outcomes of pregnancy such as fetal wastage, low birth weight, and congenital infections,
this area is also a priority.
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.
The role of HPV in development of cervical dysplasia and malignancy, development of animal
models of genital HPV infection, and improved methods for detection and management of HPV
infection are among the research areas of interest to NIAID.
The expansion of research on the pathogenesis and natural history of genital ulcer
disease and on the interrelationship between these diseases and HIV is of high 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 break down. 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 new
chemotherapeutic agents or improve the efficacy of existing drugs. Development of drug
resistance is a rapidly increasing problem, particularly in malaria. Application of modern
biochemical and molecular technology to determine how resistance develops may reveal ways
to reverse the phenomenon.
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.
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. This is also
the goal of the Childrens Vaccine Initiative, a global project of which NIAID is an
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 NIAIDs Division of AIDS.
The institutes 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.
Other international activities include the NIAID-USAID Middle East Regional Cooperation
Program, carried out through Jordan, Morocco, Lebanon, Tunisia, and Israel, to study
leishmaniasis and hydatid disease. NIAID also coordinates studies on the immunology of
infectious diseases as part of the Indo-U.S. Science and Technology Initiative.
Division of Allergy, Immunology and Transplantation
This division focuses on the immune system as it functions in the maintenance of health
and as it malfunctions in the production of disease. It encompasses basic and clinical
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. NIAIDs approach
integrates the basic science disciplines with relevant clinical specialties.
Basic Immunology. The biology and chemistry of the immune system and its
products are the concerns of this program area. Immunobiologic studies focus on the
origin, maturation, and interactions of the immune system's major cells, lymphokines, and
other substances produced by theses and other cells that mediate immune reactions. 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;
- Elucidate the chemical nature and structure of small organic
molecules that generate allergic and hypersensitive responses; and
- Investigate the interactions of selected immunotoxicants with
the secretory immune subsystems of the gut and respiratory tract.
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, including
- Determine how these gene products condition the response to
foreign antigens; and
- Develop regimens to modulate the immune response and facilitate
engraftment 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. It also supports
studies on the relationship of the human major histocompatibility complex (MHC) HLA
antigens to disease susceptibility.
Research projects in this area are designed to:
- Investigate the mechanisms and innovative use of
- Develop new monoclonal antibodies directed against specific
cells to prevent graft rejection;
- Further develop reagents for precise typing of MHC or tissue
- 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 antigens both within and outside of the major
histocompatibility complex that play a role in immune response.
Some of these reagents are available for use in workshops or similar large-scale
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. Various types of
allergic problems under investigation include: immediate type hypersensitivity and its
disorders, including asthma, allergic rhinitis, atopic dermatitis, urticaria and
angioedema; allergic reactions and disorders caused by insect bites and stings, foods,
airborne allergens, and infectious agents; manifestations of delayed hypersensitivity and
contact dermatitis; and mechanisms of drug reactions and chemical sensitization. Studies
also include structure of antibodies, particularly IgE, and chemical mediators released by
interaction of antigen and antibody with target cells; isolation and chemical
characterization of the active fractions of allergenic agents; and therapy and prevention
of allergic disorders and hypersensitivity reactions by immunotherapy with specific
antigens or drugs.
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. It is believed that this will lead to an understanding of the
pathophysiologic, biochemical, and immunologic mechanisms of these disorders.
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
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
- 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. b>
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 is ensuring 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
HIV Pathogenesis. Research on the pathogenesis of HIV infection will advance
understanding 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;
- the Centers for AIDS Research (CFARS), designed to support
coordinated scientific and administrative activities that enhance the capacity for
collaboration between basic and clinical research.
Epidemiology and Natural History. The divisions 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 large 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 Mens Health Study, and
- Womens Inter-Agency HIV Study.
In addition to collecting clinical data obtained at serial examinations and interviews,
all of 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
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. Fifty-eight grants are currently funded
in the following research 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. Some exciting
research include: twinning and cloning of monkeys, transgenic small animal models,
strategies to target HIV T cell epitopes, and new vectors.
- 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 Program
funds the iterative processes of product development, optimization, and refinement.
Through this program, consortia vaccine and development teams conduct research on
promising vaccine concepts that are amenable to product development and are likely to lead
to preliminary studies in humans.
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 NCVDGs, SIV-VEUs, 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
- 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
Therapeutics Research and Development. The divisions 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. Upon this are built programs of targeted drug
discovery with the National Cooperative Drug Discovery Groups (NCDDGs) for HIV and
opportunistic infections (OIs) at the center. These 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.
NIAIDs 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 underrepresented in HIV research.
The Pediatric AIDS Clinical Trials Group supports resources specifically for children
Division of Intramural Research
The institutes Division of Intramural Research (DIR) consists of 16 laboratories,
of which 13 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 systems ability to react to
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. Patients with a variety of
diseases under study, including AIDS, vasculitis, immunodeficiencies, host defense
defects, unusual fungal infections, asthma, allergies, various parasitic diseases and
disorders of inflammation, are seen. 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 associated with 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 immunopatho-genesis of HIV infection as well as immune
response to the virus. Cytokines have been shown to induce the expression of HIV in
latently or chronically infected cell lines, thus providing tools for understanding
mechanisms of the insidious 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 under way.
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. Bacterial agents that cause sexually
transmitted diseases such as chlamydia and gonorrhea, and Lyme disease are under active
investigation. Approaches to the development of a vaccine against malaria are being
explored. Promising new vaccine candidates are tested in the clinical setting for safety,
immunogenicity, and if warranted, efficacy.
Basic immunologic studies are aimed at defining components and mechanisms of action of
humoral and cellular responses. Receptors on T lymphocytes and peptides linked to the
surface of antigen-presenting cells are being defined. Information derived from these
studies may allow design of peptides that can inhibit specific immune responses and may
have great importance in controlling rejection associated with transplantation.
DIR researchers carry out intensive studies of the role of newly discovered cytokines
in T-cell differentiation. Researchers have found that interleukin 12 (IL-12) plays a
pivotal role in induction of T-cell responses, which are important for control of
B lymphocytes, critical components of the immune response and responsible for antibody
responses, are being dissected for studies of structure and function. Among studies being
conducted are those related to control of B-cell immunoglobulin class switching. It has
been shown, for instance, that IL-4 and INF-gamma reciprocally regulate IgG1 and IgE
responses in mouse systems. In addition, the role of TGF-beta in IgA class-switching has
been clarified. 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. One important mediator of inflammation
is a series of nine proteins called the complement system. NIAID scientists identified a
new protein present in large concentrations in plasma of 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. The inhibitor also interacts with
kinin-generating and coagulation systems. 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 first evidence that immunodeficiency can be treated with a naturally occurring
product of lymphocytes was recently demonstrated by DIR scientists. Chronic granulomatous
disease of childhood (CGD), a disease in which there is a defect in the ability of
scavenger cells of the immune system to produce hydrogen peroxide, renders the patient
susceptible to certain infectious agents. A multicenter clinical trial of interferon gamma
in patients with CGD followed in vitro studies which demonstrated the effectiveness of
interferon gamma in correcting the defect in phagocytes from these patients. Interferon
gamma was shown to significantly reduce the number of serious infections in CGD patients.
These studies led to FDA approval of this drug for use in CGD.
Studies of immune response to the causative agent of leishmaniasis have demonstrated
that immunity to the parasite is not only to a specific antigen, but also to a certain
immune cell. DIR scientists have shown that outcome of leishmaniasis depends on whether
the animal develops a TH1 response with T cells that produce IL-2 and IFN-gamma, or a TH2
response with T cells that produce IL-4 and IL-5. In the former case, granulomas develop
that wall off and kill leishmania in the latter, the infection is disseminated.
Studies of allergy are carried out by investigators working in basic immunology
laboratories as well as by clinical and laboratory investigators working within the Asthma
and Allergic Diseases Center. One effort has been the study of IgE antibody which mediates
allergic responses by causing mast cells to release mediators of allergic responses. IL-4,
produced by T cells, is essential for production of IgE in mice. Administration of IL-4 to
mice prevented increases in IgE antibodies normally observed in immune responses to
certain antigens. In other studies, DIR scientists have developed a "knockout"
mouse that lacks receptors for IgE antibodies on the surface of mast cells. These mice
will facilitate a better understanding of the role of IgE responses in the production of
Studies of the mechanisms of allergies have emphasized work on mast cells. Mast cells
are the central cells of allergic responses because when activated by an allergen and IgE
they release the mediators of allergy. New techniques have been developed in order to grow
human mast cells in culture, an advancement that will enable more detailed investigations
into their biology. An improved approach to the treatment of asthma has been devised by
DIR researchers. The concept is based upon separating bronchodilators from agents that act
to reverse specific processes in the pathogenesis of asthma. Specifically, patients are
placed on symptomatic therapy in order to permit the more specific therapy to act. Inhaled
cromolyn, systemic corticosteroids and immunotherapy are employed as specific agents while
beta adrenergic agonists, theophylline, and atropine are symptomatic agents. This approach
is gaining increased acceptance and should improve long-term treatment of asthma.