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Testimony on Infectious Diseases Research at NIH by Anthony S. Fauci, M.D.
National Institute of Allergy and Infectious Diseases
Duane F. Alexander, M.D.
National Institute of Child Health and Human Development
William E. Paul, M.D.
Office of AIDS Research
National Institutes of Health

U.S. Department of Health and Human Services

Before the Senate Committee on Labor and Human Resources
March 7, 1996

Madam Chairman and members of the Committee, we are pleased to appear before you today to discuss our programs at the National Institutes of Health.

During the twentieth century, new vaccines diagnostic tests, and treatments, as well as improved sanitation and control of disease-transmitting insects have made enormous contributions to public health by reducing the burden of many infectious diseases. Smallpox has been eradicated from the world and polio eliminated from the western hemisphere; diseases such as scarlet fever, measles, typhoid fever and diphtheria, once major killers in this country, are now rare.

Despite this progress, infectious diseases today are the leading cause of death worldwide and the third leading, cause of death in the United States. We remain vulnerable to new epidemics as well as to old diseases that re-emerge, sometimes more deadly than ever. For example, in this century alone, in the potential lifespan of a single individual, we have experienced two major pandemics with devastating global consequences: the 1918 influenza pandemic that killed 20 million people worldwide, and the ongoing epidemic of disease due to the human immunodeficiency virus (HIV), which so far has killed approximately 300,000 Americans.

Basic research in infectious diseases is more important than ever and requires contributions from a wide variety of scientific disciplines. Microbiologists, for example, study the precise mechanisms by which microorganisms cause disease, leading to the identification of vulnerable points to which to target therapeutic strategies. Understanding the differences in the disease-causing abilities of viruses as compared to bacteria or fungi enables us to design therapies tailor-made for each class of organism. Molecular biologists help us understand the genetic mechanisms of microbic emergence, infection and virulence. Immunologist delineate the factors critical to immune competence and the protective inflammatory response. Epidemiologists identify the mechanisms of disease transmission, including behavioral factors that place individuals at risk for infection.

Support for these disciplines can be found in every Institute and Center of the National Institutes of Health (NIH); they all contribute to our efforts to prevent and treat infectious diseases. We recognize that all tissues of the body are susceptible to invasion by infectious organisms: neurologists focus on brain infections, while dentists study organisms found in the mouth. Doctors who study the digestive tract now know that the major cause of pelvic ulcers is infection with the organism Helicopter pylon; antibiotics, not dietary changes, cure the disease, and a vaccine could potentially prevent this common gastronomical disease. Diseases and treatments that suppress the immune system, such as drugs used to treat cancer or to prevent organ transplant rejection, can weaken the body's ability to mount a defense against invading microbes. Thus, research in infectious diseases cuts across all Institutes at NIH. Today we will highlight three components of the NIH that are central to the fight against infectious diseases, old and new, that threaten the health of people in this country and around the world.

The National Institute of Allergy and Infectious Diseases (NIAID) is the lead NIH agency for infectious disease research. NIAID conducts and supports research into developing better means of preventing and diagnosing - and treating - these illnesses. A particular focus of the Institute is the area of emerging and re-emerging- infectious diseases. Another Institute pivotal to infectious disease research at NIH is the National Institute of Child Health and Human Development (NICHD). NICHD was established by Congress in 1962 to reduce infant mortality, improve material health and address the causes and problems of birth defects and mental retardation in this country, many of which are due to infectious diseases.

Since the recognition of AIDS in 1981, the government has marshaled these research programs to comprehensively fight HIV and AIDS, enlisting the resources of each of the NIH Institutes and Centers, and setting in place central leadership by empowering the NIH Office of AIDS Research (OAR) to plan, coordinate and evaluate the NIH AIDS research effort.

The ongoing threat of infectious diseases

The multidisciplinary research programs conducted and supported by each of the Institutes of NIH, from basic studies of pathogens and how they cause disease, through clinical research and product development, are central to the Nation's ability to effectively meet the continuing challenges of infectious diseases. The importance of NIH-sponsored infectious disease research is underscored by the re-emergence in recent years of ancient diseases such as tuberculosis, cholera, malaria and plague. In addition, the United States has experienced the emergence and re-emergence of previously poorly recognized diseases such as Lyme disease, caused by the bacterium Borrelia burgdorferi; the often lethal respiratory distress syndrome caused by a new form of hantavirus; gastrointestinal disease caused by the foodborne Escherichia coli 0157:H7 bacteria and cryptosporidium in municipal water supplies; and the increasing incidence of a particularly invasive form of Group A streptococcus referred to in the lay press as " flesh-eating bacteria."

The emergence and re-emergence of infectious diseases are a result of many factors. Microbes have the capacity to adapt rapidly to changes in their environment, through genetic change and environmental selection. These genetic changes often result in increased infectivity, virulence and resistance to drugs and the body's immune defense system.

A familiar example of how microbial changes can influence disease transmission is the annual occurrence of influenza outbreaks. New versions of the virus are constantly appearing due to the remarkable ability of genes from different types of influenza to recombine. People who have been infected with one strain become resistant to reinfection; when confronted with a new form, however, they are as susceptible as if they had never before seen the virus. Another example of the influence of microbial changes is seen with cholera. For the first time in more than 100 years, cholera was reintroduced to the western hemisphere in 1991. The newly introduced organism, the 01 El Tor strain of Vibrio cholerae imported from Asia, has become endemic in many areas of South and Central America, including areas of Mexico adjoining the southern U.S. border; almost 300,000 cases were reported in South America in 1993. More recently, another new variant has emerged in Asia that threatens to become the cause of the world's next pandemic. This 0139 strain is so different from the 01 strain that individuals who have developed a protective immune response to the 01 strain remain susceptible to the new 0139 strain. This new cholera strain has already spread widely in Asia, the Middle East and Russia.

Through mutation and evolution, microorganisms that had previously been controlled by antibiotics and other drugs have re-emerged. Widespread and often suboptimal treatment set up the perfect conditions to select for drug-resistant mutant organisms. For example, the availability of a relatively inexpensive drug, chloroquine, contributed to the emergence of chloroquine-resistant malaria seen in most parts of the world. The global situation for treatment and prophylaxis of the most severe type of malaria, caused by Plasmodium falciparum, has become desperate. According to WHO, by 1994 the only malaria-endemic countries that did not report some level of resistance to chloroquine were in Central America. Moreover, resistance to newer alternative drugs is increasingly common, and sensitivity to the old stand-by quinine also appears to be diminishing.

Hospitals in this country and worldwide are facing unprecedented crises from the rapid emergence and dissemination of antibiotic-resistant microorganisms. Strains of Staphylococcus aureus resistant to many common antibiotics are endemic in hospitals and chronic-care facilities, leaving only one drug (vancomycin) as an effective treatment for these infections. As a result, increasing reliance on vancomycin has led to the emergence of vancomycin-resistant enterococci. Until 1989, vancomycin resistance had not been reported in U.S. hospitals; by 1993, more than 10 percent of hospital-acquired enterococci reported to the CDC were resistant. Some enterococcal strains are now untreatable because of simultaneous resistance to several different families of drugs.

Tuberculosis (TB) also has become increasingly problematic because of the development of resistance to currently used drugs. Globally, approximately 8 million people develop active TB every year, and 3 million die. In the United States, TB cases increased dramatically in the mid 1980's, with many people infected by TB strains resistant to two or more drugs. Failure to complete a lengthy treatment regimen, combined with the immunosuppression associated with the developing HIV epidemic, contributed to the emergence of multidrug-resistant tuberculosis. In 1992 in New York City, more than one third of the strains tested were resistant to one drug and nearly one fifth were resistant to two front-line drugs. These drug-resistant strains are as contagious as those that cause drug susceptible TB. Drug-resistant TB is more difficult and vastly more expensive to treat that drug-sensitive TB, and patients with drug-resistant TB may remain infectious longer due to inadequate treatment.

Ecological or environmental changes also lead to the emergence or re-emergence of disease. A recent example is the 1993 emergence of hantavirus in the Southwestern U.S. Scientists now think that the virus emerged in part as a result of climatic and environmental conditions which favored an increase in native rodent populations harboring the virus. Altered land-use influenced the appearance of Lyme disease, which has become the most reported tick-borne disease in the United States. Reforestation and suburban residential expansion into wooded areas have created optimal conditions for transmission of this organism to man.

These and other infectious diseases will continue to threaten the United States, not only because of changes in the microbes themselves and in the environment, but also because of chances in human behavior and advances in technology. Most cities in this country can be reached by commercial flights from any area of the world within 36 hours. The world is truly a global village, and infectious disease problems of other countries are very much on the minds of the American public, as illustrated by the extensive media coverage of the recent outbreaks of Ebola hemorrhagic fever in Africa.

The importance of research

In preparing our country to respond to the threat of emerging and re-emerging infectious diseases, early detection through disease surveillance, a function primarily of the Centers for Disease Control and Prevention (CDC), is important. Equally crucial, however, is the role of biomedical and behavioral research. These research programs, which range from basic research in microbiology and immunology, to product development in the areas of diagnostics, vaccines, and therapeutics, to and clinical trials that evaluate these products, are being actively pursued by NIH. Continued investment in these programs leads to the creation and refinement of new tools for intervention and are critical to our ability to respond to the ever-present threat of emerging and re-emerging microbes.

An excellent example of the public health threat of a decreasing investment in research is the recent re-emergence of TB. In the 1970's the Public Health Service developed a comprehensive plan for the elimination of TB by the year 2000. The program was initially successful and the incidence of TB steadily declined. As a result, scientists thought TB was cured or at least well-controlled; the research community became complacent and investment in TB research and the health care delivery infrastructure declined. The changing social ecology in this country, including increasing numbers of homeless individuals often housed in crowded shelters, greater numbers of immigrants from TB-endemic countries, and rising numbers of immune-compromised HIV-infected individuals, in combination with the decaying, public health infrastructure resulted in the re-emergence of TB in the early 1980's. With the recognition of this renewed epidemic, the NIH made a major commitment to TB research, recruiting new investigators, initiating training programs, and increasing financial support for investigator-initiated research. Now, within the NIH, multiple Institutes contribute to TB research. For instance, NIAID-supported researchers have developed a new class of anti-TB drugs that appears to be effective against some strains of TB that are resistant to existing-drugs; the National Heart, Lung and Blood Institute (NHLBI) has focused a complementary effort on research aimed at developing drug delivery systems that would be optimally effective in delivering TB drugs to the lung. The stabilization in the number of new TB cases in the United States over the last two years, likely a result of increased surveillance and early and aggressive therapy, demonstrates the ability of a rejuvenated infrastructure to respond to a known problem, i.e., drug-sensitive TB. It is NIH's increased investment in basic research and product development that should result in an improved ability to respond to new global challenges, such as drug-resistant TB.

Lyme disease is an emerging problem that also has benefited greatly from a multidisciplinary research effort. Not only did an NIH investigator identify the causative organism, but NIH-supported research has delineated the mechanisms of transmission and how disease results. Research in vector biology identified the tick vector and traced the life cycle of the bacterium through deer and rodent hosts. This has allowed us to predict regions where Lyme disease is likely to pose the greatest threat, and has led to improved prevention based on public information about the dangers of tick-borne infection. Basic research has identified bacterial antigens that form the basis of experimental vaccines and improved diagnostic assays. Complementary research on the immune response, sponsored by NIAID and the National Institute of Arthritis and Musculoskeletal and Skin Disease (NIAMS), has contributed insights into the way the bacteria cause arthritis and other long-term health problems.

Thus, the multidisciplinary effort of NIH has resulted in our ability to successfully treat and prevent many diseases. A continued commitment to research is necessary to prepare us for the challenge of new infectious diseases that are certain to appear.

The challenge of HIV and AIDS

HIV is the prototype of a new and emerging pathogen. No other disease so thoroughly transcends every area of clinical medicine and scientific investigation, crossing the boundaries of every NIH institute.

Approximately one million Americans are currently infected with HIV. Worldwide, the World Health Organization (V;HO) estimates that 18.5 million adults and 1.5 million children and infants have become infected with HIV since the beginning of the epidemic. More than 2.5 million of these individuals have died. Estimates of the number of infected individuals worldwide expected by the year 2000 range from 40 to I 10 million people. In the United States and many other countries, AIDS is the leading cause of death among young adults.

The HIV/AIDS epidemic in the United States is shifting into new populations, disproportionately affecting women, young adults and people from racial and ethnic minorities. Additionally, the proportion of newly reported AIDS cases resulting from heterosexual transmission has increased dramatically.

A commitment to HIV/AIDS research

The United States government and NIH have made a remarkable research commitment to confront the health emergency of HIV and AIDS. Research on HIV infection and AIDS has reached an important juncture, as the Nation's investment in AIDS research is reaping tangible benefits and opening new and exciting scientific avenues. To plot the course through the many research opportunities in AIDS, the OAR has spearheaded two important initiatives: the development of an annual trans-NIH research plan and budget, and a nearly completed evaluation of the entire NIH AIDS research program. A unique and inclusive process was utilized to formulate the AIDS research plan, involving the NIH Institute and Center Directors; NIH intramural and extramural scientists and program managers; distinguished scientists and researchers from other government agencies, academia, foundations, and industry; and community representatives. This plan sets the scientific priorities and objectives for NIH AIDS research and is used to guide scientific and budgetary decisions about the research portfolio. The goal of the current evaluation process is to determine whether each of the components of the AIDS research program is appropriately designed and coordinated to answer the critical scientific questions to lead to better treatments, prevention, and a cure for AIDS. These activities have provided a frank assessment of the successes and shortcomings of NIH-sponsored AIDS research based on a broad consensus of the scientific community. Utilizing the legislative authorities of the OAR, NIH is refocusing scientific priorities and redirecting resources to meet new scientific opportunities.

The fundamental basic knowledge that we have developed in infectious diseases, molecular biology, microbiology and immunology has allowed us to make significant progress in understanding the pathogenesis of HIV disease, that is, how the virus destroys the immune system and causes disease. Indeed, the identification of HIV so soon after recognition of the epidemic was possible because of the earlier discovery of the existence of other human retroviruses. NIH-sponsored scientists first identified these types of viruses when studying cancer and all retrovirology; researchers were thus poised to look for a retrovirus when they recognized that the agent causing this new syndrome was transmitted in a manner similar to the malignancy-associated retroviruses.

Since that early discovery, NIH-supported research has provided a wealth of information on the molecular virology of HIV. However, our understanding of the virus itself is not yet matched by our understanding of how HIV infection leads to disease and how it induces inunune deficiency. The complexity of the immune system has proven to be a formidable obstacle for rapid research progress in elucidating the pathogenesis of AIDS. A significant challenge facing, AIDS researchers is to understand the normal functioning of the immune system while at the same time defining the mechanisms by which HIV infection disrupts it.

To meet this challenge, NIH has intensified its efforts toward fundamental research, the foundation that supports the entire AIDS research enterprise. Animal models, particularly macaque monkeys that can understanding the details of pathogenesis and in establishing the nature of protective with weakened HIV mutants can studying, how the immune responses elicited by vaccination w of from infection with fully virulent HIV. As these so-called "correlates of immunity" protect animal Scientists are determining whether attenuated viruses can be developed that are sufficiently safe to be considered as human vaccine candidates.

Understanding HIV disease

A broad NIH effort, consisting of the contributions of individual Institutes Centers, each with unique areas Of expertise, has greatly advanced our understanding of how HIV causes disease in the body. For instance, HIV, NIH-supported investigators have shown that the levels of HIV RNA in a patient's plasma are predictive of progression to AIDS. NIH intramural investigators have further demonstrated that the levels of HIV in plasma reflect HIV replication in the lymph nodes, which are the major reservoirs of virus in the body of an infected person. These and other studies support the concept that the level of virus in the plasma is the most useful parameter on which to base therapeutic decisions regarding the initiation and modification of anti-retroviral therapy.

Progress in HIV therapy

The largest proportion of NIH AIDS research spending is devoted to studies of therapies to improve and prolong the lives of HIV-infected individuals. The NIH sponsors intramural and extramural clinical trials of potential anti-HIV agents, in single or multidrug regimens, for the prevention of HIV infection, intervention early in disease, and treatment of HIV infection and its accompanying opportunistic infections (Ols) and malignancies in children and adults.

Several important advances were reported this year in the search for effective antiretroviral therapies for HIV-infected individuals. In a large NIH-supported clinical trial known as ACTG i75, the combinations of AZT plus ddl or AZT plus ddC, used during early - to intermediate - stage disease, resulted in delayed disease progression and improved survival as compared to standard therapy. This study provided the first conclusive evidence that anti-retroviral therapy could result in clinically measurable benefits, such as reduced risk of death in individuals who had not yet advanced to the symptomatic stage of disease.

The concept of combination anti-retroviral therapy first tested in studies performed by NIH intramural scientists in the mid-1980's, is now being expanded to include combinations that use a newly developed class of drugs called protease inhibitors. These powerful drugs block the HIV protease enzyme that is critical for the later staues of the virus life cycle. Other anti-HIV drugs such as AZT work at an earlier stage of the viral life cycle by blocking another enzyme.

Collaboration between the biotechnology and pharmaceutical industries, the federal ,government, and academia in the AIDS research effort is an important priority of NIH. An excellent example of such collaboration is the development of protease inhibitors. Basic research initiated and supported by NIH was instrumental in identifying the importance of the HIV protease enzyme, developing the concept of blocking this enzyme, crystallizing the protease enzyme so that protease-blocking drugs could be developed, and developing an assay to test these drugs. National Cancer Institute (NCI) investigators were pivotal in the actual crystallization of the protease enzyme; the substantial body of crystallization research supported by the National Institute of General Medical Sciences (NIGMS) was key to the crystallization of another HIV enzyme and provided a base of knowledge that allowed the protease work to go forward. In addition, early work on discovery of protease inhibitors at one pharmaceutical company was partially supported through NIAID's National Cooperative Drug Discovery Groups for Treatment of HIV (NCDDG-HIV).

Recent results of clinical trials conducted by pharmaceutical companies assessing protease inhibitors in combination with other anti-retroviral drugs have shown the greatest effect noted to date in decreasing the amount of virus in patients' blood and increasing their CD4+ T cell counts. In addition, one study demonstrated an impressive improvement in survival and delay in the onset of the symptoms of AIDS in patients receiving a combination of a protease inhibitor and other drugs. NIH is now initiating further clinical studies to evaluate the effects of the newer protease inhibitors in combination with other anti-retroviral agents, and in patients at various stages of disease.

Our therapeutic successes against HIV have been substantial. Five reverse transcriptase inhibitors and one protease inhibitor are currently approved by the U.S. Food and Drug Administration for the treatment of people with HIV infection, based in large part on data from NIH-supported clinical trials. An important task before us is to improve upon the magnitude of viral suppression we have achieved thus far, to build on the improvements seen in immunologic parameters such as CD4+ T cell counts, and determine if the limited clinical efficacy of anti-retroviral agents currently available can be prolonged.

Because infection with HIV results in a damaged immune system, investigators are emphasizing new innovative therapies to restore immune function, including cell replacement therapies and the use of naturally occurring, immune-boosting proteins. In addition, investigators are actively developing a variety of gene therapy approaches to render cells resistant to HIV.

Treatment of opportunistic infections

Because of advances in the treatment and prevention of Ols associated with HIV, HIV-infected individuals are living longer and with a better quality of life now than they did a decade ago. At least twenty-five drugs are currently licensed for the treatment of HIV associated opportunistic infections and malignancies. However, HIV-associated infections, including cryptosporidium and microsporidium, continue to present new challenges in the care of HIV-infected people. Furthermore, in the current era of increasing antibiotic resistance, many common microbes once thought vanquished now plague HIV-infected people, as well as those in the general population. Multi-drug-resistant TB, discussed above, is a good example of this.

To address the need to develop new anti-infectives, NIH is intensifying efforts in drug discovery. Additional biomedical and clinical research is needed to better understand dosing, drug formulations, pharmacokinetics, drug interactions, and toxicity issues associated with compounds administered singly as well as in the multi-drug combinations often required in the treatment of HIV-infected individuals.

AIDS-associated malignancies

A dramatic increase in the incidence of several malignancies has been observed in HIV-infected individuals. These include Kaposi's sarcoma, Hodgkin's lymphoma, nonHodgkin's lymphoma, and ano-genital cancers, particularly cancer of the cervix in HIV infected women. Treatment of these malignancies in patients who are already severely immunocompromised is complex, as these cancers are frequently more resistant to standard anti-cancer drugs, and patients tolerate treatment less well. NIH supports a large research effort in the area of AIDS-associated malignancies, with particular emphasis on the development of novel and improved cancer therapies.

Research into Pediatric AIDS

The increasing numbers of HIV-infected women, usually infected through injection drug use or heterosexual contact (often with HIV-infected injection-drug users), have resulted in more infants becoming infected. HIV-infected women give birth to about 7,000 babies each year in the United States; until recently, approximately 25 percent of these infants became infected with the virus.

Investigators supported by NIAID and NICHD have found that the drug zidovudine (AZT) can reduce by two-thirds the rate of HIV transmission from mother to infant when given to HIV-infected women during the last 20 weeks of pregnancy and during, labor and delivery, and to their infants during the first six weeks of life. Scientists anticipated that the use of AZT in HIV-infected pregnant women could prevent the infection of 1200 infants each year in this country, with a Potential savings to the U.S. health care system of as much as $170 million annually. In fact, two recent studies have shown that the use of AZT in pregnant women has increased dramatically in several states since the dissemination of the results of the above study. This has resulted in marked reductions in perinatal transmission of infection, from 19 percent to 6 to 8 percent.

A collaborative approach to research into HIV disease in children and adolescents, coordinated by OAR and carried out within several NIH Institutes, has resulted in other significant advances. For example, an early NICHD study of HIV infection in children demonstrated that intravenous administration of immunoglobulin effectively reduced secondary infections in children whose immune systems were weakened by the virus.

A diverse portfolio of pediatric HIV research continues to be a high priority of NIH. The major components of this portfolio include the intramural research program of the NCI and the collaborations of NICHD and NIAID through the pediatric ACTG network. Recently, NHLBI joined the ACTG collaboration in trials designed to determine whether HIV-hyperimmune immunoglobulin (HIVIG) added to the AZT regimen can further reduce HIV transmission from mother to baby. These and other studies are central to our goal of bringing an end to pediatric AIDS.

A vaccine against HIV

The development of an effective anti-HIV vaccine is a high priority for NIH investigators. A vaccine to completely prevent HIV infection, our greatest hope for the eradication of HIV, remains a challenge. A more realistic goal may be to develop a vaccine to prevent disease caused by infection with HIV. To achieve this goal, scientists must have a much better understanding of the mechanisms of transmission of HIV between individuals, the processes by which the infection becomes established and persists, and the nature of the immune response to the virus. NIH is the major sponsor of research in these important areas worldwide and a continued strong commitment to basic research into these questions is critical for success.

Despite significant challenges, a number of promising vaccines are in the "pipeline" at various stages of development. To further the development of promising HIV vaccine candidates, a strategic plan for research and development in HIV vaccinology was recently announced. Government/industry partnerships are being prospectively formed to develop specific vaccine concepts, and these collaborations also involve the HIV community. In addition, NIAID has established a large infrastructure for eventual efficacy trials of HIV vaccines and has supported many early phase trials. These trials have shown the feasibility of developing a safe vaccine that can induce effective immune responses.

Behavioral and social science research

While vaccines represent one approach to disease prevention, another critical prevention strategy involves behavioral and social science research. NIH AIDS research in these sciences focuses on three key areas: improving primary prevention of HIV infection through interventions to change behavior; developing the basic science that underlies these behavior chance interventions; and addressing the individual and societal consequences of HIV and AIDS. Cutting across these areas is a continued commitment to improving the methodologies employed in behavioral and social sciences research, and to better link research with communities most affected by HIV and AIDS . NIH-supported researchers have made significant advances in this area, but much more remains to be learned.

AIDS research benefits other areas

In the last 15 years, the investment in AIDS research has led to scientific advances that will benefit people with many other diseases as well. Extensive study of the human immune system has contributed to insights and advances in understanding cancer and such autoimmnune diseases as type I diabetes mellitus, rheumatoid arthritis, and multiple sclerosis. The design of drugs for all disorders will benefit from the development, through HIV research, of methods of rational drug design using sophisticated techniques of structural biology and advanced computer imaging methods. Advances in the treatment and prevention of HIV-associated opportunistic infections have enhanced the care of patients with other immunodeficiency states such as cancer patients and organ transplant recipients. Infectious agents that may be responsible for malignancies have been identified through HIV research, such as the recent discovery of the agent that causes Kaposi's sarcoma. HIV research has led to a better understanding of the mechanisms by which infectious agents and inflammatory cells gain access to the brain, thereby contributing to the study of Alzheimer's disease, dementia, multiple sclerosis, neuropsychological disorders, encephalitis, and meningitis. Research on HIV-related wasting has provided important information for research on nutritional disorders, metabolic abnormalities and gastrointestinal dysfunctions.

HIV research: the future

Clearly, important progress has been made in our fight against HIV disease. However, the long-term effectiveness of newly developed therapies is still uncertain and a preventive vaccine against infection has proven elusive. The most important scientific opportunities lie in our insight into the virus and the disease that it causes. Through the legislated authorities provided to the OAR, NIH is refocusing efforts and redirecting resources to guide research that will lead to the ultimate goal of eliminating AIDS worldwide. A strong collaboration with Industry will be critical for these efforts.

STD research

Other sexually transmitted diseases (STDs), in addition to HIV infection, remain a significant problem. Each year, an estimated 10 to 12 million Americans acquire an STD other than HIV disease. Approximately 65 percent of these infections occur in people under 25 years of age, with 3 million cases among teenagers. These infections may be present without symptoms and often are unknowingly passed to others causing serious complications, particularly in women and their offspring. In addition, the risk of becoming infected with HIV is much higher in an individual with another STD such as herpes, syphilis, gonorrhea or chlamydial infection.

Because of the urgency of the STD epidemic, initiatives to prevent and control urge are a key priority of NIH. Scientists are making, important progress in the areas of vaccines, diagnostics, therapy, behavioral interventions and other methods that promise to facilitate the prevention of STDs and HIV infection.

Recently, NIH-funded research has led to simple tests for vaginitis and chlamydial infection. NIH scientists also have developed an experimental vaccine to prevent chlamydial infections that shows promise in laboratory tests. Such a vaccine has the potential to reduce the more than 4 million chlamydial infections that occur each year and the associated costs, which exceed $2.4 billion annually.

NIAID and NICHD are funding, research to test the potential of microbe-killing chemicals that could be used topically in the vagina to protect women from STDS, including HIV, and prevent the spread of STDs to their partners. A three-pronged strategy to develop these topical microbicides has been developed. The first part of this strategy consists of basic research to delineate the precise mechanisms by which STD organisms infect the host vaginal surfaces. The second arm is pre-clinical product development, including in vitro screening against STD organisms, animal toxicity studies and the development of specific drug, formulations for topical use. Finally, clinical trials are being initiated using the NIAID large international trials network to study both safety and efficacy of therapies. The development of these agents is important in that it may provide women with a method by which they can control, independently of their partner, their exposure to and risk of infection with STDS, including HIV.

We have long known that infections such as rubella or cytome-alovirus can result in miscarriage or otherwise harm the fetus. Recently, NIH research has taught us more about the role played by other infections in causing adverse outcomes of pregnancy. A recent large-scale study supported by NICHD and NIAID demonstrated that many women have an asymptomatic vaginal infection during pregnancy called bacterial vauinosis; this condition is associated with premature labor and low-birth-weight delivery. Low-birth-weight infants are at high risk for mental retardation, respiratory disorders and other adverse effects, and for death. Studies indicate that screening pregnant women for bacterial vaginosis and, if they are infected, treating them with an appropriate antibiotic, markedly reduces premature delivery. Thus, for the first time, we may have an effective intervention to prevent this persistent and unyielding problem of prematurity.

New and improved vaccines

Prevention research is a central component to NIH efforts against all infectious diseases and includes both behavioral and biomedical approaches. At a minimum, behavioral research can result in reduction of risk of transmission and prevention of progression of disease, while biomedical research may elucidate mechanisms of transmission and disease progression. The ultimate prevention goal is the development of effective vaccines. NIH has made many important contributions to the improved management and prevention of infectious diseases. In this regard, development of new and improved vaccines is an extremely high priority. Vaccines provide safe, cost-effective, and efficient means of preventing illness, disability and death from infectious diseases. In addition to vastly improving the health and well-being of our citizens, vaccines can markedly decrease both direct and indirect health care costs. For example, experts have calculated that $14 are saved for every dollar spent on measles, mumps, and rubella immunization in this country. Considering that infectious diseases account for 25 percent of all visits to physicians each year, at a total annual cost to society that may exceed $120 billion, the importance of research into disease prevention by vaccination cannot be overstated.

NIH efforts have contributed to the development or improvement of many vaccines. Recent successes include the development and licensure of hepatitis A vaccines and Haemophilus influenza type B (Hib) conjugate vaccines.

Hepatitis A virus, transmitted by contaminated food and water, affects more than 130,000 individuals each year in the U.S. Protection of persons at high risk for infection, such as travelers to countries where the disease is endemic, promises substantial reduction of the $300 million in annual hepatitis A-associated costs in this country.

In the 1960's the leading cause of acquired mental retardation in the U.S. was brain damage from meningitis caused by Hib. Despite the availability of antibiotic therapy, children who contracted Hib meningitis often had brain damage or deafness, and many died. At that time, NICHD intramural investigators and NIAID-funded grantees developed a vaccine composed of the polysaccharide surface coat of Hib. Investigators determined that the purified polysaccharide was safe and stimulated protective levels of antibody, first in animals, then in adults, and finally in children. With the added involvement of industry, three Hib polysaccharide vaccines were produced and licensed in 1985.

The polysaccharide vaccines by themselves had limitations because they did not stimulate protective antibody levels in infants and very young children, the age group with the highest incidence of serious disease. Over several years, NIH investigators developed a new concept, a "conjugate vaccine," linking the "weak" polysaccharide to a carrier protein that improved the protective properties of the Hib vaccine for infants. These researchers demonstrated that the conjugate vaccines were effective in both infants and adults.

Since 1987, four Hib conjugate vaccines have been licensed and marketed. These vaccines have become part of the routine pediatric immunization series that is given babies starting at age 2 months. Since routine use of Hib conjugate vaccines began in the U.S., the number of cases of Hib meningitis or sepsis has fallen from 15-20,000 per year to less than 100. Hib conjugate vaccines are also now used routinely in Canada, Chile, Iceland, western Europe, and other parts of the world. Wherever these vaccines have been used, Hib meningitis and other serious effects caused by this pathogen have virtually disappeared. This accomplishment is one of the most important recent contributions of the NIH that directly benefits the public health. The introduction of vaccination against Hib in this country has virtually eliminated this disease, saving more than $400 million each year in direct and indirect costs. Today there is every expectation that this organism, which is found only in humans, will, like smallpox, be eliminated.

More recently, NIAID and NICHD have supported research toward the development of safe and effective pertussis (whooping cough) vaccines, which are expected to be licensed shortly. The pertussis vaccine currently used in the United States is composed of whole bacteria cells. While safe and effective, this vaccine sometimes causes side effects that caused concern among parents to the point where some were reluctant to have their children immunized. Scientists at NICHD and NIAID responded to this serious public health problem using two approaches. NICHD's scientists developed a new, single-component vaccine using a unique method of inactivating the pertussis toxin to make it a safe toxoid, but still preserving its immunizing properties. As an excellent example of the inter-Institute collaboration within NIH, NIAID's Vaccine Evaluation Units were used for NICHD's Phase 1 studies of their toxoid vaccine in children. Results from Phase III field trials show a good protective effect for the vaccine with far fewer side effects, and the approval and licensing process with FDA is moving ahead expeditiously. The NICHD pertussis toxoid vaccine is L acceptable for vaccination of adults, and thus can be used to eliminate the remaining reservoir of whooping cough in the entire population.

At the same time, NIAID-supported scientists developed and evaluated acellular pertussis vaccines that contain only portions of the pertussis organism, thus avoiding the toxicity observed with the licensed whole-cell vaccine. In two landmark studies, these vaccines have proven to be efficacious and better tolerated than the current whole-cell vaccines. The availability of these improved and better-tolerated acellular pertussis vaccines should revitalize worldwide public acceptance of this important public health tool. Of additional importance, the acellular vaccines hold promise as a potential component of new combination vaccines, which may enable physicians to reduce the number of immunizations required for prevention of childhood infections.

NIH scientists also have demonstrated that a single component vaccine using the Vi antigen protects against typhoid fever. This Vi vaccine is now licensed in the U.S. and at least 30 other countries and provides one-shot, side-effect-free inexpensive protection against typhoid, not only for residents of areas of the world with poor sanitation, but for U.S. travelers and military personnel in those areas as well.

Other studies suggest that a conjugate vaccine developed by NIH researchers can prevent the diarrhea and dysentery caused by shigella, a major cause of death in infants worldwide. Preliminary clinical evaluation of a vaccine to prevent infection with E. coli 0157:H7, often responsible for serious intestinal infections in children, is now being completed. In addition, a pharmaceutical manufacturer is evaluating a NICHD-developed conjugate vaccine for Staphylococcus aureus, a leading cause of hospital-acquired infections, and an organism that is becoming, resistant to most antibiotics.

Major and original contributions to vaccines for pneumococcus, Group B streptococcus and hepatitis B have resulted from NIH-supported research. NIH has also had a critical role in both fundamental and early clinical research currently ongoing for vaccines against gonococcal and herpes infections. NIH-supported scientists also are studying a new approach to developing a vaccine for tuberculosis.

The future of vaccine technology is exciting. New biomedical advances in various areas are being applied to the development of methods to prevent diseases that have not previously yielded to immunization, such as Lyme disease, certain pneumonias, malaria, rotavirus, respiratory syncytial virus, and many others.


We are currently in the midst of the HIV pandemic and have within this century experienced pandemics or epidemics of influenza, cholera, malaria and other infections. Clearly, we remain vulnerable to infectious diseases, which must be fought on many fronts.

The continued support of basic research in microbiology and immunology, as well as clinical research in infectious diseases, are critical to prepare the Nation against newly emerging and re-emerging microbes. Continued biomedical and behavioral research will equip us with the tools to effectively combat future threats of infectious diseases to the health of people in this country and around the world.

This concludes our remarks. We would be pleased to answer any questions you may have.

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