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Before the House Appropriations Committee, Subcommittee on Labor, Health and Human Services, Education and Related Agencies
February 27, 1997

The past year has been a time of considerable accomplishment at the National Institute of Allergy and Infectious Diseases (NIAID), as NIAID-supported scientists made major strides in understanding, preventing and treating important infectious and immunologic diseases that threaten the health of people in the United States and abroad.

NIAID-supported investigators reported significant new advances in fighting several of the leading reportable infectious diseases in the United States, including the acquired immunodeficiency syndrome (AIDS), chlamydia and other sexually transmitted diseases, tuberculosis, and Lyme disease. Significant progress was made in the research effort against infectious killers of children, such as diarrheal diseases. Other findings suggested new approaches for treating autoimmune diseases such as multiple sclerosis.

Each of these recent accomplishments was facilitated by knowledge gleaned through basic research. For example, the fundamental discovery in the 1970s of how the immune system distinguishes "self" from "non-self," for which two long-time NIAID grantees were awarded the 1996 Nobel Prize for Physiology or Medicine, influenced many of the advances I will discuss.

The translation of basic research findings into practical applications has been particularly noteworthy in the fight against the human immunodeficiency virus (HIV), the virus that causes AIDS. Fundamental research into the structure and function of the HIV protease enzyme led to the development of a powerful new class of anti-HIV medications that block this enzyme, and hence the replication of the virus. Three of these drugs, called protease inhibitors, were recently approved for marketing in the United States; others are in late stages of clinical testing. Protease inhibitors are now widely prescribed as part of combination treatment regimens for HIV-infected people, and in some patients have controlled the replication of HIV to a degree not previously possible. NIAID currently is conducting clinical trials to determine how best to use protease inhibitors and whether their significant short-term benefits are sustainable for prolonged periods without prohibitive toxicities or the widespread development of drug resistance.

In another major development in AIDS research, two separate fields of scientific inquiry converged to provide long-sought information on the HIV disease process and important new targets for therapies. One group of researchers demonstrated that certain immune signalling molecules called chemokines, normally secreted as part of the body's inflammatory response, can suppress certain strains of HIV. Other investigators identified molecules on the surfaces of immune system cells that play key roles in enabling different strains of HIV to infect the cells.

It soon became clear that these findings were related and complementary. In important instances, chemokines suppress HIV because they bind to the same cell surface molecules needed by the virus for entry. These discoveries suggest that it might be possible to treat HIV infection with drugs that block these cell surface molecules, or to prevent infection with vaccines that elicit antibodies that inhibit the binding of HIV to the molecules. Scientists around the world are now pursuing these and related approaches, building on the exceptional leads provided by NIAID-supported researchers.

The development of an HIV vaccine remains an important goal of the Institute, one we are pursuing with a two-pronged strategy of basic and applied research. Basic researchers are uncovering important clues about the specific immune responses that might protect an individual from HIV infection or disease progression. Parallel with basic research efforts, the Institute continues to test candidate vaccine products in small-scale trials around the world. Since 1988 more than 2,300 non-HIV infected adult volunteers have enrolled in approximately 30 phase I and II vaccine trials conducted in the United States by NIAID's AIDS Vaccine Evaluation Group (AVEG). These trials have involved 16 experimental vaccines, 12 immune-stimulating substances called adjuvants and a variety of delivery vehicles and routes, dosages and immunization schedules.

Early clinical studies of experimental HIV vaccines focused on products based on a single protein from the envelope of HIV. These have given way to more complex strategies, including a two-step approach in which a person is injected with a harmless virus genetically engineered to make HIV proteins, and later given a booster shot of an HIV-derived protein. This so-called "prime-boost" strategy has shown promise in non-human primate models of AIDS, protecting a significant proportion of animals. Small-scale studies in human volunteers suggest that the approach is safe and can stimulate anti-HIV antibodies, as well as cytotoxic T cells, which kill HIV-infected cells.

The HIV epidemic is inextricably linked to other sexually transmitted diseases (STDs). HIV and other STDs share a common mode of transmission, and people with STDs are more likely to transmit HIV or become infected with HIV than people without STDs. It is often underappreciated, however, that STDs are an enormous problem in their own right; they comprise a "hidden epidemic" that the Institute of Medicine recently addressed in a lengthy report. Altogether, more than 12 million Americans acquire a sexually transmitted disease (STD) other than HIV each year, at a total cost to the Nation that exceeds $10 billion (Institute of Medicine, 1997). In addition to their huge economic burden, STDs can have devastating health consequences. For example, hepatitis B virus is a leading cause of liver cancer, and certain types of human papillomavirus account for nearly all cancers of the cervix, vagina, vulva, anus and penis. Untreated chlamydial and gonorrheal infections frequently lead to pelvic inflammatory disease (PID), which in turn can result in life-threatening tubal pregnancies and scarring of a woman's fallopian tubes leading to infertility.

The NIAID has addressed the challenges posed by STDs with a multidisciplinary research strategy encompassing basic, applied and behavioral research. For example, the Institute is developing topical microbicides, substances that a woman can use in her vagina before intercourse to prevent the transmission of sexually transmitted microbes, including HIV. Several promising microbicides are in various stages of pre-clinical and clinical development. NIAID-supported scientists also are developing better diagnostic tests to help clinicians detect and treat asymptomatic STDs before they cause serious health problems. Sensitive, non-invasive urine tests for chlamydia and gonorrhea hold particular promise for detecting both symptomatic and asymptomatic cases of these diseases, especially in the context of large-scale screening programs. Screening for asymptomatic STDs can have a notable effect: a recent NIAID-funded trial demonstrated that women screened and treated for asymptomatic chlamydial infection were 60 percent less likely than unscreened women to develop pelvic inflammatory disease.

Dehydration due to diarrheal diseases is a leading causes of death worldwide, particularly among children. Rotaviruses cause 35 to 50 percent of the world's severe diarrhea cases in infants and young children, resulting in more than 800,000 deaths annually. In the United States, more than 1 million cases of rotaviral diarrhea and 50,000 hospitalizations occur each year. Because of a lack of a specific drug to treat this condition, scientists at NIAID designed and tested a vaccine that combines human and animal rotavirus genes. In large-scale clinical trials, this vaccine has been found safe, with only mild side effects, and effective 80 to 90 percent of the time. The vaccine is now nearing licensure and promises to have a major impact on the health of the world's children. The successful development of this vaccine exemplifies the synergy between basic and applied research, as well as the fruitful collaborations that are possible between the private and public sectors.

NIAID-funded investigators are now working on the vaccines of the future: "naked DNA" vaccines, which contain the gene or genes for the antigenic portion of a pathogen, injected directly into the muscle of a patient. These vaccines have many potential advantages over conventional vaccines, including greater purity and stability, economy and ease of purification, and relative safety in immunocompromised individuals. The use of naked DNA vaccines may offer a way to develop a better childhood vaccine that is easily delivered and provides durable immunity against multiple pathogens without requiring refrigeration.

Recent studies in mice show the feasibility of designing naked DNA vaccines to prevent tuberculosis. Naked DNA vaccines also have shown promise for many other conditions. For instance, a naked DNA influenza vaccine has protected laboratory animals from multiple strains of influenza virus. Further development of this approach may one day reduce the need to prepare new vaccines each year to prevent epidemics caused by different strains of influenza virus.

Lyme disease, first recognized in the 1970s, is the most common vector-borne infection in the United States. Much of the progress in understanding this condition has been facilitated by NIAID-supported discoveries. An NIAID investigator identified the causative bacterium, and NIAID-supported research subsequently revealed how the bacterium is transmitted and causes disease. NIAID-supported researchers also identified the bacterial surface antigens on which improved diagnostic tests and experimental vaccines are based.

Although most patients diagnosed with Lyme disease are successfully treated soon after infection, a small proportion develop a chronic condition called Post-Lyme Disease Syndrome, characterized by persistent musculoskeletal and peripheral nerve pain, fatigue and memory impairment. Scientists have speculated that the syndrome may be caused by ongoing infection with the Lyme bacterium or another tick-borne pathogen, or perhaps by persistent inflammatory or immune responses; however, the precise pathogenesis is unclear. Recently, the Institute launched a five-year initiative to study the pathogenesis and treatment of this elusive syndrome.

The Institute also continues its concerted efforts to unravel the mysteries of the chronic fatigue syndrome (CFS), a debilitating illness for which a definitive cause or treatment remains elusive. In a recent NIAID-supported study, investigators found that therapy for abnormally low blood pressure alleviated the symptoms of chronic fatigue syndrome (CFS) in 9 out of 23 patients. This finding has led to an NIAID-supported clinical trial involving treatment of CFS with a specific drug typically used to treat hypotension.

Autoimmune diseases such as multiple sclerosis (MS) occur in 5 percent of adults in the United States, two-thirds of them female. MS is the most common progressive neurologic disease of young Americans, affecting an estimated 250,000 to 350,000 people in the United States. Using a mouse model of multiple sclerosis (MS) called experimental allergic encephalomyelitis (EAE), NIAID-supported scientists have discovered that a specific interaction between two types of critical immune cells is associated with the symptoms of EAE and MS. Moreover, they found that blocking this interaction prevented EAE in mice and dramatically improved symptoms in mice that already had EAE. These findings suggest a potential new approach for alleviating symptoms of MS in people.