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Over the past four decades, the research mission of the National Institute of Allergy and Infectious Diseases (NIAID) has evolved to encompass illnesses ranging from allergies to AIDS, from the common cold to exotic diseases that devastate populations throughout the world. These diverse areas of research are all solidly grounded in the foundation of our Institute, which is basic research on microbes that infect people and on the immune system that protects us against these invaders. This common theme underlies all of our efforts.

Today, even as biomedical researchers break new ground in immunology, usher in the era of gene therapy, and design drugs that are highly specific and effective against a wide range of infectious agents, such achievements create a new challenge. The public's expectations of what biomedical research can do to alleviate suffering and death caused by human diseases far surpasses


our available resources.

How then can NIAID best employ its sophisticated technologies to fulfill its mission of improving public health? The most effective way to narrow the growing gap between expectations and available resources is to prevent diseases before they occur. In the area of infectious diseases, this is best achieved through vaccines.

Our foundation of basic research and our accomplishments in vaccine development make NIAID uniquely positioned to lead the renaissance in vaccinology that is being realized in the decade of the 1990s. Historically, vaccines have dramatically decreased or even completely eliminated infectious diseases that have taken heavy tolls on past civilizations. A classic example is the complete eradication of the scourge of smallpox from the world. Nonetheless, we have realized only a fraction of the full potential of vaccines to prevent a wide array of infections that cause considerable morbidity and mortality throughout the world. Over the past several years. natural products and synthetic peptides of organisms and, most recently, recombinant DNA products have largely replaced whole killed or attenuated organisms that have traditionally been used to make vaccines. These newer approaches have resulted in more specific and potentially less toxic vaccines.

Something more theoretical, but with considerable potential, is the concept of intracellular immunization, which employs a form of gene therapy to

"immunize" cells against viral infection. It involves inserting into an individual's blood cells a gene encoding for a protein that inhibits the growth of the target virus. This past year, several NIAID-supported researchers identified mutant genes of the AIDS virus that are promising candidates for such a strategy.

Vaccines benefit people of all ages, but their impact on the health of children is particularly important. Many of you may be aware of a new concept known as the "Children's Vaccine Initiative." First proposed by the executive director of the United Nations Children's Emergency Fund, its goal is lofty: immunize children worldwide with an oral vaccine that provides lifelong immunity to the major infectious diseases of childhood. NIAID is committed to focusing our basic research activities on surmounting the technical obstacles inherent in creating such a vaccine.

In fact, I am pleased to be able to tell you about an important advance in the technology for producing childhood vaccines. In 1990, the FDA licensed two new vaccines to protect infants against Haemophilus influenzae type B (Hib), the leading cause of bacterial meningitis in young children. Each year, more than 700 children die of Hib meningitis, and several thousand suffer long-term neurologic consequences of the disease, including mental retardation and hearing loss. The new vaccines now make it possible to prevent Hib disease in children at highest risk for developing severe disease, those between 2 and 15 months of age.

The Hib vaccines use a new technology with far-reaching implications for protecting young infants against other serious bacterial infections. Because of the immaturity of their immune systems, very young children do not respond to vaccines made from the outer polysaccharide coats of some bacteria. supported extramural investigators and other scientists at the National Institute of Child Health and Human Development overcame this problem by pairing the Hib polysaccharide with a protein that children can respond to at birth. Use of the Hib conjugate vaccines will save an estimated $359 million for every annual cohort of children that is vaccinated. This compares with the $17.4 million NIAID spent on research leading to the development of these



We are continuing our search for an improved pertussis (whooping cough)

vaccine, focusing on highly purified acellular vaccines containing only part of the disease-causing bacterium. An NIAID-sponsored multicenter clinical trial involving more than 2,000 children is now underway to compare simultaneously a number of acellular pertussis vaccines with 2 conventional whole-cell vaccines. The data generated from this study will be used to select vaccine candidates for a larger efficacy trial that will begin before the end of 1991.

Effective control of other, non-infectious diseases continues to be a goal of NIAID's basic and clinical research endeavors. Asthma is one of these diseases and, as I mentioned last year, it is affecting a disproportionate number of inner-city minority children. Reports published this past fall confirmed that despite advances in treatment, the numbers of children who are suffering and dying from asthma are climbing in the United States. NIAID recently announced eight awards to establish a network of centers to study asthma in inner-city children. The goal of the program is to identify the factors contributing to this problem and to develop interventions to help reverse this trend.

We are finding increasing evidence that viruses may directly or indirectly contribute to the pathogenesis of a broad range of diseases whose etiologies are unknown. Last year, a newly discovered human retrovirus was linked to Sjogren's syndrome, an uncommon autoimmune disease characterized by dryness of the mouth and eyes. Recent preliminary evidence from studies of heart transplants indicates that a virus may accelerate the development of atherosclerosis. It appears likely that in the future viruses will be shown to play a role in at least some connective tissue disorders and degenerative neurological diseases, as well as cancers.

Fundamental studies in immunology have led to major advances in organ transplantation. In the decade of 1990s, organ and bone marrow

transplantation have entered the mainstream of clinical practice.
Last year I
told you that NIAID grantees had developed a new hybrid molecule linking
diphtheria toxin to interleukin 2, one of several powerful chemicals known as
cytokines that are produced by the immune system. This molecule binds to
cells that cause transplant rejection and the toxin kills the cells. In other
studies, a monoclonal antibody was used to eliminate the cells responsible for

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transplant rejection. A recent clinical trial compared the efficacy of the new monoclonal in combination with cyclosporine' A (standard immunosuppressive treatment for transplant patients) versus cyclosporine A alone in preventing early kidney graft rejection episodes. There was a statistically significant reduction in early kidney graft rejection episodes in the group receiving the combination therapy.

History has taught us that new and re-emerging microbes are a constant threat to the survival of our species. AIDS offers the most striking example in recent times of the potentially catastrophic impact of a new infectious Worldwide, an estimated 10 million people are infected with the human immunodeficiency virus (HIV). In the United States, more than 1 million people are infected, and as of January 1 there have been 160,000 cumulative cases of AIDS and 100,000 deaths. AIDS is now the second leading cause of death for young men ages 25 to 44 in the United States, surpassing heart disease, cancer, and suicide.

The pattern of AIDS in the United States, however, is changing


Increasingly, AIDS is becoming a disease of heterosexuals, infants and children, women, and minorities. By the end of 1988, AIDS had become the fifth leading cause of death in the United States among Black women ́ ages 25 to 44; by the end of this year, it is expected to be among the five leading causes of death among all women of reproductive age.

We have taken several steps to identify research needs associated with HIV infection in women, including establishment of a women's health committee within the NIAID AIDS Clinical Trials Group, to ensure that the issues involving HIV-infected women are fully integrated into the NIAID research agenda. In December 1990, NIAID coordinated the first national Public Health / Service-sponsored conference on women and HIV infection. The conference highlighted how the complex roles of women in the family and society compound not only their own suffering but also their ability to participate in clinical research studies.


NIAID has also focused on improving participation of minority constituents and health professionals in our research programs. To help recruit minorities into clinical trials, we have provided supplemental grants to AIDS Clinical Trials Units. In addition, we have recently awarded funds to three

institutions that primarily serve minority populations to help them build the infrastructure necessary to conduct clinical trials.

This past year has yielded benefits from prior investments in basic and clinical research in AIDS. One of the major advances in prolonging the lives of people infected with HIV has been the use of zidovudine (AZT) and prophylaxis for Pneumocystis carinii pneumonia (PCP). Preliminary evidence indicates that in people with low T4 cell counts, appropriate therapy doubles their expected survival time after diagnosis from 12 to 24 months.

AZT, however, is an imperfect drug, and hence we are actively searching for new drugs to treat HIV infection. Preliminary studies suggest that the combination of AZT and dideoxycytidine (ddC), given in alternating doses, has the same benefit but is less toxic than continuous therapy with AZT. Another promising drug, dideoxyinosine (ddI), is being studied in Phase II clinical trials in parallel with expanded distribution to patients not eligible to enroll in the controlled trials. Several studies of interferon alpha, either alone or in combination with AZT, have been conducted in persons with early HIV infection. These studies have shown that interferon alpha appears to both slow virus production and reduce the risk of developing AIDS-related opportunistic infections when administered to asymptomatic HIV-infected


We have also made major strides in treating AIDS-related opportunistic infections. As a result of a large multicenter clinical trial, the drug fluconazole has replaced an effective but more toxic drug as maintenance therapy to prevent recurrences of cryptococcal meningitis, a life-threatening infection of the brain and nervous system. Studies conducted by NIAID and the National Eye Institute also showed foscarnet to be effective in delaying progression of cytomegalovirus retinitis, a sight-threatening eye infection affecting many people with AIDS.

There have been encouraging results from AIDS vaccine research studies this past year. Studies in monkeys using whole killed simian immunodeficiency virus (a monkey AIDS virus) vaccination followed by live virus challenge show promising indications of protection. Other developments included the entry of several new AIDS vaccines into Phase I clinical trials. We are now confident

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