About the Director

NIAID Targets Four Major Areas

Anthony S. Fauci, M.D.
Director
National Institute of Allergy and Infectious Diseases
Bethesda, Maryland

This article appeared in U.S. Medicine — January 2001

Contents

Introduction
Immune-Mediated Diseases
HIV/AIDS
Global Health And Emerging Infectious Diseases
Vaccine Development
Addressing Health Disparities
Conclusion

Introduction

FOR MORE THAN 50 years, the National Institute of Allergy and Infectious Diseases (NIAID), a component of the National Institutes of Health (NIH), has conducted research to better understand, treat and prevent infectious, immunologic, and allergic diseases.

NIAID is the third largest institute at NIH, with an estimated fiscal 2001 budget of more than $1.9 billion, a figure that has increased six-fold since 1984. This growth has been driven by new challenges, such as the emergence of HIV/AIDS and other newly recognized diseases, in addition to unprecedented scientific opportunities made possible by outstanding basic research in immunology, microbiology and infectious diseases, as well as extraordinary advances in areas such as pathogen and human genomics, computer and mathematical modeling, synthetic chemistry, robotics, and information technology.

To meet the challenges of the new millennium and take advantage of unprecedented scientific opportunities, the Institute has developed a strategic research plan for the 21st century centered around four major areas (http://www3.niaid.nih.gov/about/whoWeAre/planningPriorities/
strategicplan/toc.htm):

• Immune-mediated diseases, including allergy and asthma.
• HIV/AIDS.
• Global health and emerging infectious diseases.
• Vaccines.

back to top

Immune-Mediated Diseases

The burden of immune-mediated diseases is staggering. In the United States, these conditions result in direct and indirect costs that exceed $100 billion. Autoimmune diseases such as rheumatoid arthritis, type 1 diabetes and multiple sclerosis together affect approximately 5 per cent of the U.S. population.

At least 7 per cent of American children are asthmatic, and more than one in five individuals in the United States are affected by allergies. In addition, immune-mediated graft rejection remains a significant obstacle to the successful transplantation of potentially life-saving organs.

Recent advances in basic and clinical immunology, many accomplished with NIAID funding and support, hold great promise for developing new treatments for individuals with immune-mediated diseases. Among the most exciting areas of inquiry-and a major goal for the treatment of immune-mediated disorders-is the induction of immune tolerance, i.e. selectively blocking (in an antigen-specific manner) deleterious immune responses while leaving protective immune responses intact. By inducing immune tolerance, it may be possible to prevent graft rejection in transplant patients without the long-term use of immunosuppressive drugs that dampen protective immune responses as well as destructive ones, thereby placing patients at increased risk of infection and malignancies.

The ability to block selectively the immune response also holds great promise for treatment of many other immune-mediated conditions, including autoimmune diseases and asthma and allergic diseases.

NIAID has developed a multi-faceted research effort in immune tolerance. In the fall of 1999, NIAID established the Immune Tolerance Network (ITN), in collaboration with the Juvenile Diabetes Foundation International and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (http://www.immunetolerance.org). The ITN is an international consortium of more than 70 research groups, involving scientists conducting basic research as well as clinical investigators testing promising tolerogenic treatment regimens.

To date, more than a dozen ITN clinical trials have been approved for implementation in four areas: islet transplantation, kidney transplantation, autoimmune diseases, and asthma and allergic diseases. The first of these involves an experimental islet transplantation protocol for "brittle" diabetics-individuals who are unable to control properly their blood sugar levels with even the most rigid insulin schedule. This trial builds on a landmark study conducted by Dr. James Shapiro and his colleagues at the University of Alberta, which resulted in insulin independence for extended periods in a small number of patients (see NEJM 2000; 343:230).

The ITN trial will further assess the safety and efficacy of this treatment regimen, commonly known as the "Edmonton protocol," and it will expand the capacity for islet preparation and clinical transplantation at 10 sites in the U.S. and Europe. We anticipate that this study will establish the baseline success rate for islet transplantation and facilitate the development of new tolerogenic islet transplant trials within the ITN.

All ITN protocols include integrated studies to identify the underlying immune mechanisms involved in disease progression and the therapeutic activity of the treatment regimen. Central to this effort are investigators in the ITN's Tolerance Assay Group. Using approaches such as microarray analyses of gene expression, bioinformatics, ELISPOT analyses of protein expression, and cellular assays for T-cell reactivity, these researchers are developing assays to guide clinical investigators as they create and monitor immune tolerance in individual patients.

For example, one study is analyzing the immune system of recipients of liver transplants who, against medical advice, discontinued their immunosuppressive drugs but maintained a healthy, functioning graft. This study will lead to a better understanding of the immune mechanisms responsible for long-term, immunosuppressive drug-free graft survival and help determine if these patients have developed true immune tolerance to their transplanted livers.

NIAID also supports the Non-Human Primate Transplantation Tolerance Cooperative Study Group, co-funded by NIDDK. This initiative is evaluating the safety and efficacy of novel tolerogenic regimens in pre-clinical trials; these results will provide information critical to the design and conduct of scientifically sound and ethically acceptable human studies. In studies of non-human primates, scientists in this study group have shown that many animals given kidney and islet allografts have attained a state of long-term graft survival that approaches functional tolerance.

It should be noted that despite the genetic similarities between humans and non-human primates, it remains to be determined if these results will be applicable to people.

Among many other initiatives in immune tolerance research are NIAID's Autoimmunity Centers of Excellence, which conduct pilot clinical trials of tolerogenic and immunomodulatory therapies for autoimmune diseases. In addition, through the Clinical Trials Network for Stem Cell Transplantation for Autoimmune Diseases, NIAID is sponsoring clinical trials and mechanistic studies to assess hematopoietic stem cell transplantation for treating severe autoimmune diseases such as multiple sclerosis, lupus and Sjogren's syndrome.

back to top

HIV/AIDS

AIDS, caused by the human immunodeficiency virus (HIV), is one of the greatest threats to global health and one of the most destructive scourges in human history. Since the beginning of the HIV pandemic, an estimated 58 million people worldwide have been infected with HIV, of whom approximately 22 million have died.

In the United States, approximately 800,000 to 900,000 people are living with HIV/AIDS; 430,000 deaths among people with AIDS had been reported to the Centers for Disease Control and Prevention by the end of 1999. The global HIV-infected population continues to expand: in 2000 alone, there were 5.3 million new infections worldwide, half of which occurred among people younger than 25 years of age. In the United States, the rate of new HIV infections has reached an unacceptable plateau of 40,000 per year, with minority communities disproportionately affected. CDC estimates that nearly three-quarters of new HIV infections in the United States occur among African-Americans and Hispanics.

Although potent combinations of anti-HIV drugs (highly active antiretroviral therapy or "HAART") have reduced the number of AIDS deaths and new AIDS cases in many western countries, the utility of these medications is limited by their substantial cost, toxicities, complicated and disruptive dosing regimens, and the development of drug resistance. Therefore, an important NIAID research priority is the development of new, less toxic therapies to control HIV replication and boost, rebuild, and/or replace immunity lost in HIV infection.

Investigators are pursuing a number of new approaches toward the long-term control of HIV infection that may help reduce a patient's reliance on HAART. These include enhancing HIV-specific immunity by vaccinating with HIV antigens, broadly expanding the immune response with immune-stimulating molecules such as interleukin-2, and strategically interrupting therapy.

The upward trajectory of the global HIV/AIDS epidemic underscores the urgent need to develop effective and affordable tools of HIV prevention. A number of recent studies provide reasons for optimism. For example, a NIAID-supported study in Uganda (see Lancet 1999; 354:795) found that two doses of the antiretroviral drug nevirapine-one given to the mother at the onset of labor and one given to the infant within 72 hours after birth -can markedly reduce perinatal HIV transmission. Follow-up data reported last summer at the World AIDS Conference in Durban, South Africa, indicated that reductions in mother-to-infant transmission of HIV were sustained for a year even though the infants were breast-fed.

Significantly, the entire nevirapine regimen used in the Ugandan study costs approximately $4 per pregnancy, making it feasible in resource-poor settings.

Other methods of preventing HIV transmission, such as education, behavior modification and the social marketing and provision of condoms, have also proven effective, both in the United States and in developing countries such as Uganda, Senegal and Thailand. For example, in New York City HIV seroprevalence among injection-drug users dropped more than 40 per cent in the 1990s. In Uganda, HIV seroprevalence has been halved since the early 1990s by strong prevention efforts.

To build on these successes, NIAID recently launched the international HIV Prevention Trials Network (http://www.hptn.org) to develop and test promising non-vaccine strategies to prevent the spread of HIV. The HPTN, a collaborative effort with the National Institute of Child Health and Human Development, the National Institute of Mental Health and the National Institute on Drug Abuse, includes research sites in the United States and countries in Latin America, Europe, Africa and Asia.

HPTN research focuses on six key areas of prevention research:

• Drugs and vaccines that are practical and easy to use to prevent mother-to-infant HIV transmission.
• Microbicides, substances designed for vaginal or rectal use, to prevent sexual transmission of the virus.
• Interventions to reduce behavior that exposes people to HIV.
• Programs to check the spread of HIV through reducing intravenous drug abuse.
• Measures to control other sexually transmitted diseases (STDs) and thereby decrease the risk of co-infection with HIV.
• Antiretroviral therapy that may protect high-risk uninfected adults before they are exposed to HIV, as well as emergency therapy to treat victims of sexual assault.

The development of a safe and effective vaccine for HIV infection is a central goal of AIDS research and a necessary tool to bring the HIV epidemic under control. In pre-clinical and clinical studies, NIAID-supported investigators are testing a diverse range of vaccine strategies such as recombinant HIV proteins, synthetic peptides, recombinant viral vectors, recombinant bacterial vectors, DNA vaccines and synthetic HIV-like particles.

To date, more than 60 phase I trials of approximately 30 candidate vaccines have been conducted in uninfected volunteers worldwide. To speed the pace of HIV vaccine discovery, many public and private agencies have dramatically increased the resources devoted to HIV vaccine research. NIAID HIV vaccine funding has risen nearly seven-fold since 1990, to an estimated $204.8 million for fiscal 2001.

The Institute recently launched the HIV Vaccine Trials Network (http://www.hvtn.org/), an international network to develop and test preventive HIV vaccines. The HVTN will conduct all phases of clinical trials, from evaluating candidate vaccines for safety and the ability to stimulate immune responses, to testing vaccine efficacy. In addition to the units based in the United States, HVTN sites are located in sub-Saharan Africa, Asia, Latin America and the Caribbean. The network's international components provide a critical capability to help identify vaccines appropriate for those regions hit hardest by AIDS.

back to top

Global Health And Emerging Infectious Diseases

The NIAID research program is predicated on the view that we live in an interconnected, global community; indeed, the Institute's international research programs span the globe. As a nation, our interest in global health stems both from humanitarian concerns and what has been called "enlightened self-interest."

In addition to our obligation to ameliorate human suffering wherever possible, history tells us that healthy, stable countries make strong allies and trading partners. Conversely, poor health status can have a profound negative impact on social and economic development, and frequently contributes to political instability.

The globalization of health problems-and their relevance to the United States-was brought emphatically to the attention of the public and policymakers by the AIDS epidemic. In the past few years, global health problems, particularly those related to emerging infectious diseases, are being recognized at the highest levels. For example, in 2000 the United Nations Security Council for the first time devoted an entire session to a health issue-AIDS in Africa-recognizing the enormous threat that the disease poses to the security not only of that continent but also to the world.

The White House, Congress, foreign governments, international organizations, industry and major philanthropies all have made major commitments to fighting infectious diseases of global importance, most notably HIV, tuberculosis and malaria.

Despite many important advances in prevention and therapy, infectious diseases remain a leading impediment to global health. The World Health Organization (WHO) estimates that 1,500 people die each hour from an infectious disease. Half of these deaths occur in children under 5 years of age, and most of the rest are working adults who frequently are breadwinners and parents.

Adding to the burden of endemic infectious diseases are newly recognized diseases (e.g., HIV, Nipah virus) and the reemergence of well-known diseases (e.g., tuberculosis, malaria) that have become increasingly problematic because of drug resistance, social conditions, and other factors. In addition, we now face the specter of a new kind of emerging disease: one deliberately spread by a bioterrorist.

These and other emerging disease threats are an important focus of the Institute's efforts to improve global health. Our research efforts in this regard are directed toward three broad goals:

• Strengthening basic and applied research on the multiple host, pathogen and environmental factors that influence disease emergence.
• Supporting the development of diagnostics, vaccines and therapies necessary to detect and control infectious diseases.
• Maintaining and expanding the national and international scientific expertise required to respond to health threats.

Many of the challenges posed by emerging infectious diseases lend themselves to research in a relatively new field: genomics. The sequencing of the entire human genome and the anticipated assignment, over the next few years, of function to the estimated 60,000-100,00 human genes will have an enormous impact on all of medicine, including our understanding of the host response to microbial pathogens. Parallel with the Human Genome Project, the many projects underway to sequence microbial pathogens will be a critical component of 21st century strategies for the development of diagnostics, therapeutics and vaccines for endemic as well as emerging pathogens.

The first microbial sequencing project, Haemophilus influenzae, was completed in July 1995 with extraordinary speed (see Science 1995; 269:496). Using newly developed techniques, investigators used a "shotgun" approach to sequence thousands of fragments of the bacterium's genome. Special computer programs read these sequences and stitched them together by comparing overlapping sequences. The result was the complete DNA sequence containing all of the genetic information of this bacterium.

Encouraged by this success, NIAID has funded projects to sequence the full genomes of many medically important microbes, including the bacteria that cause tuberculosis, gonorrhea, chlamydia and cholera, as well as individual chromosomes of important organisms such as the malaria parasite Plasmodium falciparum: (http://www.niaid.nih.gov/about/organization/dmid/publications.htm). Many of these microbes have been completely sequenced and are now being annotated and analyzed.

NIAID grantees deposit the sequence data in specialized and public databases such as GenBank, run by the National Center for Biotechnology Information, where it can be accessed by anyone through the Internet (http://www.ncbi.nih.gov/Genbank/). Access to the sequence data, prior to publication in peer-reviewed journals, enables the broader research community to jump-start and accelerate its experimental studies.

back to top

Vaccine Development

Vaccination has been recognized as the greatest public health achievement of the 20th century, and vaccine research has long been a cornerstone of the NIAID research portfolio. NIAID-supported research has been instrumental in the development of many new and improved vaccines, such as those against hepatitis A and B, Haemophilus influenzae type b, pertussis, typhoid, varicella, and pneumococcal disease. The rapidly evolving science base in pathogen genomics, immunology and microbiology will facilitate further progress in developing new and improved vaccines.

The use of currently available and future technologies in the 21st century promises to provide a renaissance in an already vital field. In particular, the availability of the genomic sequences of major microbial pathogens will facilitate the identification of a wide array of new antigens for vaccine targets.

Vaccines that target mucosal surfaces such as those in the intestine or respiratory tract are of great importance, because many pathogens gain entry to the host via mucosal sites. Vaccines administered orally, nasally or transdermally are easy to administer and therefore have potentially great utility in developing countries and for mass immunization programs. The development of new adjuvants, which boost the immune response to vaccines, is another important area of research that has progressed rapidly in recent years.

In addition to the development of vaccines against classic infectious diseases, vaccines are being pursued to fight potential agents of bioterrorism; chronic diseases with infectious origins; and autoimmune diseases and other immune-mediated conditions.

back to top

Addressing Health Disparities

Much of the NIAID research effort is relevant to the health disparities that exist in the U.S., as well as to the growing gap in health status between developed and developing countries. One example of this is the development of vaccines to prevent infectious diseases, which disproportionately affect the poor, both in the U.S. and abroad.

Other research addresses conditions that exact a significant toll in minority communities, such as HIV treatment and prevention research, hepatitis C research, asthma research, tissue typing and other transplantation research, and research into certain autoimmune diseases. In addition, NIAID has a long-standing commitment to increasing the number of minority investigators involved in biomedical research, as well as to education and outreach activities.

As part of a broad NIH effort to eliminate health disparities, NIAID has developed a strategic plan for addressing health disparities in the new millennium, available at (http://www.niaid.nih.gov/healthdisparities/NIAID_HD_Plan_Final.pdf). As discussed in this plan, NIAID will continue to strengthen our efforts to help eliminate health disparities due to infectious and immunologic diseases.

back to top

Conclusion

In the 21st century, NIAID is poised to exploit the unprecedented scientific opportunities in immunology, microbiology and infectious diseases. As has been the case for more than 50 years, a commitment to the best possible science-basic as well as clinical research-will drive our efforts to improve health in this country and abroad.

With a strong research base, talented and committed investigators, and the availability of powerful new research tools, we are confident that our initiatives will help solve seemingly intractable clinical and public health problems and improve global health in the 21st century.

back to top