About the Director

This article appeared in U.S. Medicine, January 2005 issue, p. 24.

The past year was one of accomplishment, as the National Institute of Allergy and Infectious Diseases (NIAID) made significant strides in our efforts to better understand, diagnose, treat and prevent infectious and immunologic diseases. The year also was tinged with sadness, as we lost John R. La Montagne, PhD, the Institute's Deputy Director and a dear friend and colleague. Throughout his career, John made significant contributions to national and international efforts against emerging and re-emerging infectious diseases. Of particular note, he played a central role in organizing the Multilateral Initiative on Malaria, chaired the WHO Task Force on Strategic Planning for the Children's Vaccine Initiative, advised the Pan American Health Organization on their programs in vaccine research implementation, and led a multinational effort to develop and license acellular pertussis vaccines. He was, in the words of Tommy Thompson, Secretary of the Department Health and Human Services, a "true public health hero."

Biodefense Research

Since the anthrax attacks of 2001, NIAID has significantly strengthened, accelerated and expanded our biodefense research program. As part of this effort, the Institute has greatly increased biodefense research capacity. For example, NIAID has funded eight Regional Centers of Excellence for Biodefense and Emerging Infectious Diseases Research. This nationwide network of multidisciplinary academic centers will conduct wide-ranging research on infectious diseases and the development of diagnostics, therapeutics and vaccines. In addition, NIAID is supporting the construction of two National Biocontainment Laboratories (NBLs) and nine Regional Biocontainment Laboratories (RBLs). These high-level biosafety facilities promise to speed the development of effective therapies, vaccines and diagnostics for diseases caused by agents of bioterror, as well as for naturally occurring emerging diseases such as severe acute respiratory syndrome (SARS) and avian influenza.

In addition, NIAID has developed and expanded contracts to screen new drugs; developed new animal models and established a reagent and specimen repository. NIAID also has made a significant investment in determining the genomic sequences of a wide range of pathogens, which will help to illuminate the pathogenic mechanisms of all classes of microorganisms. NIAID-supported researchers and their international colleagues have sequenced genomes representative of all bacteria considered bioterror threats (including multiple strains of the anthrax bacterium), as well as at least one strain of every potential viral and protozoan bioterror pathogen. NIAID also is funding research to better understand host immunity. For example, the Cooperative Centers for Translational Research on Human Immunology and Biodefense will conduct research to better understand the human immune response to potential agents of bioterror, with the objective of developing new countermeasures against these agents. Another large-scale program is funding sophisticated studies of the human innate immune system. Boosting innate immunity holds great promise for developing fast-acting countermeasures to mitigate the effects of bioterror pathogens or toxins.

The ultimate goal of all NIAID biodefense research is the development of medical countermeasures. NIAID-supported scientists have identified: a) antivirals that may play a role in treating smallpox or the complications of smallpox vaccination; b) several approaches to blocking the toxins of the anthrax bacterium; as well as c) antibiotics, antivirals and antitoxins against other major bioterror threats. New and improved vaccines against smallpox, anthrax and other potential agents also are being developed, with the objective of adding them to the Strategic National Stockpile (SNS). For example, NIAID has sponsored the development of a next-generation anthrax vaccine known as recombinant protective antigen (rPA). The Department of Health and Human Services (HHS) recently awarded a contract to procure 75 million doses of rPA for the SNS to protect U.S. citizens. Clinical trials of rPA are ongoing; results to date build on similar findings in animal studies and suggest that the vaccine is safe and capable of evoking a robust immune response.

NIAID-supported researchers also are testing several new smallpox vaccines that may prove at least as effective as the current smallpox vaccine, but with fewer side effects. One of these, modified vaccinia Ankara (MVA), is based on a strain of the vaccinia virus that replicates less robustly than the traditional Dryvax vaccinia virus, and is known to cause fewer side effects than the latter. Human trials of MVA vaccines are underway at the NIAID Vaccine Research Center (VRC) and elsewhere. Encouragingly, recent studies by NIAID intramural scientists and their colleagues have shown that MVA protects monkeys and mice from smallpox-like viruses. The NIAID VRC also has launched the first human trial of a vaccine designed to prevent infection with Ebola virus.

HIV/AIDS Research

Recent estimates on the scope of the HIV/AIDS pandemic are profoundly sobering. Approximately 40 million people worldwide are living with HIV/AIDS. In 2004 alone, an estimated 5 million people worldwide were newly infected with HIV—about 14,000 each day. As shocking as these numbers are, they do not begin to adequately reflect the physical and emotional devastation to individuals, families and communities coping with HIV/AIDS, nor do they capture the huge deleterious impact of HIV/AIDS on the economies and security of nations, and indeed entire regions. Even as the burden of HIV/AIDS continues to grow, recent developments provide some measure of optimism. For example, more than 25 antiretroviral medications have been licensed by the Food and Drug Administration (FDA), each of which built on NIAID-sponsored research and/or has been tested in NIAID clinical trials networks. Many other “next-generation” anti-HIV drugs are in clinical trials, including agents that inhibit the entry of HIV into host cells or the integration of HIV DNA into the nuclei of host cells.

A vaccine that prevents HIV infection—or at least slows the progression of disease—is a critical NIAID priority. HIV vaccine developers face formidable scientific challenges, including determining whether any of the current vaccine candidates are protective, and whether it is possible to further improve vaccine design to induce broader neutralizing antibody and CD8+ T cell responses. In addition, operational challenges must be overcome, including the production of clinical grade vaccines, expansion of clinical trials capacity in rich and poor countries, and strengthening public-private collaborations. To address these and other concerns, new cross-sector collaborations are essential to accelerate HIV vaccine development by enhancing coordination, information sharing and collaboration globally. In this regard, a virtual consortium known as the Global HIV Vaccine Enterprise has been established to prioritize the scientific challenges to be addressed and fill the identified gaps in knowledge; coordinate product development efforts; and help align and channel existing and new resources to the needs at hand. As part of the enterprise, the NIAID-supported Center for HIV/AIDS Vaccine Immunology (CHAVI) will support an intensive, multi-resourced, coordinated consortium approach to address key scientific roadblocks in the identification of a safe and effective HIV vaccine. Other such efforts will follow and are critical to HIV vaccine research and development by improving research transparency, cooperation and collaboration globally.

Concurrent with our HIV vaccine research and development efforts, novel approaches to HIV prevention are being studied and validated, including topically applied microbicides that individuals could use to protect themselves from HIV and other sexually transmitted pathogens. As discussed in the NIAID Topical Microbicide Strategic Plan numerous candidate agents have shown laboratory activity against HIV and other STDs, and several of these agents have demonstrated safety and efficacy in animal models, and safety in small human trials. In the near future NIAID’s HIV Prevention Trials Network (HPTN), in conjunction with the National Institute of Child Health and Human Development, will launch a large international study to test two promising products in more than 3,000 women at high risk of acquiring HIV in the United States, five African countries and India.

Research On Other Emerging And Re-Emerging Infectious Diseases

Infectious diseases have always afflicted humanity, and they will continue to confront us as long as man and microbes co-exist. Unfortunately, the microbes that cause infectious diseases do not remain static, but continually and dramatically change over time as new pathogens (such as HIV and the SARS coronavirus) emerge and as familiar ones (such as influenza virus and West Nile virus) re-emerge with new properties or in unusual settings.

West Nile virus (WNV) first appeared in the western hemisphere in 1999, and by 2004 had infected humans and/or mosquitoes, birds and other species in all the continental United States. NIAID has moved quickly to address this threat with basic research on the virus and its maintenance in nature, the development of countermeasures, and the provision of reagents and other resources to the research community. NIAID is supporting the development of three types of vaccines, as well as the screening and testing of WNV therapies. For example, the NIAID-sponsored Collaborative Antiviral Study Group is assessing the safety and efficacy of WNV immunoglobulins in patients with, or at high risk of, serious brain diseases caused by WNV.

Severe acute respiratory syndrome (SARS) is a new infectious disease first identified in humans in early 2003. The prompt recognition that SARS is caused by a new type of coronavirus, and the rapid progress in SARS research reflect the dedication of and collaboration by the world’s medical researchers and public health experts, including NIAID-sponsored scientists in the United States and abroad. NIAID supports research to understand the epidemiology and biology of the SARS virus and how it spreads, and to develop SARS countermeasures. Several approaches to SARS countermeasures are being pursued by the NIAID Laboratory of Infectious Diseases, the NIAID VRC, and by our contractors and grantees. For example, NIAID is participating in a project to screen up to 100,000 antiviral drugs and other compounds for activity against the SARS virus, and will test the most promising in animal models and human clinical trials.

NIAID scientists and grantees are pursuing several parallel approaches in the search for a SARS vaccine. Once these experimental vaccines are ready, NIAID plans to test them in human clinical trials in our network of Vaccine and Treatment Evaluation Units (VTEUs). New research suggests that a SARS vaccine is within reach: NIAID researchers have developed two candidate vaccines based on the SARS coronavirus spike protein that protect mice against SARS. Another promising vaccine protects against infection in monkeys when delivered intranasally.

Influenza is a classic example of a re-emerging disease; it is not a new disease, but it continually changes. To address the yearly challenge of inter-pandemic influenza, as well the ever-present threat of a global pandemic caused by a novel influenza strain, NIAID supports a broad program to develop more effective approaches to controlling influenza virus infections. Research includes initiatives to understand the pathogenesis, transmissibility, evolution, epidemiology and the immune response to influenza viruses, as well as to develop new diagnostics, antiviral drugs and vaccines. NIAID currently supports several research projects to develop vaccines that could be manufactured more rapidly, are more broadly cross-protective, and are more effective than current influenza vaccines. The use of reverse genetics—a tool developed by NIAID grantees—holds the promise for more rapid generation of vaccine candidates that match the anticipated strain expected to circulate during the influenza season. Reverse genetics also can be used to turn highly pathogenic influenza viruses into vaccine candidates more suitable for vaccine manufacturing by removing or modifying certain virulence genes. NIAID also is funding the development of new influenza vaccine technologies, including the production of vaccines in cell culture systems as an alternative to egg-based production.

In recent years, several avian influenza virus strains that can infect humans have emerged. In 1999 and 2003, an H9N2 influenza strain caused illness in three people in Hong Kong. The H5N1 “bird flu” virus, first detected in humans in 1997, infected at least 44 people and killed 32 in 2004, and has spread widely among wild and domestic birds. To address the threat posed by these viruses, NIAID has contracted with industry to produce investigational lots of inactivated H5N1 and H9N2 vaccine preparations that will be tested within the VTEUs. Because NIAID has had remarkable success in the past with groundbreaking vaccine research—including advances that led to hepatitis B, Haemophilus influenzae b, pneumoccocal pneumonia and acellular pertussis vaccines—we are confident that one of the approaches that we are pursuing also will lead to a useful, “next-generation” influenza vaccine that can readily be adapted to emerging influenza strains.

Research On Immune-Mediated Diseases

Immune-mediated diseases such as autoimmune diseases, allergic diseases and asthma are important health challenges in the United States and abroad. Autoimmune diseases afflict 5 to 8 per cent of the U.S. population; asthma and allergic diseases combined represent the sixth leading cause of chronic illness and disability in the United States, and the leading cause among children. The past two decades of fundamental research in immunology have resulted in a wealth of new information and extraordinary growth in our conceptual understanding of the immune system and the pathogenesis of immune-mediated diseases, which has led to the development of many useful therapies. For instance, we now have powerful treatments that selectively target several of the immune system molecules that cause inflammation, a hallmark of many autoimmune diseases. NIAID-sponsored researchers are now developing novel ways of selectively blocking inappropriate or destructive immune responses, while leaving protective immune responses intact, an area of research known as tolerance induction. In the Immune Tolerance Network, a consortium of basic and clinical scientists, promising studies are underway using tolerance induction to treat autoimmune diseases, such as rheumatoid arthritis, type 1 diabetes, and multiple sclerosis, asthma and allergic diseases, and the rejection of transplanted organs, tissues, and cells. So-called “tolerogenic” therapies would replace current lifelong non-specific immunosuppressive regimens (and their often debilitating side-effects) with short-term specific regimens that hold the promise of being curative.

Another important NIAID research focus is the development of new interventions to reduce the burden of asthma, a significant and growing public health problem in the United States and many nations worldwide. NIAID has long been at the forefront of discoveries leading to the characterization of asthma and allergic diseases and is vigorously pursuing the translation of basic knowledge into more effective treatment and prevention strategies. Institute-sponsored researchers recently published important results of a home-based environmental intervention among urban children with asthma (NEJM 2004 351:1068-80). NIAID’s Inner-City Asthma Consortium (ICAC) is now embarking on a large study to define and analyze immunological and environmental influences upon the development of childhood asthma in a cohort of urban children followed from birth.

With a strong research base, talented investigators in the United States and abroad, and the availability of powerful new research tools, NIAID anticipates that our basic and applied research programs will provide the countermeasures to improve our defenses against those who would attempt to harm us with bioterrorism, to develop new tools in the fights against HIV/AIDS and other infectious diseases, and to improve therapies and management of immune-mediated diseases.