Mr. Chairman and Members of the Committee, thank you for inviting me here today to discuss the medical response to bioterrorism as well as current efforts by the National Institutes of Health (NIH) to accelerate basic and clinical research related to bioterrorism agents.

In just the last two months we have witnessed the deliberate mailing of spores of anthrax bacterium, including the exposure of members of this esteemed body to this deadly bacteria. The recent misuse of microorganisms has shocked the scientific and public health communities, but I can assure you that we are all working tirelessly to advance our nation's ability to respond to bioterrorism and to advance research to address such threats.

Federal health agencies are evaluating and accelerating measures to protect the public from the health consequences of such an attack. Today I will describe one component of this national effort. As part of the NIH, the National Institute of Allergy and Infectious Diseases (NIAID) supports research on the diagnosis, prevention and treatment of infections caused by a wide variety of pathogens, including those that rarely occur in the United States and that have otherwise received relatively little attention. It is important to note that much of our current knowledge about pathogens can be attributed to many years of NIH-supported basic research. NIH-sponsored studies are also yielding key insights into organisms of bioterrorism including agents that cause anthrax, plague, tularemia, botulism, smallpox, and viral hemorrhagic fevers (diseases caused by agents on the Centers for Disease Control and Prevention (CDC) Category A list of bioterrorist agents). I would like to describe our current efforts in pathogen research and plans to increase research in this area.

Our ability to detect and counter bioterrorism depends to a large degree on the state of biomedical science. Basic and applied research supported by NIH complements the efforts of other agencies by developing the essential tools -- diagnostic tests, therapies and vaccines -- needed by physicians, nurses, epidemiologists and other public health workers to prevent and control a disease outbreak.

To meet the challenges posed by bioterrorism, especially to civilians, NIH supports research in four broad areas: basic research, diagnostics, vaccines and therapeutics.

Basic Research. Research into the basic biology and disease-causing mechanisms of pathogens underpins efforts to develop interventions against agents of bioterrorism. NIH supports research to better understand the factors that influence a pathogen's virulence and invasiveness, as well as those that determine antibiotic resistance. NIH also supports research on the host/pathogen interactions. For example, NIAID and the NIH Office of Dietary Supplements co-sponsored a workshop to draw attention to the scientific gaps in our knowledge of the relationship between micronutrients, such as vitamins and minerals, and infectious diseases. The summary of this workshop can be found in a supplement to the Journal of Infectious Diseases: 182; Sept, 2000. Most recently, NIAID has co-sponsored a targeted solicitation to the research community indicating our interest in further understanding this relationship. In total, knowledge from basic research findings is crucial to the development of preventive and therapeutic strategies.

Another important tool is our ability to rapidly obtain genome sequence information of microbial pathogens, including potential agents of bioterrorism. Some agents, such as smallpox and other orthopoxviruses related to smallpox, have already been sequenced; the sequences of others, such as Bacillus anthracis (the anthrax bacterium), Enterococcus faecalis, and Staphylococcus aureus and the organisms that cause brucellosis, Q-fever, glanders, cholera, and botulism are in progress. The fruits of genomics research, coupled with other biochemical and microbiological information, are expected to facilitate the achievement of critical new goals, including the discovery of new targets for drugs and vaccines. In particular, comparative genomics (comparing the sequences of different strains of particular organisms) will be an important component of future research, helping us to understand what makes a particular organism either harmful or benign.

In addition to these activities, and as part of our broader research agenda, other Institutes at NIH support research on new and emerging infectious agents, the metabolic effects of toxic agents, hazardous chemicals, and biological mechanisms of action of certain organophosphate chemicals, which mimic the effects of chemically similar nerve agents.

Diagnostics. The overall goal of this research is to establish methods for the rapid, sensitive, and specific identification of natural and bioengineered microbes as well as the determination of the microbe's sensitivity to drug therapy. These scientific advances will allow health care workers to diagnose and treat patients more accurately and quickly.

Vaccines. NIH-supported researchers are developing vaccines effective against many infectious agents, including those considered to be bioterrorism threats (brucellosis, tularemia, Q-fever, dengue, ebola, anthrax, smallpox, and cholera), with the goal of producing products that are safe and effective in civilian populations of varying ages and health status. Vaccines against pathogens are being developed using both traditional and novel technologies. Some novel technologies include the development of "DNA vaccines" and innovative systems for the rapid creation of vaccines against unfamiliar or genetically altered pathogens; these technologies are in various stages of development. As one example, researchers at the Vaccine Research Center of NIAID have developed a DNA vaccine that has protected monkeys from infection with Ebola virus; this vaccine could soon enter human trials.

Therapeutics. NIH therapeutics research focuses on the development of new antimicrobials and antitoxins, as well as the screening of existing antimicrobial agents to determine whether they have activity against organisms that might be employed by bioterrorists (activities include drug screening of potential treatments for smallpox, plague, and hantavirus). Knowledge gained from basic and applied research is helping to identify additional targets for medications against agents of bioterrorism.

The development of antimicrobial resistance is an important issue with the treatment of most infectious diseases. The design of therapeutic drugs active against known drug-resistant variants of microbes and the development of broad-spectrum agents are important NIH research priorities. For example, NIAID is exploring an opportunity to sequence the genomes of a variety of clinical isolates of Bacillus anthracis in order to investigate the potential for antimicrobial resistance in these strains. I have included in Appendix D a copy of the Department of Health and Human Services report entitled "A Public Health Action Plan to Combat Antimicrobial Resistance," which outlines the Department's efforts to address issues of antimicrobial resistance in general.

I have just described NIAID's overall agenda for pathogen research. NIAID-funded research and a bibliography of published research articles related to vaccines and treatments for the potential agents of bioterrorism requested by this committee are also included in Appendices A and B, respectively. In addition, the current recommendations for medical care for these agents are included in Appendix C.

Now I would like to talk about how this agenda translates to research on two specific pathogens that are of particular concern as bioterrorist threats, smallpox and anthrax.

Prevention and Treatment of Smallpox

Smallpox is considered one of the most dangerous, potential biological weapons because it is easily transmitted from person-to-person, and few people carry full immunity to the virus. The mortality of smallpox infection is approximately 30 percent; those patients who recover frequently have disfiguring scars.

Smallpox vaccine has proven to be highly effective in preventing infection. In addition, the vaccine can lessen the severity of, or even prevent, illness in unvaccinated people exposed to smallpox, if given within a few days after exposure. Based on its effectiveness in prevention and treatment of smallpox, this vaccine was the essential factor in the global eradication of smallpox in 1977. Vaccinations to prevent smallpox have not been required in the United States since 1972.

In the near-term, a bioterrorist attack involving smallpox would require the utilization of stores of the existing smallpox vaccine to protect those at immediate risk. The current stock of DryvaxÒ vaccine, approximately 15 million doses, clearly would not be enough to respond to a national smallpox epidemic. Last year, NIAID initiated a study to determine the feasibility of expanding the use of the existing stores of the DryvaxÒ vaccine by testing various dilutions. The results of this study showed that the full-strength vaccine had maintained its potency, and that 70 percent of people who received a single dose of a 1:10 dilution of vaccine mounted a sufficient immune response. In the first week of November, a new smallpox vaccine study began that is designed to compare the use of a 1:5 dilution, 1:10 dilution, and undiluted vaccine in order to determine if a diluted vaccine combined with an alternative vaccination schedule could protect a greater number of people than does the standard dose and regimen. This study will provide data that will guide the use of the remaining stockpile of smallpox vaccine if needed to protect the general population.

NIAID plans to support the clinical testing of new smallpox vaccines that may be safely used in other segments of the population. At the same time, we are looking into alternative vaccine strategies, including the development of "DNA vaccines" and other innovative systems, with the goal of designing safer and more effective vaccines.

NIAID is also accelerating efforts to identify antiviral drugs that will be effective in treating smallpox and related viruses. One of these agents is an antiviral called cidofovir, which is approved by the Food and Drug Administration (FDA) for treating certain AIDS-related viral infections. Cidofovir has shown potent activity against smallpox and related viruses in test tube studies and in animal models. NIH has taken the lead in developing a protocol that would allow cidofovir to be used in emergency situations for the treatment of smallpox. Other anti-smallpox agents are also being investigated. For the past three years, NIAID and the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) have screened approximately 500 compounds for potential antiviral activity against smallpox.

Prevention and Treatment of Anthrax

Several characteristics of Bacillus anthracis, the agent that causes anthrax, help to establish it as a formidable bioterrorist threat, including its stability in spore form, its ease of culture, and the absence of natural immunity in industrialized nations.

Human anthrax has three major clinical forms: cutaneous, inhalation, and gastrointestinal. If left untreated, anthrax in all forms can lead to septicemia and death. Early treatment of cutaneous and gastrointestinal anthrax with appropriate antibiotics is usually curative, and early antibiotic treatment of all forms is important for recovery. Although case-fatality estimates for inhalational anthrax are based on incomplete information, the historical rate is extremely high, approximately 75%, even with all possible supportive care including appropriate antibiotics.

Anthrax vaccine adsorbed (AVA) is the only currently licensed anthrax vaccine. At this time, AVA is recommended only for high-risk populations such as veterinarians. The Department of Defense (DOD) also uses this vaccine to protect U.S. military personnel in high-threat areas. The current schedule for receiving vaccine, 6 doses over the course of 18 months, is cumbersome and efforts are underway to identify a simpler immunization schedule.

Assuring the safety of the very young, the aged, and immunocompromised individuals requires a different approach to drug therapy and vaccine prevention than would be applicable in a military population. NIAID has been working with DOD to support the development of the next generation of anthrax vaccines that may be more appropriate than AVA for use in the civilian population. NIAID is also exploring rapid diagnosis of anthrax and the utility of alternative antimicrobial or antitoxin therapies. Together with the Food and Drug Administration (FDA), CDC, and USAMRIID, NIH is working to prioritize and accelerate testing of promising candidates for use as antimicrobial therapies for anthrax in order to increase the pool of available treatments. NIAID-supported investigators have recently published two studies in the scientific journal Nature that help to explain how anthrax toxin destroys cells. In the first study, researchers have identified the site on the cell that binds the anthrax toxin and have developed a compound that may disable it. Another group of investigators has characterized the structure of a major component of the anthrax toxin. The information gained through these studies will likely hasten the development of new drugs to treat anthrax.

Together with our many research partners, NIH has made substantial progress in the research effort that is critical to our Nation's fight against terrorism. In addition to previously mentioned collaborations with other government agencies, NIAID maintains important partnerships with industry that are essential to the development of new technologies and treatments in the infectious diseases arena.

Much remains to be accomplished, however, and the challenges posed by bioterrorism will require a protracted and sustained commitment. NIH will announce in the next few weeks several new initiatives to provide the academic and industrial research communities with an opportunity to propose studies targeting new approaches to research on agents of bioterrorism. The submission, review, and funding of these proposals will be expedited in order to facilitate the rapid advance of these important research endeavors.

With a strong research base, talented investigators throughout the country, and the availability of powerful new research tools, we fully expect that our basic and applied research programs will provide the essential elements that will help enhance our defenses against those who attempt to harm us with bioterrorism.

That concludes my testimony. I would be happy to respond to any questions you might have.