Summary of NIAID Accomplishments in Biodefense Research The National Institute of Allergy and Infectious Diseases (NIAID) is the principal institute among the National Institutes of Health that supports biodefense research. NIAID has markedly expanded, intensified, and accelerated its ongoing research programs in biodefense. NIAID developed more than 50 biodefense initiatives to stimulate research in Fiscal Years 2002 and 2003. About 75 percent of these are new initiatives and 25 percent are significant expansions of existing contracts. A summary of selected NIAID accomplishments in biodefense follows. New Initiatives Ongoing Initiatives Scientific Accomplishments Clinical Evaluations of New Drugs, Diagnostics, and Vaccines Strategic Planning New Initiatives In Fiscal Year 2004, NIAID plans to support an Antibody Production Facility to ensure that sufficient quantities of monoclonal antibodies against diseases caused by potential agents of bioterrorism can be produced for preclinical and clinical evaluations. July 2003. Announced two new programs, the Food and Waterborne Diseases Integrated Research Network and the Respiratory Pathogens Research Network. These programs expand NIAID’s capacity to conduct clinical research studies of food and waterborne pathogens, including those that could be potential agents of bioterrorism. July 2003. Announced two initiatives to develop new drugs, diagnostics, and vaccines related to biodefense: the Biodefense Partnerships and the Cooperative Research for the Development of Vaccines, Adjuvants, Therapeutics, Immunotherapeutics, and Diagnostics for Biodefense Program. Grants under these programs will be awarded by September 2003. July 2003. Began funding a multidisciplinary team of scientists from both academia and the biotechnology industry who are using high-throughput proteomic technologies to identify possible drug targets from arenaviruses and Lassa virus. June 2003. Announced the expansion of NIAID’s Vaccine Treatment and Evaluation Units (VTEUs) by approximately 60 percent. In the past year, eight clinical trials of various smallpox vaccines have been completed or are underway at VTEU sites. In addition, clinical trials for new anthrax and West Nile vaccines are being planned for the VTEUs. Ongoing Initiatives Greatly expanded genomic sequencing of potential agents of bioterrorism, including anthrax, plague, and many others. Became part of an interagency, comprehensive microbial genome sequencing effort that includes the Department of Defense, the Central Intelligence Agency, the Federal Bureau of Investigation, and the National Science Foundation (http://www.niaid.nih.gov/cgi-shl/genome/genome.cfm). Continued support of the Poxvirus Bioinformatics Resource Center, a Web-based resource for scientists that facilitates basic research on poxviruses as well as research into new therapies and vaccines against them. The center provides databases of genetic information, software for genome data mining and analysis, a literature database, and more (http://www.poxvirus.org). Expanded intramural studies of the anthrax toxin in small animal models to better understand the action of the anthrax toxin and to identify possible anthrax therapies. Scientific Accomplishments Basic Research July 2003. Identified a single protein that acts as a key switch point in frontline immune system reactions to both bacterial and viral infections. This molecule may serve as a target for a broad spectrum of antimicrobial drugs. April 2003. Sequenced the complete genome of the anthrax bacterium, Bacillus anthracis, a category A agent and cause of inhalation anthrax. Investigators found a number of genes that this bacterium may use to enter host cells and therefore may be important targets for vaccines and drugs. NIAID is now funding more than 50 individual research projects to better understand the mechanisms by which the anthrax bacterium causes disease. April 2003. Sequenced the complete genome of the bacterium that causes Q fever, Coxiella burnetii. This category B agent can cause a debilitating, though rarely fatal, flu-like illness in humans. This genetic information should allow researchers to better understand how this organism causes diseases and to identify genes that could be targets for drugs or vaccines. January 2003. Demonstrated that today's predominant strains of Toxoplasma gondii, a bacterium classed as a category B agent, gained the ability to infect nearly all warm-blooded vertebrates about 10,000 years ago through a genetic cross. This study established that parasites like T. gondii can sometimes rapidly adapt to new hosts and present potential new public health threats. August 2002. Discovered that the influenza virus uses a protein called NS1 to block interferon—one of the body's main weapons against viral infections—and escape the body’s first line of defense. This knowledge could help defend against influenza virus if it is used as a bioterrorist weapon. June 2002. Showed that cholera bacteria isolated directly from human diarrheal stool possesses an infectivity in mice up to 700 times greater than that of laboratory-grown organisms. This super-infective state was completely lost after the bacteria were grown in laboratory conditions. This knowledge could help treat or prevent infections of cholera, which is classed as a Category B priority pathogen. May 2002. Conducted comparative genomic studies of anthrax isolates from victims of the 2001 anthrax attacks, providing investigators with important data connecting the different cases (http://www.niaid.nih.gov/newsroom/releases/anthraxgen.htm). Drug and Vaccine Target Identification July 2003. Announced plans to screen existing FDA-approved drugs for efficacy against inhalation anthrax. Five licensed antibiotics have been selected for the study, which is planned to being in fiscal year 2004. July 2003. Screened 650 compounds for antiviral activity against poxviruses, including the smallpox virus. So far, cidofovir appears to be the best candidate to treat both smallpox disease and vaccine complications. This program has also screened 370 compounds for antiviral activity against the West Nile virus, with results pending. January 2003. Demonstrated that a simple molecule, called D6R, can block toxins produced by the dangerous bacteria Psuedomonas aeruginosa in experiments with mice. This discovery could lead to drugs that block toxins from a variety of bacteria in humans, including the diphtheria and anthrax bacteria. August 2002. Showed that only three genes are necessary and sufficient for the Ebola virus to assemble itself. The scientists also discovered some new aspects of the assembly process that may become targets for antiviral drugs. April 2002. Discovered a genetic basis for transmission of plague, Yersinia pestis, by infected fleas to humans, and continued studies of the microbe and its insect vector. This knowledge could lead to new plague treatments (http://www.niaid.nih.gov/newsroom/releases/geneleap.htm). October 2001. Determined how anthrax toxin gains entry into a cell, and demonstrated how the toxin can be effectively blocked from entering the cell, suggesting development of anthrax toxin-blocking compounds could be a viable approach to treating anthrax disease (http://www.niaid.nih.gov/newsroom/releases/anthrax.htm). Preclinical Development of New Drugs, Diagnostics, and Vaccines August 2003. Developed a fast-acting, experimental Ebola vaccine that successfully protects monkeys from the virus after only one month. If this vaccine proves similarly effective in humans, it could one day be used to quickly contain Ebola outbreaks with ring vaccination—the same strategy used in the past against smallpox. August 2003. Created a hybrid vaccine that protects monkeys from West Nile virus infection. The vaccine consists of a weakened, or attenuated, combination of two viruses formed by removing key genes from dengue virus and replacing them with West Nile virus genes. July 2003. Announced plans to support advanced development of one or more candidate vaccines against plague in 2004. These candidate vaccines are based on two antigens of the plague bacterium that appear to play a major role in mediated protective immunity. July 2003. Announced support of a program to test FDA-approved antibiotics for efficacy against pneumonic plague in monkeys. This program is conducted in collaboration with the United States Army Research Institute of Infectious Diseases (USAMRIID). July 2003. Plans to support new grants with the aim of developing recombinant vaccines against botulism in 2003. February 2003. Awarded contracts to two companies—Acambis of Cambridge, Massachusetts, and Bavarian Nordic of Copenhagen—to develop potentially safer, next-generation smallpox vaccines using modified vaccinia Ankara (MVA). January 2003. Initiated studies to evaluate a new recombinant plague vaccine, developed by the U.S. Army Medical Research Institute of Infectious Diseases, for its ability to protect mice against flea-borne transmission of the plague bacterium. March 2002. Demonstrated that the antiviral drug cidofovir is active against the smallpox virus in animal model systems. Scientists have developed a form of cidofovir that can be taken orally, and this drug is currently being tested in animals, with plans for human studies in 2004. (See Clinical Evaluations of New Drugs, Diagnostics, and Vaccines.) March 2002. Found that certain vaccines provide a surprising amount of cross-protection against West Nile and other related viruses in a hamster model system. October 2002. Awarded contracts to two companies—Avecia of Manchester, England and VaxGen of Brisbane, California—to spur development of a new anthrax vaccine based on a component of the anthrax bacterium called recombinant protective antigen (rPA). Ongoing. Initiated efforts to develop monoclonal antibodies as alternatives to vaccinia immune globulin, a substance used to treat complications caused by the smallpox vaccine that is in very short supply. Ongoing. Mining the completely sequenced smallpox virus genome, NIAID-supported scientists have identified five genes whose protein products may be good targets for neutralizing antibodies that could stop smallpox infection. About ten promising antibodies to one smallpox protein are being tested so far, with plans to test many more. New Research Facilities and Resources July 2003. Finalizing awards to make research resources, such as animal models, reagents, production facilities, and genomic and proteomic resources, available to the scientific community to assist with conducting research. July 2003. Finalizing awards for extramural biodefense infrastructure, such as large biocontainment facilities and a research network to conduct multidisciplinary research on biodefense agents. February 2003. Moved forward with plans to establish a vaccine development and production facility in Frederick, Maryland, for NIAID’s Vaccine Research Center by leasing a building that will be renovated for the facility. This facility will allow a government contractor to quickly and efficiently produce pilot lots of experimental vaccines for use in clinical trials. January 2003. Announced establishment of a consortium to investigate innate immunity—the human body's first line of defense against disease. The knowledge generated could help scientists develop treatments for many diseases, including those caused by potential agents of bioterrorism. September 2002. Established two Emerging Viral Diseases Research Centers with the expertise to study and quickly respond to diseases caused by emerging viruses or viruses that may be potential bioterrorist threats. These include West Nile, Rift Valley fever, Venezuelan equine encephalitis, and tick-borne encephalitis viruses. Ongoing. Initiated plans to renovate and construct biosafety level (BSL) -3 and BSL-4 facilities to enable safe research on medical countermeasures against bioterrorism. These facilities will include National Biodefense Laboratories and some of the planned NIAID Regional Centers of Excellence in Biodefense and Emerging Diseases Research. They will also include new facilities on the NIAID campus in Bethesda, Maryland; at NIAID’s Rocky Mountain Laboratories in Hamilton, Montana; and at Frederick, Maryland. http://www.niaid.nih.gov/biodefense/rblrce.htm and http://www.niaid.nih.gov/dir/infobsl4/bsl4faq.htm http://www.niaid.nih.gov/contract/archive/RFP0336-0.pdf http://www.niaid.nih.gov/contract/archive/rfp0336-1-8.pdf http://www.niaid.nih.gov/factsheets/qanda.htm http://www.nih.gov/news/NIH-Record/10_14_2003/story01.htm Clinical Evaluations of New Drugs, Diagnostics, and Vaccines Anthrax studies February 2002 . Initiated a long-term study to examine the physical effects and immune response to anthrax in survivors of the anthrax attacks of 2001. The knowledge generated could help doctors respond more quickly and effectively in the event of another such attack. Cidofovir smallpox studies July 2003. Announced plans to begin a study in 2004 to assess initial safety and tolerability of a new oral form of cidofovir, a promising therapy for poxvirus infections including smallpox, in healthy human volunteers. Next-generation smallpox vaccine studies February 2003 . Initiated a study at the NIAID Vaccine Research Center to test a potential alternative smallpox vaccine, called modified vaccinia Ankara (MVA), in adults previously vaccinated against smallpox (ages 31-60). MVA might be safe for individuals at high risk of complications from existing vaccines. September 2002. Initiated a study at the NIAID Vaccine Research Center to test MVA in non-vaccinated adults (ages 18-30). Dryvax smallpox vaccine studies October 2002 . Initiated studies to determine 1) the proportion of previously vaccinated individuals who respond to re-vaccination with a major reaction, or “take,” and 2) to determine the take rate of diluted vaccine (1:5 and 1:10) in previously vaccinated adults. October 2002. Initiated a study of laboratory researchers and other health care workers who receive the smallpox vaccine as a routine safety precaution. This study will test improved methods for measuring the immune response to smallpox vaccination and provide information about protective antibody levels. March 2002. Successfully completed and published the results of a 680-person, multicenter vaccine dilution study in the NIAID Vaccine and Treatment Evaluation Units. This study demonstrated that the currently available stock of Dryvax smallpox vaccine could be diluted (1:5) without loss of activity, effectively expanding the existing stockpile of smallpox vaccine from 15 million to 75 million doses (http://www.niaid.nih.gov/newsroom/releases/smallpox.htm). Aventis Pasteur smallpox vaccine studies May 2002. Initiated a series of studies to test the safety and efficacy of the smallpox vaccine produced by Aventis Pasteur at various concentrations in both previously vaccinated and non-vaccinated adults. Strategic Planning March 2003. On behalf of the NIH, convened a special meeting of experts to review ongoing research efforts in the development of medical countermeasures for chemical threats. The meeting included representatives of academia, the chemical industry, poison control centers, private and governmental research institutions, the Office of Homeland Security, the Society of Toxicology, the Department of Defense, the Department of Health and Human Services, the Centers for Disease Control and Prevention, the Central Intelligence Agency, the U.S. Department of Agriculture, the National Academy of Sciences, and the Institute of Medicine. February 2003 . On behalf of the NIH, convened a special meeting of experts to review ongoing research efforts in the development of medical countermeasures for radiological threats. With the assistance of organizations such as the National Cancer Institute, the Armed Forces Radiobiology Research Institute, and the Department of Energy, gaps were identified and short- and mid-term research priorities were recommended. October 2002. Established a broad-based collaboration with the U.S. Army Medical Research Institute of Infectious Diseases to conduct biodefense research. This partnership includes the planning and designing of new laboratory facilities at Fort Detrick, Maryland, including a new BSL-4 laboratory (http://www.niaid.nih.gov/newsroom/releases/usamriid.pdf). October 2002. Convened a Blue Ribbon Panel of experts to provide objective recommendations on NIAID’s research agenda for Category B and C priority pathogens, those organisms that are not as dangerous at category A agents but have the potential to be used as agents of bioterrorism. Developed and published The NIAID Biodefense Research Agenda for CDC Category B and C Priority Pathogens (http://www.niaid.nih.gov/biodefense/research/categorybandc.pdf). June 2002. Convened an Expert Panel on Immunity and Biodefense, composed of internationally recognized immunologists from academia, industry, and government to address the immunological aspects of biodefense research. Panel members identified high priority research areas in immunology that would lead to improved biodefense strategies and recommended methods for achieving those research goals (http://www.niaid.nih.gov/publications/pdf/biodimmunpan.pdf). June 2002. Convened an Expert Panel on Atopic Dermatitis and Vaccinia immunization. The panel developed a research plan to reduce the risk of eczema vaccinatum, a serious and sometimes deadly complication of smallpox immunization in atopic dermatitis patients. February 2002. Convened a Blue Ribbon Panel of experts to provide objective scientific advice on NIAID’s biodefense research agenda by assessing current research and identifying goals for the highest priority areas. With this advice, developed and implemented the NIAID Strategic Plan for Biodefense Research and the NIAID Biodefense Research Agenda for CDC Category A Agents, those agents that have the greatest potential to adversely affect public health (http://www.niaid.nih.gov/biodefense/research/strategic.pdf and http://www.niaid.nih.gov/biodefense/research/biotresearchagenda.pdf) NIAID is a component of the National Institutes of Health (NIH), which is an agency of the Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, illness from potential agents of bioterrorism, tuberculosis, malaria, autoimmune disorders, asthma and allergies. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov. Prepared by: Office of Communications and Public Liaison National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, MD 2089204, 2003 (nq)