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Responding to the Challenges of the 21st Century:
NIH's Role in Vaccine Research and Development
Statement of
Anthony S. Fauci, M.D.
Director
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Department of Health and Human Services
November 29, 2001
Mr. Chairman and Members of the Subcommittee, thank you for inviting me here today to provide an update on the current bioterrorism research activities of the National Institutes of Health (NIH) and our plans for the future. Any program that will effectively counter bioterrorism out of necessity would be a comprehensive program involving multiple government agencies, local and state health departments, and private industry. An important component of such a comprehensive effort is biomedical research. The role of the NIH in the overall government effort against bioterrorism is to conduct and support such research.
The NIH bioterrorism research program is spearheaded by the National Institute of Allergy and Infectious Diseases (NIAID) and encompasses four broad areas: basic research, diagnostics, vaccines and therapeutics. I would like to briefly describe our research in these broad areas as well as summarize several specific NIAID-supported smallpox and anthrax studies.
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. Knowledge from basic research findings is crucial to the development of preventative and therapeutic strategies.
One of the most important basic research tools that has evolved in recent years is the ability to rapidly sequence the entire genomes 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) and other bacteria relevant to bioterrorism are in progress and close to completion. 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.
NIH also supports research leading to the development of new and improved diagnostics. The 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.
NIH-supported researchers are developing vaccines that are effective against many infectious agents, including those considered to be bioterrorism threats, with the intention of developing 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", various vector vaccines, and innovative systems for the rapid creation of vaccines against unfamiliar or genetically altered pathogens; these technologies are in various stages of development.
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. Knowledge gained from basic and applied research is helping to identify additional targets for medications against agents of bioterrorism. The design of therapeutic drugs active against known drug-resistant variants of microbes, and the development of broad-spectrum agents are also important NIH research priorities.
Together, these efforts create the strong foundation from which the NIH carries out bioterrorism research activities. Two cogent examples of this multifaceted research approach are the specific NIH projects in the areas of smallpox and anthrax.
Smallpox is considered one of the most dangerous, potential biological weapons because it is easily transmitted from person-to-person, and very few people carry full immunity to the virus. Historically, the mortality of smallpox infection has been approximately 30 percent; those patients who recover frequently have disfiguring scars.
NIAID research on smallpox focuses primarily on extending existing vaccine stocks to increase the number of available doses, and developing new vaccines and treatments for the entire population, as well as diagnostic tools to detect the disease quickly.
At present, the approximately 15 million doses of the traditionally employed and highly effective "Dryvax" vaccine that have been stored since production stopped in 1983 would not be enough to respond to a national smallpox epidemic. In response to this shortage, NIAID initiated a study last year to determine the feasibility of expanding the use of the existing stores of the Dryvax vaccine by dilution. In this study, investigators examined and compared the skin and immune system responses of normal unimmunized adult volunteers who were given undiluted Dryvax vaccine, a 1:10 dilution (10 percent) of vaccine or a 1:100 dilution (1 percent) of vaccine. The results showed that the full-strength vaccine had maintained its potency, and that 70 percent of people who received a single dose of the 10-percent diluted vaccine developed a sore followed by a scab at the injection site and antibodies in their blood, strongly suggesting protection. The 1:100 dilution had an unacceptably low take rate.
Based on these findings, a larger study is underway to determine the best strategy for optimal use of available vaccine. This study, which will enroll up to 684 people, is evaluating three different doses (undiluted, 1:5, 1:10) of Dryvax. Researchers will study the ability of the various vaccine formulations to stimulate a scab, or "take," at the vaccination site and to produce neutralizing antibodies in the blood. If participants have not developed a scab in seven to nine days after vaccination, they will be revaccinated with the same vaccine dose they received the first time. By that strategy, researchers hope to learn which vaccine dose given in a single injection elicits the desirable response among the largest number of people and whether "boosters" can increase the take rate on a population basis.
NIAID is also designing clinical protocols for testing of Dryvax in previously immunized adults and in children. At the same time, we are investigating the newer cell culture based smallpox vaccines as well as alternative vaccination strategies with the goal of designing safer and more effective vaccines.
NIAID/NIH also supports long-established contracts that conduct in vitro and in vivo screening of known antiviral compounds to determine if they are effective against viruses that are similar to smallpox (vaccinia virus and cowpox virus). Compounds with promising in vitro activity are further evaluated in animal models of orthopoxvirus infection by both United States Army Medical Research Institute of Infectious Diseases (USAMRIID) and NIAID-supported investigators. To date, NIAID and USAMRIID have screened approximately 500 compounds. The drug cidofovir has been shown in multiple test systems to have activity against all orthopoxviruses tested in vitro and in vivo. NIAID submitted an Investigational New Drug (IND) application for use of this drug as a backup to vaccinia immune globulin (VIG) in our dilutional vaccine studies and possibly for the emergency treatment of smallpox should a bioterrorism attack occur.
One key collaborative activity that will accelerate the development of new treatments and vaccines for smallpox is the recent establishment of the "Orthopoxvirus Genomics and Bioinformatics Resource Center." NIAID, the Defense Advanced Research Projects Agency (DARPA), the Centers for Disease Control and Prevention (CDC), USAMRIID and the American Type Culture Collection have all contributed toward this Center, which will conduct sequence and functional comparisons of genes to provide insights for the selection of targets for the design of antivirals and vaccines.
With regard to anthrax research, NIAID has been collaborating with the Department of Defense (DOD) to support the development of the next generation of anthrax vaccines that may be more appropriate than the current anthrax vaccine for use in the civilian population. At present, we are currently planning Phase 1 safety and immunogenicity trial for the USAMRIID recombinant protective antigen (rPA), one of the leading anthrax vaccine candidates. In addition, NIAID is utilizing its vaccine production and support contractor, Science Applications International Corporation (SAIC) to facilitate and expedite the development of additional rPA vaccines.
NIAID is also exploring rapid diagnosis of anthrax and the utility of available antimicrobial or antitoxin therapies. Together with the Food and Drug Administration (FDA), CDC, and USAMRIID, NIH is working to prioritize and accelerate testing of existing antimicrobials for use against anthrax. Last month, NIAID-supported investigators 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.
In addition, the NIAID, through an Inter-Agency Agreement with the Office of Naval Research, has provided funds to help complete work on sequencing the genome of B. anthracis. The information derived from this genome-sequencing project should be of great value in developing rapid diagnostic tests, as well as new vaccines and antibiotics therapies against mutant strains of B. anthracis.
Although the focus of national attention has been on smallpox and anthrax, we must not overlook other organisms of bioterrorism, including agents that cause plague, tularemia, botulism, and viral hemorrhagic fevers. NIH-supported research is yielding insights in these areas. For example, intramural investigators at NIAID's Dale and Betty Bumpers Vaccine Research Center have developed a DNA vaccine that has protected monkeys from infection with Ebola virus; this vaccine could soon enter human trials.
Together with our many research partners, NIH has made substantial progress in the research effort that is critical to our Nation's fight against emerging diseases, including those that are intentionally released as agents of 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 arena of infectious diseases.
Much remains to be accomplished, however, and the challenges posed by bioterrorism will require a sustained commitment over the years to come. Within the next few weeks, NIH will announce new initiatives for funding in Fiscal Year 2002 to provide the academic and industrial research communities with an opportunity to propose studies targeting new approaches to research on agents of bioterrorism. For example, we will unveil an initiative entitled "Partnerships for Novel Therapeutic, Diagnostic and Vector Control Strategies in Infectious Diseases," which will involve substantive involvement by a private sector partner and focus on areas that are currently not a high priority or that may be too financially risky for industry to pursue alone, but are likely to have a high impact on public health. The submission, review, and funding of these proposals will be expedited in order to facilitate the rapid advance of these important research endeavors. This information is being made available to the public and the research community through our Web site.
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 greatly 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 that you might have.
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