OVERCOMING CHALLENGES TO DEVELOP COUNTERMEASURES AGAINST AEROSOLIZED BIOTERRORISM AGENTS
APPROPRIATE USE OF ANIMAL MODELS
THE NATIONAL ACADEMIES PRESS
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NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance.
This study was supported by the Department of Health and Human Services, National Institutes of Health through Contract No. N01-OD-4-2139 Task Order 152. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views of the organizations or agencies that provided support for the project. The content of this publication does not necessarily reflect the views or policies of the National Institutes of Health, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.
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THE NATIONAL ACADEMIES
Advisers to the Nation on Science, Engineering, and Medicine
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COMMITTEE ON ANIMAL MODELS FOR TESTING INTERVENTIONS AGAINST AEROSOLIZED BIOTERRORISM AGENTS
Charles H. Hobbs (Chair),
Lovelace Respiratory Research Institute, Albuquerque, New Mexico
David C. Dorman,
CIIT Center for Health Research, Research Triangle Park, North Carolina
Diane E. Griffin,
Johns Hopkins University, Baltimore, Maryland
Jack R. Harkema,
Michigan State University, East Lansing, Michigan
Beth L. Laube,
Johns Hopkins University, Baltimore, Maryland
David E. Lenz,
U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland
Stephen S. Morse,
Columbia University, New York, New York
Robert F. Phalen,
University of California, Irvine, California
Staff
Jennifer Obernier, Study Director
Kerry Brenner, Study Director (through August 2005)
Joe Larsen, Postdoctoral Fellow
Seth Strongin, Senior Program Assistant
Anne Jurkowski, Senior Program Assistant
Karen Imhof, Administrative Assistant
John Horigan, Christine Mirzayan Science and Technology Policy Graduate Fellow
BOARD ON LIFE SCIENCES
Corey S. Goodman (Chair),
Renovis, Inc., South San Francisco, California
Ann M. Arvin,
Stanford University School of Medicine, Stanford, California
Jeffrey Bennetzen,
University of Georgia, Athens, Georgia
Ruth Berkelman,
Emory University, Atlanta, Georgia
Deborah Blum,
University of Wisconsin, Madison, Wisconsin
R. Alta Charo,
University of Wisconsin, Madison, Wisconsin
Dennis Choi,
Merck Research Laboratories, West Point, Pennsylvania
Jeffrey L. Dangl,
University of North Carolina, Chapel Hill, North Carolina
Paul R. Ehrlich,
Stanford University, Stanford, California
James M. Gentile,
Research Corporation, Tucson, Arizona
Jo Handelsman,
University of Wisconsin, Madison, Wisconsin
Ed Harlow,
Harvard Medical School, Boston, Massachusetts
David Hillis,
University of Texas, Austin, Texas
Kenneth Keller,
University of Minnesota, Minneapolis, Minnesota
Randall Murch,
Virginia Polytechnic Institute and State University, Alexandria, Virginia
Gregory A. Petsko,
Brandeis University, Waltham, Massachusetts
Stuart L. Pimm,
Duke University, Durham, North Carolina
James Tiedje,
Michigan State University, East Lansing, Michigan
Keith Yamamoto,
University of California, San Francisco, California
Staff
Fran Sharples, Director
Denise Grosshans, Financial Associate
INSTITUTE FOR LABORATORY ANIMAL RESEARCH COUNCIL
Stephen W. Barthold (Chair),
University of California, Center for Comparative Medicine, Davis, California
William C. Campbell,
Drew University, Madison, New Jersey
Jeffrey I. Everitt,
GlaxoSmithKline Research and Development, Comparative Medicine and Investigator Support, Research Triangle Park, North Carolina
Michael F. Festing,
Leicestershire, United Kingdom
James G. Fox,
Massachusetts Institute of Technology, Division of Comparative Medicine, Cambridge, Massachusetts
Estelle B. Gauda,
Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland
Janet Gonder Garber,
Pinehurst, North Carolina
Coenraad F.M. Hendriksen,
Netherlands Vaccine Institute, Bilthoven, The Netherlands
Jon H. Kaas,
Vanderbilt University, Nashville, Tennessee
Jay R. Kaplan,
Wake Forest University School of Medicine, Department of Pathology, Winston-Salem, North Carolina
Joseph W. Kemnitz,
University of Wisconsin, Primate Research Center, Madison, Wisconsin
Leticia V. Medina,
Abbott Laboratories, Abbott Park, Illinois
Abigail L. Smith,
University of Pennsylvania, University Laboratory Animal Resources, Philadelphia, Pennsylvania
Stephen A. Smith,
Virginia Polytechnic Institute and State University, Department of Biomedical Sciences and Pathobiology, Blacksburg, Virginia
Peter Theran,
Massachusetts Society for the Prevention of Cruelty to Animals, Angell Animal Medical Center, Boston, Massachusetts
Staff
Joanne Zurlo, Director
Kathleen Beil, Administrative Assistant
Preface
The terrible events of September 11, 2001, and the dissemination of Bacillus anthracis by mail in October 2001, markedly increased awareness of the possibility of bioterrorism attacks and of the need for new vaccines and therapeutics to protect U.S. citizens from them.
Following this, Congress markedly increased the funding for research for new vaccines and therapeutics to protect the United States from a bioterrorist attack. Such research had largely been conducted by the U.S. Army Medical Research Institute of Infectious Diseases at Ft. Detrick, Maryland. Much of this research is now being directed by the National Institute of Allergy and Infectious Disease of the National Institutes of Health.
An integral part of the development of new vaccines and therapeutics is obtaining the necessary approvals from the U.S. Food and Drug Administration both for their initial use in people and their eventual licensure for general use. The present accelerated pace of development, however, has led to several additional needs: standardization of methods for the generation and characterization of aerosols of bioterrorism agents for use in animal studies (necessary for licensure of vaccines and therapeutics), characterization of the threat to the population, and expansion of the number of laboratories conducting the research. The Committee on Animal Models for Testing Interventions Against Aerosolized Bioterrorism Agents was convened by the National Research Council to address these issues. It was tasked by its sponsor, the National Institute of Allergy and Infectious Disease, to prepare a short consensus report that articulates the difficulties of testing countermeasures to aerosolized bioterrorism agents and considers whether there are opportunities for improving current approaches to animal testing of countermeasures against aerosols by applying knowledge from other fields of science.
Thus, the Committee organized a workshop, titled “Animal Models for Testing Interventions Against Aerosolized Bioterrorism Agents,” which was held July 6th – 7th, 2005, in Washington, D.C. The Committee selected as participants scientists, from diverse disciplines, who made presentations that ultimately were integral to the development of this report.
As chairman, I thank the committee members for contributing their expertise and time to the committee, the workshop, and the report. And the entire committee thanks NRC staff members Kerry Brenner and Jennifer Obernier for their organizational skills and hard work in arranging the workshop and preparing the report. Thanks too to Seth Strongin for providing logistical support. The report would not have been possible without their assistance.
The report has been reviewed in draft form by individuals chosen for their diverse perspective and technical expertise, in accordance with procedures approved by the NRC’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The reviewers’ comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following people for their review of the report:
Lynn Andersen, Johns Hopkins University, Baltimore, Maryland
Chris Gennings, Virginia Commonwealth University, Richmond, Virginia
Michael T. Kleinman, University of California, Irvine, California
Roger O. McClellan, Toxicology and Human Health Risk Analysis, Albuquerque, New Mexico
Matthew S. Meselson, Harvard University, Boston, Massachusetts
Stanley Perlman, University of Iowa, Iowa City, Iowa
David Y. H. Pui, University of Minnesota, Minneapolis, Minnesota
Chad Roy, U.S. Army Medical Research Institute for Infectious Diseases, Fort Detrick, Maryland
Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of the report was overseen by:
Peter Ward, University of Michigan, Ann Arbor, Michigan
Peter Palese, Mount Sinai School of Medicine, New York, New York
Appointed by the NRC, these individuals were responsible for ensuring that an independent examination of the report was carried out in accordance with institutional procedures and that all review comments were carefully considered.
Glossary
aerodynamic diameter An equivalent diameter for a particle defined as the physical diameter of a smooth solid sphere (of density 1 gram/cm3) that has the same terminal settling velocity in still air (under standard laboratory conditions) as the particle in question.
aerosol A relatively time-stable two-phase system consisting of finely-divided particles (that can be solids or liquids) suspended in a gas (which is usually air). Aerosol particles typically range in diameter from 0.001 to 100 μm.
bioterrorism agent A microorganism or a toxin derived from a microorganism that causes human disease and is used to harm people, or to elicit widespread fear or intimidation, for political or ideological goals.
countermeasure A drug, biological product, chemical, or other therapeutic technology that prevents or treats an illness caused by a bioterrorism agent.
dose The amount (for bioaerosol particles this could be number, mass, viable units, or another metric related to biological effect) of an agent normalized to some property of the biological target (which could be mass, surface area or other
descriptor of an individual, organ, or tissue). For example: mg of particles deposited in the subject; μg of particles deposited in the respiratory tract; μg of particles in the tracheobronchial region; or number of viable organisms in the alveolar spaces of the lung.
geometric standarddeviation (GSD) A measure of dispersion for a log-normal distribution that is analogous to the standard deviation for a normal distribution. The GSD is the ratio of the 84.13 percentile to the 50 percentile.
mass median aerodynamicdiameter (MMAD) For aerosols, the MMAD equals the particle diameter at which particles larger than the MMAD contribute half of the collected mass and particles smaller than the MMAD contribute the other half.