OVERCOMING CHALLENGES TO DEVELOP COUNTERMEASURES AGAINST AEROSOLIZED BIOTERRORISM AGENTS

APPROPRIATE USE OF ANIMAL MODELS

Committee on Animal Models for Testing Interventions Against Aerosolized Bioterrorism Agents

Board on Life Sciences

Institute for Laboratory Animal Research

Division on Earth and Life Studies

NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, DC
www.nap.edu



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Committee on Animal Models for Testing Interventions Against Aerosolized Bioterrorism Agents Board on Life Sciences Institute for Laboratory Animal Research Division on Earth and Life Studies THE NATIONAL ACADEMIES PRESS Washington, DC www.nap.edu

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THE NATIONAL ACADEMIES PRESS • 500 Fifth Street, NW • Washington, DC 20001 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. International Standard Book Number 0-309-10211-1 Additional copies of this report are available from The National Academies Press, 500 Fifth Street, NW, Lockbox 285, Washington, DC 20001; (800) 624-6242 or (202) 334- 3313 (in the Washington metropolitan area); Internet, http://www.nap.edu Copyright 2006 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Wm. A. Wulf is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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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 v

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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 vi

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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 vii

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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. ix

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x DEVELOPING COUNTERMEASURES AGAINST AEROSOLIZED AGENTS 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.

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xi PREFACE Responsibility for the final content of the report, however, rests entirely with the authoring committee and the institution. Charles H. Hobbs, Chair Committee on Animal Models for Testing Interventions Against Aerosolized Bioterrorism Agents

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Contents GLOSSARY xv SUMMARY 1 Charge to the Authoring Committee, 2 Principal Findings and Recommendations, 3 1 INTRODUCTION 7 Statement of Task, 7 Committee Process, 8 Animal Rule, 8 Biological Weapons Convention, 9 Key Issues Examined, 10 2 SELECTION OR DEVELOPMENT OF AN ANIMAL MODEL 11 Pathogenesis, 13 Host-pathogen Interactions, 13 Pulmonary Anatomy and Physiology, 14 3 GENERATION AND CHARACTERIZATION OF AEROSOLIZED AGENTS 21 Principles for Generation of Aerosol, 21 Characterization of Aerosol, 24 4 DOSIMETRY CONSIDERATIONS 29 Dose Metrics, 29 xiii

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xiv DEVELOPING COUNTERMEASURES AGAINST AEROSOLIZED AGENTS 5 EXPERIMENTAL DESIGN 33 Delivery of Dose, 33 Experimental Design and Selection of Dose, 36 6 RESOURCE ISSUES 41 Personnel Needs and Training, 41 Infrastructural Issues, 43 Agency Considerations, 47 REFERENCES 51 ABOUT THE AUTHORS 59 APPENDIX A 63 Public Workshop Agenda, 63 Biographical Information about the Speakers, 66

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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 xv

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xvi DEVELOPING COUNTERMEASURES AGAINST AEROSOLIZED AGENTS 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 standard A measure of dispersion for a log-normal deviation (GSD) 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 aerodynamic For aerosols, the MMAD equals the particle diameter (MMAD) diameter at which particles larger than the MMAD contribute half of the collected mass and particles smaller than the MMAD contribute the other half.