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Future State of Smallpox Medical Countermeasures Lawrence O. Gostin, Lisa Brown, Shalini Singaravelu, and Matthew Masiello, Editors Committee on the Current State of Research, Development, and Stockpiling of Smallpox Medical Countermeasures Board on Health Sciences Policy Board on Global Health Board on Life Sciences Health and Medicine Division Division of Earth and Life Studies PREPUBLICATION COPYâUncorrected Proofs Consensus Study Report
NATIONAL ACADEMIES PRESS 500 Fifth Street, NW, Washington, DC 20001 This activity was supported by contracts between the National Academy of Sciences and the Administration for Strategic Preparedness and Response (75A50121C00061). Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project. International Standard Book Number-13: 978-0-309-XXXXX-X International Standard Book Number-10: 0-309-XXXXX-X Digital Object Identifier: https://doi.org/10.17226/27652 This publication is available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. Copyright 2024 by the National Academy of Sciences. National Academies of Sciences, Engineering, and Medicine and National Academies Press and the graphical logos for each are all trademarks of the National Academy of Sciences. All rights reserved. Printed in the United States of America. Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2024. Future state of smallpox medical countermeasures. Washington, DC: The National Academies Press. https://doi.org/10.17226/27652. PREPUBLICATION COPYâUncorrected Proofs
The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institution to advise the nation on issues related to science and technology. Members are elected by their peers for outstanding contributions to research. Dr. Marcia McNutt is president. The National Academy of Engineering was established in 1964 under the charter of the National Academy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contributions to engineering. Dr. John L. Anderson is president. The National Academy of Medicine (formerly the Institute of Medicine) was established in 1970 under the charter of the National Academy of Sciences to advise the nation on medical and health issues. Members are elected by their peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau is president. The three Academies work together as the National Academies of Sciences, Engineering, and Medicine to provide independent, objective analysis and advice to the nation and conduct other activities to solve complex problems and inform public policy decisions. The National Academies also encourage education and research, recognize outstanding contributions to knowledge, and increase public understanding in matters of science, engineering, and medicine. Learn more about the National Academies of Sciences, Engineering, and Medicine at www.nationalacademies.org. PREPUBLICATION COPYâUncorrected Proofs
Consensus Study Reports published by the National Academies of Sciences, Engineering, and Medicine document the evidence-based consensus on the studyâs statement of task by an authoring committee of experts. Reports typically include findings, conclusions, and recommendations based on information gathered by the committee and on the committeeâs deliberations. Each report has been subjected to a rigorous and independent peer-review process, and it represents the position of the National Academies on the statement of task. Proceedings published by the National Academies of Sciences, Engineering, and Medicine chronicle the presentations and discussions at a workshop, symposium, or other event convened by the National Academies. The statements and opinions contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies. Rapid Expert Consultations published by the National Academies of Sciences, Engineering, and Medicine are authored by subject-matter experts on narrowly focused topics that can be supported by a body of evidence. The discussions contained in rapid expert consultations are considered those of the authors and do not contain policy recommendations. Rapid expert consultations are reviewed by the institution before release. For information about other products and activities of the National Academies, please visit www.nationalacademies.org/about/whatwedo. PREPUBLICATION COPYâUncorrected Proofs
COMMITTEE ON THE CURRENT STATE OF RESEARCH, DEVELOPMENT, AND STOCKPILING OF SMALLPOX MEDICAL COUNTERMEASURES LAWRENCE GOSTIN (Chair), Distinguished University Professor, OâNeil Chair in Global Health Law, OâNeill Institute for National and Global Health Law, Georgetown University GEORGES BENJAMIN, Executive Director, American Public Health Association NAHID BHADELIA, Director, Boston University Center on Emerging Infectious Diseases, Associate Professor, Boston University School of Medicine INGER DAMON, Adjunct Clinical Faculty, Emory University Department of Medicine ANDREW ENDY, Martin Family University Fellow in Undergraduate Education, Faculty Co- Director of Degree Programs, Hasso Plattner Institute of Design, Core Faculty, Stanford University Center for International, Security and Cooperation, Senior Fellow (courtesy), Hoover Institution DIANE E. GRIFFIN, University Distinguished Service Professor, W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health NOREEN HYNES, Associate Professor of Medicine (Infectious Diseases) and Public Health (International Health), Director of Research and Associate Medical Director (Infectious Diseases), Johns Hopkins Hospital Biocontainment Unit, Director, Geographic Medicine Center for the Division of Infectious Diseases, Johns Hopkins University School of Medicine, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins Hospital RICHARD KENNEDY, Professor of Medicine, Mayo Clinic and Foundation, Co-Director, Mayo Clinic Vaccine Research Group KENT KESTER, Vice President, Translational Medicine, International AIDS Vaccine Initiative ANNE RIMOIN, Professor, Department of Epidemiology, Gordon Levin Endowed Chair in Infectious Diseases and Public Health, Director, Center for Global and Immigrant Health Jonathan and Karin Fielding School of Public Health, University of California, Los Angeles HENRY WILLIS, Senior Policy Researcher, Professor, RAND Corporation, Pardee RAND Graduate School OYEWALE TOMORI, Professor of Virology, African Center of Excellence for Genomics of Infectious Diseases MATTHEW WYNIA, Director, Center for Bioethics and Humanities, University of Colorado ZHILONG YANG, Associate Professor, Department of Veterinary Pathobiology, School of Veterinary Medicine & Biomedical Sciences Texas A&M University v PREPUBLICATION COPYâUncorrected Proofs
Study Staff LISA BROWN, Study Director SHALINI SINGARAVELU, Program Officer MATTHEW MASIELLO, Associate Program Officer MARGARET MCCARTHY, Research Associate (until December 31, 2023) CLAIRE BIFFL, Research Associate (from January 1, 2024) RAYANE SILVA-CURRAN, Senior Program Assistant KAVITA BERGER, Board Director, Board on Life Sciences JULIE PAVLIN, Senior Board Director, Board on Global Health CLARE STROUD, Senior Board Director, Board on Health Sciences Policy Consultants ELLEN CARLIN, Parapet Science & Policy Consulting vi PREPUBLICATION COPYâUncorrected Proofs
REVIEWERS This Consensus Study Report was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published report as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We thank the following individuals for their review of this report: DAVID BLAZES, Bill & Melinda Gates Foundation MIKE BRAY, Georgetown Medical School WILLIAM GREG BUREL, Hamilton Grace, LLC JOHN H. CONNOR, National Emerging Infectious Diseases Laboratories (NEIDL), Boston University Chobanian and Avedisian School of Medicine R. ALTA CHARO, University of Wisconsin-Madison RICHARD HATCHETT, Coalition for Epidemic Preparedness Innovations (CEPI) BERNARD MOSS, National Institutes of Health UMAIR SHAH, Washington State Department of Health ERICA SHENOY, Massachusetts General Hospital JILL TAYLOR, Association of Public Health Laboratories (APHL) CRYSTAL WATSON, Johns Hopkins Bloomberg School of Public Health Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations of this report, nor did they see the final draft before its release. The review of this report was overseen by ANN M. ARVIN, Stanford University, and LAWRENCE COREY, Fred Hutchinson Cancer Center. They were responsible for making certain that an independent examination of this report was carried out in accordance with the standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the authoring committee and the National Academies. vii PREPUBLICATION COPYâUncorrected Proofs
CONTENTS ACRONYMS AND ABBREVIATIONS xii SUMMARY S-1 Study Approach, S-2 Overarching Conclusions on Medical Countermeasures Readiness, S-2 State of Smallpox MCM Research, S-2 Evolving Biothreat and Technology Landscape, S-6 Smallpox Research Agenda, S-7 Overall Conclusions on Systems Readiness, S-9 Operational Considerations for MCM Readiness and Stockpile Planning, S-9 The SNS and the Smallpox MCM Portfolio, S-10 Global Cooperation, S-13 Concluding Remarks, S-13 1 INTRODUCTION 1-1 Rationale and Study Charge, 1-1 About this Report, 1-3 Study Approach, 1-3 Study Scope, 1-3 Report Audiences and Key Stakeholders, 1-4 Report Organization, 1-5 Background and Context, 1-6 Smallpox Research and Medical Countermeasures Post-Eradication, 1-6 Global and U.S. Smallpox Medical Countermeasures Stockpiles, 1-6 Conclusions on Global Stockpiling, 1-7 Lessons Learned from Responding To COVID-19 and Mpox, 1-7 Diagnostic Availability and Testing Delays, 1-7 Vaccines and Therapeutic Availability, Access, and Uptake, 1-9 Global Cooperation, 1-11 Smallpox Emergence and Response Considerations, 1-12 Overarching Conclusions, 1-15 2 STATE OF SMALLPOX MEDICAL COUNTERMEASURES READINESS 2-1 Diagnostics, Detection, and Surveillance, 2-1 Testing Options and Utility, 2-2 Gaps and System Pain Points, 2-2 Future Opportunities and Emerging Diagnostic Technologies, 2-3 Genomic and Environmental Surveillance, 2-5 Conclusions on Diagnostics, Detection, and Surveillance, 2-5 Vaccines, 2-6 Vaccine Options and Utility, 2-6 Gaps and Pain Points, 2-10 Future Opportunities and Emerging Vaccine Technologies, 2-14 Conclusions on Vaccines, 2-15 viii PREPUBLICATION COPYâUncorrected Proofs
Therapeutics, 2-15 Therapeutic Options and Utility, 2-15 Gaps and Pain Points, 2-17 Future Opportunities and Emerging Therapeutic Technologies, 2-18 Conclusions on Therapeutics, 2-19 Overarching Conclusions, 2-19 3 FACTORS INFLUENCING SMALLPOX READINESS AND RESPONSE 3-1 Evolving Biothreat Landscape, 3-1 Comparative Poxvirology and Implications for MCMs, 3-3 Utility of Orthopoxviruses for Vaccines and Therapeutics, 3-8 Remaining Gaps, 3-9 Conclusions on Contribution of Basic Poxvirus Research to Smallpox Readiness, 3-10 Evolving Research and Technology Landscape, 3-11 Potential Risks of Technological Advancements on MCM Readiness, 3-11 Potential Benefits of Technological Advancements on MCM Readiness, 3-14 Conclusions on Benefits and Risks of Scientific and Technological Advances, 3-15 Operational Considerations for MCM Readiness and Response, 3-16 Manufacturing Capacity, 3-16 Access and Uptake, 3-17 Frontline Readiness and Biosafety, 3-20 Regulatory Readiness, 3-23 Conclusions on Factors that Influence Readiness and Response Posture, 3-26 Overarching Conclusions, 3-26 4 WAY FORWARD: PRIORITIES FOR RESEARCH, DEVELOPMENT, AND 4-1 STOCKPILING Smallpox Research Agenda, 4-1 Non-Variola Orthopoxvirus and Live Variola Virus Research, 4-5 Research Readiness, 4-15 Conclusions on the Continued Role of Live Variola Virus for Research and Public Health Purposes, 4-16 Stockpiling Considerations, 4-16 International Sharing of Burden and Benefit, 4-17 Lessons From Mpox MCM SNS Deployment, 4-18 Considerations for the Smallpox MCM Portfolio, 4-19 Conclusions on the SNS and Smallpox MCM Portfolio, 4-23 Overarching Conclusions, 4-23 APPENDIXES A STUDY METHODS AND PUBLIC MEETINGS AGENDAS A-1 B COMMITTEE AND STAFF BIOGRAPHICAL SKETCHES B-1 ix PREPUBLICATION COPYâUncorrected Proofs
Boxes, Figures, and Tables BOXES S-1 Considerations for Smallpox MCMs in the SNS, S-11 S-2 Summary of Priorities for Improved Smallpox Readiness and Response, S-14 1-1 Statement of Task, 1-2 1-2 Summary of Factors Considered by the Committee, 1-12 2-1 Smallpox Vaccine Summary and Terminology, 2-9 3-1 Notable Orthopoxvirus Outbreaks (as of February 2024), 3-3 3-2 Poxvirus Knowledge Gaps, 3-9 3-3 Opportunities to Strengthen National Laboratory Systems for Smallpox, 3-22 4-1 Research Program Using Live Variola Virus, 2020â2023, 4-7 4-2 Considerations for and Questions about the Smallpox MCMs in the SNS, 4-21 FIGURES 1-1 PHEMCE stakeholders and engagement, 1-5 1-2 Minimum smallpox MCM needs according to containment strategy, 1-14 3-1 Basic orthopoxvirus lifecycle, 3-7 4-1 Smallpox research agenda, 4-5 TABLES S-1 Summary of Smallpox Vaccines and Therapeutics in the U.S. Strategic National Stockpile, S-3 2-1 Summary of Smallpox Vaccines in the U.S. Strategic National Stockpile, 2-7 2-2 Potential Adverse Events Associated with Smallpox Vaccination with Replicating Vaccine, 2-11 2-3 Summary of Smallpox Therapeutics in the U.S. Strategic National Stockpile, 2-16 3-1 Poxviruses that Infect Humans, 3-4 4-1 List of Conclusions from the IOM Reports Assessment of Future Scientific Needs for Live Variola Virus (1999) and Live Variola Virus: Considerations for Continuing Research (2009) and Recommendations from the 2022 ACVVR Report, 4-2 4-2 Smallpox MCM Readiness as a Function of Live Variola and Non-Variola Viral Research: Opportunities for MCM Improvement, 4-10 x PREPUBLICATION COPYâUncorrected Proofs
Acronyms and Abbreviations ACIP Advisory Committee on Immunization Practices ACVVR Advisory Committee on Variola Virus Research AI artificial intelligence AIDS acquired immunodeficiency syndrome APSV Aventis Pasteur smallpox vaccine ASPR Administration for Strategic Preparedness and Response ARPA-H Advanced Research Projects Agency for Health BARDA Biomedical Advanced Research and Development Authority BioMADE BioIndustrial Manufacturing and Design Ecosystem BioMap National Biopharmaceutical Manufacturing Partnership CBRN chemical, biological, radiological, and nuclear CDC U.S. Centers for Disease Control and Prevention CDV cidofovir CEPI Coalition for Epidemic Preparedness CIADM Centers for Innovation in Advanced Development and Manufacturing CLIA Clinical Laboratory Improvement Amendments CMS Centers for Medicare & Medicaid Services CMV cytomegalovirus COVID-19 the disease caused by the virus SARS-CoV-2 CRISPR clustered regularly interspaced short palindromic repeats DNA deoxyribonucleic acid DoD Department of Defense DPA Defense Production Act EA IND expanded access for an investigational new drug EIND emergency investigational new drug ELISA enzyme-linked immunosorbent assay EM electron microscopy EUA emergency use authorizations EU European Union EV enveloped virion FDA Food and Drug Administration FD&C Food, Drug, and Cosmetic Act FY Fiscal Year GAO Government Accountability Office GMP good manufacturing practice HERA Health Emergency Preparedness and Response Authority HIV human immunodeficiency virus HHS Department of Health and Human Services IgG immunoglobulin G IgM immunoglobulin M IND investigational new drug IOM Institute of Medicine IR inverted repeat ITAP Independent Test Assessment Program xi PREPUBLICATION COPYâUncorrected Proofs
IV intravenous KFF Kaiser Family Foundation LAMP loop mediated isothermal amplification LDT laboratory developed tests LLM large language model LRN Laboratory Response Network mAbs monoclonal antibodies MCM medical countermeasure MERS-CoV Middle East respiratory syndrome coronavirus MPXV monkeypox mRNA messenger ribonucleic acid MV mature virion MVA Modified Vaccinia Ankara MVA-BN Modified Vaccinia Ankara-Bavarian Nordic NIAID National Institute of Allergy and Infectious Diseases NIH National Institutes of Health NYCBOH New York City Board of Health OPXV orthopoxvirus OWS Operation Warp Speed PCR polymerase chain reaction PHEMCE Public Health Emergency Medical Countermeasures Enterprise PON point-of-need POC point-of-care PPE Personal Protective Equipment qPCR quantitative polymerase chain reaction RT-PCR real-time polymerase chain reaction SAGE Strategic Advisory Group of Experts on Immunization SARS severe acute respiratory syndrome SARS-CoV-2 severe acute respiratory syndrome-related coronavirus SCARDA Strategic Center of Biomedical Advanced Vaccine Research and Development for Preparedness and Response SNS Strategic National Stockpile STOMP Study of Tecovirimat for Human Monkeypox Virus SVES Smallpox Vaccine Emergency Stockpile TPP target product profile USG U.S. government VARV variola virus VECTOR State Research Center of Virology and Biotechnology VIG vaccinia immunoglobulin VIGIV vaccinia immune globulin intravenous WHA World Health Assembly WHO World Health Organization xii PREPUBLICATION COPYâUncorrected Proofs
Acknowledgments This Consensus Study Report would not have been possible without the many experts who generously contributed their time and expertise to inform the development of this report. The committee thanks all the speakers (Appendix A) for their timely participation and expert contributions to the public workshops: Steve Adams, Paul Chaplin, Matthew Clark, John Connor, Gavin Cloherty, Nicole Dorsey, Manoj Gandhi, Noel Gerald, Matthew Hepburn, Dennis Hruby, Nathaniel Hupert, Christy Hutson, Stuart Isaacs, Cyrus Javan, Ewa King, Brett Leav, Seth Lederman, Rosamund Lewis, Julia Limage, Karen Martins, Cathryn Mayes, Bernard Moss, Marcus Plescia, Chris Sinclair, Margaret Sloane, Crystal Watson, Daniel Wolfe, and Kevin Yeskey. The committee is deeply appreciative of the following individuals who contributed their expertise on poxvirus research: Grant McFadden, Jia Liu, Stefan Rothenburg, and Yan Xiang. The committee would also like to thank the sponsor of this study. Funds for the committeeâs work was provided by the Administration for Strategic Preparedness and Response (ASPR). The committee also extends their gratitude to the group of interagency federal experts for informing the committeeâs charge. Many others within the National Academies supported this project. The committee thanks the staff of the Health and Medicine Division (HMD) Executive Office, Office of Communications, Office of Governmental Affairs, and Research Center. The committee is grateful to Ellen Carlin for her invaluable contributions to conducting research, report writing, and editing. Finally, Robert Pool is to be credited for his editorial assistance in preparing this report. We are deeply grateful to all those who collaborated on this project for working so diligently under a very short timeline. xiii PREPUBLICATION COPYâUncorrected Proofs
