BATTLING MALARIA

STRENGTHENING THE U.S. MILITARY MALARIA VACCINE PROGRAM

Patricia M. Graves, Myron M. Levine, Editors

Committee on U.S. Military Malaria Vaccine Research: A Program Review

Medical Follow-Up Agency

INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program BATTLING MALARIA STRENGTHENING THE U.S. MILITARY MALARIA VACCINE PROGRAM Patricia M. Graves, Myron M. Levine, Editors Committee on U.S. Military Malaria Vaccine Research: A Program Review Medical Follow-Up Agency INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program THE NATIONAL ACADEMIES PRESS, 500 Fifth Street, N.W., 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 Contract No. DAMD 17-99-1-9478 between the National Academy of Sciences and the Department of Defense. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number 0-309-10168-9 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2006 by the National Academy of Sciences. All rights reserved. Printed in the United States of America. The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin.

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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program “Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES Advising the Nation. Improving Health.

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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and Medicine 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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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program COMMITTEE ON U.S. MILITARY MALARIA VACCINE RESEARCH: A PROGRAM REVIEW Myron M. Levine, (Chair) Director, Center for Vaccine Development at the University of Maryland School of Medicine, Baltimore Graham V. Brown, James Stewart Professor of Medicine at the University of Melbourne, Australia Michael F. Good, Director, Queensland Institute of Medical Research (QIMR), Brisbane, Australia David C. Kaslow, Chief Scientific Officer, Vical Inc., San Diego, California Margaret A. Liu, Vice-chair, Transgene, Strasbourg, France, and Visiting Professor at the Karolinska Institute in Stockholm, Sweden Gary J. Nabel, Director, Vaccine Research Center at the National Institute of Allergy and Infectious Diseases, Bethesda, Maryland Elizabeth Nardin, Associate Professor, Division of Molecular Medicine, New York University School of Medicine N. Regina Rabinovich, Director, Infectious Diseases Division, Bill & Melinda Gates Foundation Global Health Program, Seattle, Washington Alan R. Shaw, President and Chief Executive Officer, VaxInnate, Cranbury, New Jersey H. Kyle Webster, Distinguished military officer (retired) with 27 years experience primarily at the Walter Reed Army Institute of Research Kathryn C. Zoon, Director, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland Staff Patricia M. Graves, Consulting Scientist and Senior Editor Frederick (Rick) Erdtmann, Director, Medical Follow-up Agency Reine Homawoo, Senior Program Assistant Pamela Ramey McCray, Administrative Assistant

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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program Reviewers This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’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 review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report: Walter E. Brandt, The PATH Malaria Vaccine Initiative, Bethesda, Maryland Carter L. Diggs, Malaria Vaccine Development Program, United States Agency for International Development, Washington, D.C. Elaine Esber, Merck Vaccine Division, Merck & Co., Inc., Blue Bell, Pennsylvania Marie-Paul Kieny, Initiative for Vaccine Research, World Health Organization, Geneva, Switzerland Phil Russell, Professor Emeritus, Johns Hopkins Bloomberg School of Public Health, Plantation, Florida Jerald C. Sadoff, Aeras Global TB Vaccine Foundation, Bethesda, Maryland Allan J. Saul, Malaria Vaccine Development Unit, National Institutes of Health, Rockville, Maryland

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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program Although the reviewers listed above have 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 this report was overseen by Adel Mahmoud, M.D., Ph.D., president of Merck Vaccines, Merck & Co., Whitehouse Station, New Jersey. Appointed by the National Research Council and Institute of Medicine, he was responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.

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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program Preface Malaria, the febrile illness caused by the protozoa Plasmodium falciparum, P. vivax, P. malariae, and P. ovale transmitted via the bites of infected female Anopheles mosquitoes, remains a cardinal endemic public health problem in much of the less developed world. Most fatal cases of malaria are caused by P. falciparum and occur in sub-Saharan Africa. Malaria also constitutes a significant threat for nonimmune travelers from industrialized countries who visit (even for short periods) developing world settings where malaria transmission is ongoing; such travelers include U.S. military personnel. For more than a century malaria has posed a serious threat to U.S. military personnel both in large-scale conflicts involving large numbers of troops deployed in endemic areas for extended periods (e.g., the Vietnam conflict) and in small-scale operations. Indeed, this risk was brought home starkly in 2003 when 80 of 290 members of a Marine expeditionary force deployed to Liberia (28 percent) developed P. falciparum malaria; 40 were so ill that they required evacuation, and several had to be admitted to intensive care. Regrettably, the increasing prevalence of drug-resistant Plasmodium strains makes chemoprophylaxis much less reliable. Scientific and biotechnological breakthroughs in the 1970s and 1980s generated widespread optimism that malaria vaccines could become a reality in the foreseeable future to provide protection for troops prior to their deployment to high-risk areas. The military has somewhat special needs for a malaria vaccine compared to pediatric populations in endemic areas. Consequently, this has been one instance where the military research establishment has had to achieve a high degree of self-reliance,

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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program while nevertheless coordinating, wherever possible, with global malaria vaccine development efforts. During the past two decades there have been two highly productive malaria vaccine research programs located within the Walter Reed Army Institute of Research (WRAIR) and the Naval Medical Research Center (NMRC). Whereas there has been considerable collaboration, cooperation, and sharing of resources and reagents by the highly committed and productive staffs of both programs, there has also been a considerable degree of duplication of core facilities, business and regulatory affairs units, and clinical trial processes. There have been divergence of strategies and sometimes direct competition (e.g., by partnering with different vaccine companies to attain access to similar viral vectors). Recognizing the great complexity and expense of the mission to develop a malaria vaccine for the U.S. military in an era of scarce resources, the Department of Defense (DoD) considered it a propitious moment to request the Institute of Medicine (IOM) to convene an expert committee to review all aspects of the DoD malaria vaccine research program. The relocation in 2000 of the WRAIR and NMRC programs to the same building has also provided an opportunity for collaboration and cooperation that did not exist when the programs were physically separate. Within its overall remit, the committee was asked to identify barriers to achieving success and to make specific recommendations of how to overcome barriers, streamline the program, and improve chances for success. Towards this goal, the IOM convened a committee with experts in malaria biology, industrial and public-sector vaccine development, immunology, basic and clinical vaccinology, regulatory affairs, and knowledge of military preventive medicine, deployments, and procedures. The findings of the committee are summarized in this report. The report also contains a series of specific recommendations, which if followed, the committee believes, will significantly improve the likelihood of successful development and licensure of a first-generation malaria vaccine and will create a knowledge base to allow accelerated development of a subsequent second-generation malaria vaccine. The committee emphasized the need to overhaul the management structure of the DoD malaria vaccine enterprise to utilize existing resources in a more rational manner, and the need for a significant infusion of additional core support to the malaria vaccine development enterprise. If these fundamental changes can be implemented, the committee is optimistic that the mission of developing and licensing a safe and efficacious malaria vaccine for protecting U.S. military personnel can be accomplished. Myron M. Levine Chair

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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program Acknowledgments Despite their considerable knowledge and experience, the members of this Institute of Medicine committee could not have completed their task without the cooperation of the USAMRMC and MIDRP staff, especially Dr. Moshe Shmuklarsky and COL David Vaughn, who responded quickly and helpfully on many occasions to requests for information and clarification. The scientific staffs of WRAIR and NMRC, under the leadership of COL Gray Heppner and CAPT Tom Richie, willingly and comprehensively shared their scientific results and plans openly with the committee during the first meeting and were responsive to later requests for further information or explanation. Thanks are also due to Dr. Filip Dubovsky who provided information on the global malaria vaccine effort. We are especially grateful to Hellen Gelband of the IOM for knowledgeable and constructive input to the report at all stages. This study was managed, coordinated, and documented by Dr. Rick Erdtmann and myself with assistance from IOM staff members Reine Homawoo and Pamela Ramey-McCray. However, there were many other staff members at the National Academy of Sciences who assisted with this study, especially Bronwyn Schrecker, Clyde Behney, and Susanne Stoiber. Andrea Cohen kept us on track with our budget, Tyjen Tsai helped move the report through the production process, Kristen Gilbertson provided invaluable help with references and formatting the report, and Lois Joellenbeck gave useful advice. The copyeditor, Mark Goodin, did excel-

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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program lent and careful work. We also thank Katie Friedell of the Beckman Center in Irvine, Calfornia, for help with meeting arrangements. We are very grateful to all of these people for their efforts. Patricia M. Graves, Ph.D. Consulting Scientist

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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program Contents     ABBREVIATIONS AND ACRONYMS   xix     SUMMARY   1      The Malaria Threat to the U.S. Military,   1      Malaria Vaccine Research and Development in the U.S. Military,   2      Malaria Vaccine Progress to Date,   2      Program Integration,   4      Need for Increased Resources,   5      Recommendations,   5 1   INTRODUCTION   9      The Review Process and Inputs,   9      Scope and Organization of the Report,   11 2   THE MALARIA THREAT AND NEED FOR A VACCINE   13      Global Malaria Problem,   13      Military Malaria Problem,   14      Cost and Time Needed to Produce a Vaccine,   19 3   MALARIA VACCINES   21      Specific Military Needs with Respect to a Malaria Vaccine,   24      Malaria Vaccine Development,   26      Preerythrocytic Stages,   26      Erythrocytic Stages,   30      Multiantigen Multistage Approaches,   30

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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program                 Scientific Barriers to Malaria Vaccine Development,   32      Insufficient Knowledge of Malaria Biology,   32      Lack of Understanding of Protective Immunity,   32      Inadequate Animal Models,   33      Poor Definition of Outcomes,   33      The Malaria Vaccine Technology Roadmap,   33      Department of Defense Scientific Contributions to the Global Malaria Vaccine Research Effort,   35      Status of Current Vaccine Candidates,   36 4   THE U.S. MILITARY MALARIA VACCINE RESEARCH AND DEVELOPMENT PROGRAM—SCIENTIFIC ASPECTS   41      Malaria Threat,   41      Department of Defense Mandate for a Malaria Vaccine,   42      Malaria Vaccine Requirements,   42      Clinical Trials to Test Efficacy of a First-Generation Malaria Vaccine,   44      Current and Planned Scientific Program,   47      RTS,S,   50      Recombinant Proteins,   50      Gene-Based Vaccines and Prime-Boost Approaches,   51      Antigen Discovery Using Genomics and Proteomics,   52      Attenuated Sporozoites,   52      Planned Clinical Trials,   52      Overall Assessment of Scientific Program,   52 5   ORGANIZATION AND MANAGEMENT OF THE PROGRAM   56      Program Management,   56      Project Management Structure,   58      IRB Approval Process for Clinical Trials,   59      Business and Intellectual Property Issues,   59      Communication and Resource Sharing,   60      Program Reorganization,   61      Previous Reports Addressing DoD Vaccine Development and Acquisition,   63      Human Resource Commitments,   65      Financial Commitment,   67     REFERENCES   71

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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program               APPENDIXES     A   Vaccine Trials   81 B   Current Requirements for a Malaria Vaccine   95 C   Suggested Design of Trials for Testing Malaria Vaccines in Nonimmune Adults Visiting Endemic Areas   96 D   Patents   99 E   Scientific Advisory Board for DoD Malaria Vaccine Research and Development Program (Draft Charter)   102 F   Recommendations of the IOM Report Protecting Our Forces   105 G   Executive Summary and Recommendations of the DoD Report Acquisition of Vaccine Production   107 H   Open Meeting Agenda   110 I   Committee and Staff Biographies   115

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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program Box, Figures, and Tables BOX S-1   Recommendations,   5 FIGURES 3-1   The malaria life cycle,   22 3-2   Current global P. falciparum vaccine development showing the developmental stage reached and the extent of MIDRP Malaria Vaccine Program involvement,   37 3-3   Results of randomized controlled trials of efficacy of RTS,S vaccine against new malaria infection, clinical malaria, and severe malaria,   39 5-1   Military infectious diseases research program working relationships,   57 5-2   Process of USAMRMC approval to conduct human subjects research,   60 5-3   WRAIR organizational elements involved in the malaria vaccine research and development program and key personnel (expressed in full-time equivalent) dedicated to the malaria vaccine effort,   66 5-4   NMRC organizational elements involved in the malaria vaccine research and development program and key personnel (expressed in full-time equivalent) dedicated to the malaria vaccine effort,   66 5-5   MIDRP funding for malaria vaccine research, 1994–2011 (projected),   68

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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program     TABLES 2-1   Major U.S. Military Actions, Deployments, or Overseas Exercises in Locations with a Malaria Threat,   14 2-2   Other Limited U.S. Military Actions/Deployments (Actual or Standby) in Locations with a Malaria Threat (1990 Onward),   16 2-3   Industry Benchmark Cost Estimates for Vaccine Production,   19 3-1   Malaria Vaccine Needs in Different Groups,   25 3-2   Top 10 Priority Initiatives for Malaria Vaccine Development According to the Malaria Vaccine Technology Roadmap,   34 4-1   Important Characteristics of a First-Generation Malaria Vaccine and a Later-Generation Ideal Vaccine,   43 4-2   Portfolio of Candidate Malaria Vaccines Under Development by the MIDRP Malaria Vaccine Program,   48 4-3   Current and Pending MIDRP Malaria Vaccine Program Clinical Trials,   53 5-1   Numbers of FTE Staff in Different Categories in United States and Overseas Labs,   67 A-1   Phase 1 Trials of Malaria Vaccines That Did Not (or Have Not Yet) Progressed to Phase 2,   82 A-2   Phase 2 Trials of Malaria Vaccines Using Experimental Challenge of Adult Volunteers from Nonendemic Areas,   84 A-3   Summarized Results of Randomized Phase 2 Human Malaria Vaccine Trials Using Natural Challenge Conducted to Date (December 2005),   87 B-1   Current Operational Requirements for a P. falciparum Malaria Vaccine,   95 G-1   Summary of the Top Report Findings and Recommendations by Deputy Secretary of Defense Focus Areas,   109

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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program Abbreviations and Acronyms AFMIC Armed Forces Medical Intelligence Center AFRIMS Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand AIBS American Institute of Biological Sciences AMA apical membrane antigen AVP acquisition of vaccine production BMF biological master file BUMED Bureau of Medicine and Surgery (U.S. Navy) BWD biological warfare defense CAPT captain CDD capability development document CDMRP congressionally directed medical research program CG commanding general CI confidence interval COL colonel CRADA cooperative research and development agreement CSI congressional special interest CSP circumsporozoite protein DALY disability adjusted life years DoD Department of Defense EPA Environmental Protection Agency

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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program FDA Food and Drug Administration FTE full-time equivalent FY fiscal year GEIS global emerging infections surveillance GMP good manufacturing practice GOCO government-owned, contractor-operated GSK GlaxoSmithKline HSRRB Human Subjects Research Review Committee HURC Human Use Research Committee IAA interagency agreement ICGEB International Centre for Genetic Engineering and Biotechnology IND investigational new drug IRB institutional review board JTF-MV Joint Task Force—Malaria Vaccine LSA liver-stage antigen MAJ major ME-TRAP multiple epitope—thrombospondin-related adhesion protein MIDRP Military Infectious Diseases Research Program MPL monophosphoryl lipid A MSP merozoite surface protein MVA modified vaccinia Ankara MVI Malaria Vaccine Initiative NAMRU Naval Medical Research Unit NIAID National Institute of Allergy and Infectious Diseases NIH National Institutes of Health NMRC Naval Medical Research Center ONR Office of Naval Research ORD operational requirements document PfEMP P. falciparum erythrocyte membrane protein POM program objective memorandum

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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program R&D research and development RAP rhoptry-associated protein RESA ring-infected erythrocyte surface antigen SBIR Small Business Innovation Research SBRI Seattle Biomedical Research Institute SG surgeon general SSP sporozoite surface protein TRAP thrombospondin-related adhesion protein USAID U.S. Agency for International Development USAMMDA U.S. Army Medical Materiel Development Activity USAMRAA U.S. Army Medical Research Acquisition Activity USAMRIID U.S. Army Medical Research Institute for Infectious Diseases USAMRMC U.S. Army Medical Research and Materiel Command WHO World Health Organization WRAIR Walter Reed Army Institute of Research

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