BATTLING MALARIA
STRENGTHENING THE U.S. MILITARY MALARIA VACCINE PROGRAM
Patricia M. Graves, Myron M. Levine, Editors
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 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.
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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
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
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.
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,
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
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-
Box, Figures, and Tables
BOX
S-1 |
Recommendations, |
FIGURES
3-1 |
The malaria life cycle, |
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3-2 |
Current global P. falciparum vaccine development showing the developmental stage reached and the extent of MIDRP Malaria Vaccine Program involvement, |
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3-3 |
Results of randomized controlled trials of efficacy of RTS,S vaccine against new malaria infection, clinical malaria, and severe malaria, |
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5-1 |
Military infectious diseases research program working relationships, |
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5-2 |
Process of USAMRMC approval to conduct human subjects research, |
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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, |
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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, |
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5-5 |
MIDRP funding for malaria vaccine research, 1994–2011 (projected), |
TABLES
2-1 |
Major U.S. Military Actions, Deployments, or Overseas Exercises in Locations with a Malaria Threat, |
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2-2 |
Other Limited U.S. Military Actions/Deployments (Actual or Standby) in Locations with a Malaria Threat (1990 Onward), |
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2-3 |
Industry Benchmark Cost Estimates for Vaccine Production, |
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3-1 |
Malaria Vaccine Needs in Different Groups, |
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3-2 |
Top 10 Priority Initiatives for Malaria Vaccine Development According to the Malaria Vaccine Technology Roadmap, |
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4-1 |
Important Characteristics of a First-Generation Malaria Vaccine and a Later-Generation Ideal Vaccine, |
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4-2 |
Portfolio of Candidate Malaria Vaccines Under Development by the MIDRP Malaria Vaccine Program, |
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4-3 |
Current and Pending MIDRP Malaria Vaccine Program Clinical Trials, |
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5-1 |
Numbers of FTE Staff in Different Categories in United States and Overseas Labs, |
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A-1 |
Phase 1 Trials of Malaria Vaccines That Did Not (or Have Not Yet) Progressed to Phase 2, |
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A-2 |
Phase 2 Trials of Malaria Vaccines Using Experimental Challenge of Adult Volunteers from Nonendemic Areas, |
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A-3 |
Summarized Results of Randomized Phase 2 Human Malaria Vaccine Trials Using Natural Challenge Conducted to Date (December 2005), |
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B-1 |
Current Operational Requirements for a P. falciparum Malaria Vaccine, |
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G-1 |
Summary of the Top Report Findings and Recommendations by Deputy Secretary of Defense Focus Areas, |
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
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
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