Summary

The Department of Defense (DoD), through the commanding general of the U.S. Army Medical Research and Materiel Command (USAMRMC), asked the Institute of Medicine (IOM) to conduct a programmatic review of the military Plasmodium falciparum malaria vaccine research and development program.

All four species of the genus Plasmodium that cause human malaria present a threat, but P. falciparum is the most severe and important. The complex life cycle of Plasmodium (including development in humans and in mosquito vectors) presents a wide array of potential vaccine targets. Vaccines against any of three stages—the preerythrocytic, blood, or transmission stages—are possible. The committee restricted its deliberations to P. falciparum malaria, which is the current focus of the military’s malaria vaccine program, and to vaccines against the preerythrocytic and blood stages.

THE MALARIA THREAT TO THE U.S. MILITARY

Malaria has affected almost all military deployments since the American Civil War and remains a severe and ongoing threat. Current prevention methods for malaria (repellents and impregnated uniforms/mosquito nets) in forces deployed to endemic areas are inadequate, and compliance with chemoprophylaxis is incomplete. In Liberia in 2003, there was a 28 percent attack rate in Marines who spent a brief period ashore, and half of the 80 Marines affected had to be evacuated by air to Germany. This



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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program Summary The Department of Defense (DoD), through the commanding general of the U.S. Army Medical Research and Materiel Command (USAMRMC), asked the Institute of Medicine (IOM) to conduct a programmatic review of the military Plasmodium falciparum malaria vaccine research and development program. All four species of the genus Plasmodium that cause human malaria present a threat, but P. falciparum is the most severe and important. The complex life cycle of Plasmodium (including development in humans and in mosquito vectors) presents a wide array of potential vaccine targets. Vaccines against any of three stages—the preerythrocytic, blood, or transmission stages—are possible. The committee restricted its deliberations to P. falciparum malaria, which is the current focus of the military’s malaria vaccine program, and to vaccines against the preerythrocytic and blood stages. THE MALARIA THREAT TO THE U.S. MILITARY Malaria has affected almost all military deployments since the American Civil War and remains a severe and ongoing threat. Current prevention methods for malaria (repellents and impregnated uniforms/mosquito nets) in forces deployed to endemic areas are inadequate, and compliance with chemoprophylaxis is incomplete. In Liberia in 2003, there was a 28 percent attack rate in Marines who spent a brief period ashore, and half of the 80 Marines affected had to be evacuated by air to Germany. This

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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program costly and dangerous episode reinforced the fact that a vaccine would be the best method of averting the threat of malaria given the likely increasing number of deployments to high-risk areas. Therefore the DoD should markedly enhance its research and development efforts to produce malaria vaccines suitable for military needs. The large investment (at least $300 million) that is required to give a high likelihood of success in producing a vaccine in the next 10 years needs to be acknowledged and planned for. MALARIA VACCINE RESEARCH AND DEVELOPMENT IN THE U.S. MILITARY Malaria vaccine research and development is carried out at the Walter Reed Army Institute of Research (WRAIR), the Naval Medical Research Center (NMRC), and at DoD laboratories overseas in Kenya, Thailand, Indonesia, Peru and Egypt . Management coordination of these activities is the responsibility of the tri-service Military Infectious Diseases Research Program (MIDRP) which is under the direction of USAMRMC. The malaria vaccine research and development programs at these institutions are referred to jointly in this report as the MIDRP Malaria Vaccine Program. Malaria Vaccine Progress to Date The MIDRP Malaria Vaccine Program is a large proportion of the global effort and has been involved in about half of all the vaccine candidates that have been or are currently in development, including several of the candidates that have progressed to clinical efficacy trials in endemic areas. The Malaria Vaccine Program has unique capabilities not readily available elsewhere, such as the well-defined sporozoite challenge model and the pilot GMP (good manufacturing practices) production facility. Early experiments with irradiated sporozoite vaccines were encouraging, providing a measure of protection against infection. However, the generation of both antibody and cellular protective responses with subunit vaccines has proved challenging, with many failed leads and disappointments. Gene-based (DNA) vaccines have not yet fulfilled their early promise generated by results in small animal models, although progress is being made. The most encouraging recent breakthrough was the development at WRAIR of the viruslike particle RTS,S with a particular adjuvant AS02A (in collaboration with GlaxoSmithKline [GSK]). The USAMRMC has a mandate to develop a malaria vaccine as part of its mission to protect the U.S. military against naturally occurring infectious diseases. The military’s vaccine needs differ from those of popula-

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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program tions living in endemic areas but are quite similar to the needs in the civilian traveler market. Ideally, a high level of efficacy against infection is required for a relatively short period of time (e.g., 6 months). The most likely scenario is a “first-generation vaccine” that is a valuable adjunct to chemoprophylaxis, followed by development of an “ideal” vaccine that could be used alone for malaria prevention. A first-generation vaccine providing about 60 percent protection against clinical disease (with a lower limit of 30 percent for the 95 percent confidence interval around the 60 percent point estimate of efficacy) for 6 months is regarded as useful. A second-generation “ideal” vaccine, which could be used to replace the routine use of chemoprophylaxis, would have to provide greater than 95 percent protection against infection over a longer time period. No vaccine candidates are currently in development that are likely to meet the military requirements for a first-generation vaccine in the next 5 to 10 years. A more realistic target date for availability of a licensed vaccine (even with more resources) is 2015–2020. The program to develop a malaria vaccine for U.S. military personnel should focus on (and have the capacity to conduct) clinical efficacy trials in immunologically naïve military personnel (off and on chemoprophylaxis) in endemic areas, for which the field sites currently maintained by the DoD are a critical resource. Suggestions for the design and size of the trials necessary to demonstrate the suggested efficacy for the first-generation vaccine are provided in Appendix C to this report. Research on all three main malaria vaccine development strategies— gene-based (e.g., DNA, plasmid, or viral vector vaccines), protein-based, and attenuated sporozoite approaches—should be continued. However, as research progresses, the number of candidate products must be limited by dropping those that perform less well. The MIDRP Malaria Vaccine Program should aggressively move into clinical trials to test specific vaccine products, and select two to three leads at phase 1 and one at phase 2 for each strategy. For protein-based and gene-based strategies, the focus should be on specific vaccine products that combine the lead antigens (CSP, SSP-2/TRAP, LSA-1, AMA-1, and MSP-1) including their use in heterologous prime-boost combinations. Given the limited time available for this review, the committee did not wish to give more detailed specific advice other than to narrow the focus to a smaller number of candidate antigens. Despite having extensive expertise in all scientific aspects of the program, the committee concluded that instead of offering one-time advice on specific antigens or approaches, it would be more productive to recommend a structure and process for ongoing review and decision making about the scientific direction of the work.

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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program PROGRAM INTEGRATION The DoD malaria vaccine research has been conducted by WRAIR and NMRC, with the former focusing on recombinant proteins and the latter on gene-based approaches. Previously located separately, these two agencies moved to occupy the same building in the year 2000. There is no scientific justification for maintaining these separate programs. 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 divergence of strategies as well as a considerable degree of duplication of core facilities, business and regulatory affairs units, and clinical trial processes. The current cumbersome, inefficient, and complex management structure and processes imposed by two separate programs constitute very critical barriers to progress. An inadequate advisory structure and project management process also impede effective strategic planning. Accordingly, the MIDRP Malaria Vaccine Program should be integrated into a unified organizational entity (Joint Task Force for Malaria Vaccine [JTF-MV]) that spans the spectrum and life cycle of responsibilities: epidemiological/threat assessment, research and development, advanced product development, clinical trials, licensure, manufacture, technology transfer, procurement, maintenance of manufacturing practice standards, and regulatory compliance. The JTF-MV should be a single organizational and legal entity led by a scientific director appointed by the commanding general of the USAMRMC. The JTF-MV should have sufficient staff assigned to it to deal with business and regulatory affairs and avoid future intellectual property conflicts and other issues. A scientific advisory board should be constituted to conduct external review and advise on long-term objectives. The annual proposal cycle should be replaced with a more programmatic approach to project management. Two previous external committees have recently reviewed DoD vaccine programs. The first was an independent panel of experts that submitted a report titled DoD Acquisition of Vaccine Production to the deputy secretary of defense in December 2000. Subsequently an IOM committee tasked with assessing vaccine policies for naturally occurring infectious diseases produced Protecting Our Forces, a report edited by Lemon et al (IOM, 2002). Both these committees recommended organizational changes similar to those proposed here, although they have encompassed the vaccine program more generally rather than just malaria. Implementation of the current recommendations should be assured by the establishment of a malaria vaccine program transition team for the period required to carry out the JTF-MV reorganization and constitution of the scientific advisory board.

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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program NEED FOR INCREASED RESOURCES Malaria remains a major problem for U.S. military personnel deployed to endemic areas, a threat that is not diminishing in importance with time. Therefore the DoD program to develop a malaria vaccine compatible with the needs for protecting U.S. military personnel should be fully supported. To increase the likelihood of achieving the current goals for a first-generation vaccine and to test the limited number of vaccine candidates described above will require a several-fold increase in the current malaria vaccine development budget by 2010, with continuation at that level to at least 2015. RECOMMENDATIONS A list of the committee’s recommendations is provided in Box S-1, which follows. BOX S-1 RECOMMENDATIONS The Malaria Threat and Need for a Vaccine Recommendation 2.1: The DoD should markedly enhance its research and development efforts to produce malaria vaccines suitable for DoD needs. Malaria is a severe ongoing threat for U.S. military personnel deployed to malaria-endemic areas of the world, and current malaria prevention and control methods are indisputably inadequate. Recommendation 2.2: The DoD should formally acknowledge the high cost of developing any new vaccine and the fact that the MIDRP Malaria Vaccine Program is severely underfunded in relation to the goal. To increase the probability of success, this discrepancy needs to be rectified. The U.S. Military Malaria Vaccine Research and Development Program— Scientific Aspects Recommendation 4.1: For a first-generation vaccine, a level of 60 percent efficacy (with a lower limit of 30 percent for the 95 percent confidence interval around the 60 percent point estimate of efficacy) against the clinical effects of P. falciparum would be a useful adjunct to chemoprophylaxis for military use. Nevertheless, research to develop a more effective second-generation vaccine that can be used in the absence of chemoprophylaxis and that would confer a much higher level of efficacy against infection should continue.

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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program Recommendation 4.2: Small, carefully designed and executed clinical efficacy trials involving U.S. military personnel (or other groups of immunologically naïve, nonmilitary personnel) off chemoprophylaxis (initial proof of principle studies) or on chemoprophylaxis (later study) should be carried out to assess the efficacy of the leading MIDRP Malaria Vaccine Program candidate in field sites in endemic areas. In this regard, field sites currently maintained by the DoD in Africa are a critical resource. Recommendation 4.3: Research on all three main malaria vaccine development strategies—gene-based (e.g., DNA, plasmid, or viral vector vaccines), protein-based, and attenuated sporozoite approaches—should be continued. However, as research progresses, the number of candidate products must be limited by dropping those that perform less well. The MIDRP Malaria Vaccine Program should aggressively move into clinical trials to test specific vaccine products, and select two to three leads at phase 1 and one lead at phase 2 for each strategy. For protein-based and gene-based strategies, the focus should be on specific vaccine products that combine the lead antigens (CSP, SSP-2/TRAP, LSA-1, AMA-1, and MSP-1) including their use in heterologous prime-boost combinations. Recommendation 4.4: Finding correlates for protection in humans relevant to each of the above vaccine strategies should be a research priority. Recommendation 4.5: The MIDRP Malaria Vaccine Program should continue research on human immune processes and responses to malaria. The current incomplete understanding of the mechanisms of protective immunity to malaria in humans constitutes a barrier that impedes malaria vaccine development. Organization and Management of the Program Recommendation 5.1: The MIDRP Malaria Vaccine Program, currently composed of two separate entities—WRAIR and NMRC, should be integrated into a unified organizational entity (Joint Task Force for Malaria Vaccine [JTF-MV]) that spans the spectrum and life cycle of responsibilities: epidemiological/threat assessment, research and development, advanced product development, clinical trials, licensure, manufacture, technology transfer, procurement, maintenance of manufacturing practice standards, and regulatory compliance.

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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program Recommendation 5.2: The JTF-MV should appoint one scientific director, reporting to the commanding general of the USAMRMC, to provide joint direction and accountability for the program. The scientific director must have operational authority and budgetary as well as scientific control. Recommendation 5.3: The JTF-MV should organizationally incorporate an industry/business model and be constituted as a single legal entity (able to share proprietary data) that would simplify the external contracting process, including cooperative research and development agreements, interagency agreements, and other contracts. The JTF-MV must include team members with specialized expertise in business and regulatory affairs. Although these individuals would be located in the existing business and regulatory affairs units, adequate staffing for these tasks must be assigned to the JTF-MV in order to avoid or minimize future intellectual property conflicts and other issues. Recommendation 5.4: The JTF-MV program for vaccine development should have an external senior expert advisory group (scientific advisory board) that conducts yearly face-to-face meetings to provide external review and evaluation of the scientific program, and also gives ongoing advice in a timely manner. The scientific advisory board can assist the program to set clear and appropriate objectives (defined up front), with benchmarks of progress. Draft terms of reference for the scientific advisory board are found in Appendix E. Recommendation 5.5: The annual proposal cycle should be replaced with a more programmatic and directed approach to project management under the newly reorganized JTF-MV. The MIDRP sets the annual budget and long-range objectives (with input from the scientific advisory board), and implementation is by the JTF-MV with a longer (approximately 3 year) time horizon for projects. Recommendation 5.6: A malaria program transition team (led by a program manager with a strong business/industry background who reports to the commanding general of USAMRMC) should be established to carry out the JTF-MV reorganization and constitution of the scientific advisory board and assist with recruitment of a highly qualified JTF-MV scientific director. This transition team will be disbanded once the reorganization is in place.

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Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program Recommendation 5.7: A workforce plan must be developed and implemented by the JTF-MV. This plan should include training and budgeting for the next generation of scientists in the military program, ways to improve recruitment and retention of civilians and foreign nationals, and succession planning to ensure availability of required staff in 5–10 years time. The DoD should respond to the lack of sufficient depth of human resources to carry through current objectives with increased resources to carry out the workforce plan. Recommendation 5.8: Sufficient funding should be made available to support the infrastructure to produce pilot-lot formulations of MIDRP malaria vaccine candidates in-house at the pilot production plant at Forest Glen (an invaluable part of the MIDRP Malaria Vaccine Program). Although pilot lots of all candidate vaccines cannot be made at Forest Glen, the ability to prepare certain candidates removes a major obstacle that would otherwise impede the program. Recommendation 5.9: A formal economic analysis would be helpful in order to clarify current costs of malaria (both P. falciparum and P. vivax) prevention, treatment, and case management. This economic analysis would reveal the direct (monetary) and indirect (lost work time) costs that would be averted by both a first-generation vaccine (to be used in conjunction with chemoprophylaxis) and a second-generation vaccine (to replace chemoprophylaxis). Recommendation 5.10: Given that malaria remains a major problem for U.S. military personnel deployed to endemic areas and this threat is not diminishing in importance with time, the MIDRP program to develop a malaria vaccine compatible with the needs for protecting U.S. military personnel should be fully supported. To increase the likelihood of achieving the current goals for a first-generation vaccine and to test the limited number of vaccine candidates described above will almost certainly require a several-fold increase in the current malaria vaccine development budget by 2010, with continuation at that level to at least 2015.