4

Current Obstacles to Development

THE SCIENCE

Why is there still no effective malaria vaccine after decades of research and several development efforts? It may have been reasonable to expect failure in the early years of malaria research, given the lack of knowledge about the parasite and the pathogenesis of the disease and a limited understanding of immunology and immune function. Since then, however, both fundamental research and vaccine development efforts have greatly advanced our understanding of these issues. The limited success in malaria vaccine development reflects, in part, that needed answers of critical importance to product development efforts have neither been sought nor obtained in a systematic and coordinated way. Currently, for example, malaria vaccine research is being conducted on multiple fronts, employing different vaccine entities and research strategies. While such an approach has been extremely productive in expanding the fundamental knowledge base, it now appears that a more focused and coordinated strategy is needed for product selection and development.

The scientific hurdles facing malaria vaccine developers are still imposing, however. There remains no known in vitro correlate of protection. The malaria parasite has multiple, immunologically distinct developmental stages and effective immune avoidance strategies. Single-antigen and single-stage vaccines have proved disappointing. Multi-antigen, multistage vaccines, which elicit different kinds of immune responses directed toward different antigens, appear more promising. High antibody levels can be effective against sporozoites and blood-stage parasites, but a cytotoxic cell response is needed to attack the critical liver stage, and antibodies are clearly needed to block transmission. Selecting the optimal antigens from among the stages in the parasite's life cycle and devising optimal formulations and delivery systems to elicit the desired immunologic response is a complex and difficult task, one that must be based on scientific knowledge, but will also require empirical testing of multiple potential vaccine products.

Current knowledge of protective immunity to malaria has been derived, in part, from studies of malaria in animals and from human trials of experimental vaccines. Animal studies have great value for elucidating immune mechanisms and for developing concepts and new approaches. Experiments in rodents, however, have very limited value for predicting human immune response to specific antigens and individual formulations, and work with primates is expensive and constrained by the limited availability of animals. Success will ultimately depend on a combination of continued research in animals and an accelerated development effort emphasizing



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 15
Vaccines Against Malaria: Hope in a Gathering Storm 4 Current Obstacles to Development THE SCIENCE Why is there still no effective malaria vaccine after decades of research and several development efforts? It may have been reasonable to expect failure in the early years of malaria research, given the lack of knowledge about the parasite and the pathogenesis of the disease and a limited understanding of immunology and immune function. Since then, however, both fundamental research and vaccine development efforts have greatly advanced our understanding of these issues. The limited success in malaria vaccine development reflects, in part, that needed answers of critical importance to product development efforts have neither been sought nor obtained in a systematic and coordinated way. Currently, for example, malaria vaccine research is being conducted on multiple fronts, employing different vaccine entities and research strategies. While such an approach has been extremely productive in expanding the fundamental knowledge base, it now appears that a more focused and coordinated strategy is needed for product selection and development. The scientific hurdles facing malaria vaccine developers are still imposing, however. There remains no known in vitro correlate of protection. The malaria parasite has multiple, immunologically distinct developmental stages and effective immune avoidance strategies. Single-antigen and single-stage vaccines have proved disappointing. Multi-antigen, multistage vaccines, which elicit different kinds of immune responses directed toward different antigens, appear more promising. High antibody levels can be effective against sporozoites and blood-stage parasites, but a cytotoxic cell response is needed to attack the critical liver stage, and antibodies are clearly needed to block transmission. Selecting the optimal antigens from among the stages in the parasite's life cycle and devising optimal formulations and delivery systems to elicit the desired immunologic response is a complex and difficult task, one that must be based on scientific knowledge, but will also require empirical testing of multiple potential vaccine products. Current knowledge of protective immunity to malaria has been derived, in part, from studies of malaria in animals and from human trials of experimental vaccines. Animal studies have great value for elucidating immune mechanisms and for developing concepts and new approaches. Experiments in rodents, however, have very limited value for predicting human immune response to specific antigens and individual formulations, and work with primates is expensive and constrained by the limited availability of animals. Success will ultimately depend on a combination of continued research in animals and an accelerated development effort emphasizing

OCR for page 15
Vaccines Against Malaria: Hope in a Gathering Storm early clinical trials of candidate vaccines in humans. Important information to be garnered includes the precise correlates of malarial immunity, the molecular basis for the duration of protection, and the necessary elements of the antigenic repertoire that must be included in an effective, multicomponent malaria vaccine. A substantial remaining problem in accelerating malaria vaccine research and development is the number of options that must be weighed and selected. Scores of parasite-derived proteins and parts of proteins have been identified, any of which may be important components of a useful vaccine. Several means for producing antigens, a number of new adjuvants, and new concepts such as nucleic acid vaccines and particle delivery systems must all be considered, and the most promising approaches tested, before substantial progress toward a new, effective malaria vaccine is ensured. COORDINATION There is currently no effective single locus of U.S. governmental activities directed toward malaria vaccine research and development. The Federal Malaria Vaccine Coordinating Committee (FMVCC) has attempted to fulfill this role, but lacks the authority and resources to do so (see Chapter 6 for a description of FMVCC). As a result, government-funded vaccine development remains disarticulated, with no overall strategy in place, and there is inadequate communication and coordination among malaria vaccine researchers and developers in government, academia, and industry. The consequences of this lack are profound. Representatives of industry at the workshop complained about the lack of a necessary “point of contact” in government that they could go to with questions or concerns relating to malaria vaccine product development. They noted that the lack of a federal strategy for vaccine development—one that necessarily focuses on a limited number of vaccine entities judged to have the highest probability of success—further discourages industry's involvement in malaria vaccine development. This lack of coordinated effort and strategic planning in the U.S. domestic arena extends to the international arena. As noted by the participants in the workshop, with the exception of FMVCC, there is no U.S. entity that effectively represents the views and concerns of the U.S. government, academia, and industry abroad.