Collaborative Efforts Under Way To Combat Malaria

Sidebars Malaria: A Statistical Index Funding Agencies For Malaria Research Researchers in the field lament what they call gross underfunding, but say a joint approach will help ensure that avaliable monies are well spent. After several years of declining interest in malaria research and decreasing support for such studies, the field is gaining much-needed momentum. Spurred in part by an international conference held in Dakar, Senegal, in January, funding agencies and scientists around the globe are planning unprecedented cooperative research and development programs to combat the disease. Each year, malaria kills between 1.5 million and 2.7 million people-mainly children younger than five years of age-according to the World Health Organization (WHO). An estimated 300 million to 500 million clinical cases of the disease occur annually, of which about 90 percent appear in sub-Saharan Africa. CHICKEN OR EGG: Countries too poor to control malaria suffer more economic losses as workers become ill, observes USAIDs Carter Diggs. Countries hit hardest by malaria are trapped in a vicious cycle, says Carter Diggs, senior technical adviser for the Malaria Vaccine Development Program at the United States Agency for International Development (USAID). They are too poor to provide adequate medical and insect-control measures to combat the disease; thus, their economies further suffer as a result of a debilitated work force. "Many people would agree that malaria declines with economic development," Diggs observes. "But the problem is, what comes first: economic development or health?" Despite malaria's staggering toll in both morbidity and mortality, research on the disease receives a fraction of the funds spent globally on less-deadly diseases, including asthma, cancer, and AIDS, according to a report issued last September by Britain's Wellcome Trust (J. Anderson et al., Malaria Research: An Audit of International Activity, London, Wellcome Trust, 1996). It's unlikely that this funding gap will be closed anytime soon. But increased international cooperation-particularly between funding agencies and researchers in developed countries and those in Africa-should promote better use of limited resources, advocates say. In the future, money may follow, especially if pharmaceutical companies return to the pursuit of malaria drugs and vaccines, which the drug industry has all but completely abandoned. "Malaria is too big a problem for any one organization to tackle," says Tim Stanley, project manager for London-based Glaxo Wellcome plc's new anti-malaria drug, Malarone. The company has a long history of research on tropical diseases and is one of the few pharmaceutical firms currently working on malaria, he notes. In conjunction with WHO and several other governmental and charitable organizations, Glaxo Wellcome is developing a controlled donation program for Malarone to ensure effective use in patients with the greatest need. "I won't presume to say why other companies are not investing in malaria research," Stanley adds, "but I'd guess that potential returns are greater in other areas." At Glaxo Wellcome, he explains, "we don't spend as much on malaria research as on asthma or HIV. But we think it would be wrong for us to ignore a disease that still has such a devastating effect on so many people." Efforts to build a coordinated global strategy for malaria control, spearheaded by the National Institutes of Health and France's Institut Pasteur, now involve several major international entities, including WHO, USAID, and the European Union (EU), as well as private charities such as Britain's Wellcome Trust. Representatives from these and other agencies joined with members of the malaria research community in Dakar to propose new strategies to confront the disease. Lee Hall, host immunity program officer in NIAID's Microbiology and Infectious Diseases division "This is a time of great opportunity in malaria research," says Michael Gottlieb, program officer for parasite biology and for international tropical disease research at the National Institute of Allergy and Infectious Diseases (NIAID), who participated in the Dakar meeting. Recent advances, particularly in genetics and molecular biology, should afford scientists a clearer understanding of this extraordinarily complex disease. However, he notes, "we need better infrastructure to support research and drug development, and better communication between . . . scientists [in developed countries] and those in Africa." A major feature article on malaria research published last month in Nature (D. Butler et al., Nature, 386:535-40, 1997) was accompanied by a "call to action" letter from meeting participants (J.-M. Bruno et al., Nature, 386:541, 1997). The letter, signed by 16 individuals, said: "The challenge is enormous. New drugs must be found to prevent and treat the disease, and vaccines need to be developed. This requires research at every level. . . . The urgent need is to put malaria on the scientific, media, and political agenda, and in particular to identify it as a priority for research, both in the developed North and in those areas of the South where the disease is endemic." Although lack of funding has significantly impeded malaria research, it is hardly the only barrier to controlling the disease. Much remains to be learned about the basic biology, epidemiology, and pathophysiology of malaria, which is caused by four different species of the protozoan parasite Plasmodium and transmitted by mosquitoes. ON THE SPOT: Johns Hopkins' Clive Shiff notes that understanding malaria depends on collaborative studies of the disease in areas where it occurs. "There are fundamental questions to be asked about how malaria affects humans in endemic situations," says Clive Shiff, a professor in the Johns Hopkins School of Public Health. For example, "we don't know all the factors that are involved in the development of resistance to malaria." Answering such questions will require decades-long community studies in endemic areas, but few such programs currently exist, Shiff notes. "In the [United States], we tend to fund interventions on the order of four to five years," he points out. "Until we set up collaborative studies of the disease in locations where it occurs, we have little chance of understanding malaria." This situation is further complicated by the fact that malaria as a disease varies widely from location to location, according to Lee Hall, host immunity program officer in NIAID's Microbiology and Infectious Diseases division. "Malaria doesn't fit our conventional vaccine paradigms, which are largely based on acute viral and bacterial diseases," he explains. The disease is tough to pin down not only because of the different species of malarial parasite, but also because of the human reaction to infection, which can range from the development of resistance to death. Thus, before a vaccine can be perfected, scientists "will need to learn how to deal with a system characterized by both parasite diversity and significantly heterogeneous host responses," Hall says. Nevertheless, many-but not all-tropical disease researchers consider vaccines to be the most promising means of controlling malaria. Several candidate antigens and their genes have been identified in recent years, and a few are entering experimental trials. Government agencies such as the U.S. Department of Defense, USAID, NIH, and Britain's Medical Research Council (MRC), along with philanthropic foundations, have provided funding for vaccine development. But some researchers contend that vaccine studies claim a disproportionate share of malaria research funds. "Since 1980, there has been an overemphasis on vaccine development at the cost of more basic research [on malaria]," states parasitologist Mike Hollingdale of the University of Leeds in England. "As a result, there are far fewer younger researchers in the field." He continues, "Read immunological journals and you will see repetitious research, especially in mice, that achieves little that is new. Perhaps only the NIH and a few academic groups retain an interest [in basic studies of malaria]." Meanwhile, public health researchers such as Jo Lines, a professor at the London School of Hygiene and Tropical Medicine, observe that "more money goes into basic research [such as the sequencing of the Plasmodium genome] and looking for new tools than into the sensible application of current tools, [such as] how to optimize the use of anti-malaria drugs." Research into the social, economic, and practical aspects of malaria treatment is drastically underfunded, Lines asserts. And when agencies do address so-called operational questions, he adds, "funding is often allocated by people who are not in and have very little experience of working in Africa and other malarious countries." Thus, he observes, such committees "often make mistaken assumptions about the situation 'out there.'" Extending basic science on tropical diseases into the clinic is a "weak link" in U.S.-funded research, agrees NIAID's Hall. "If a novel intervention were discovered today, we wouldn't know how to take advantage of it without first doing a great deal of clinical and field research," he says. "We need more research across the board, from basic science all the way to clinical studies." "The problems underlying malaria control are enormous-too large for any single agency to address," Hall concludes. As the leading American supporter of malaria research, NIAID supports approximately 80 research projects at U.S. universities, as well as a substantial intramural effort in its Laboratory of Parasitic Diseases, according to Hall. The National Heart, Lung and Blood Institute; the National Institute of General Medical Sciences; and the National Institute of Diabetes and Digestive and Kidney Diseases also fund malaria research. However, Hall says, "NIAID is the lead institute and has by far the largest number of research projects on malaria, especially those that focus principally on malaria per se. The other institutes have research interests that overlap, such as red blood cell membrane projects, [and] blood group antigens." That opinion appears to be shared by NIH director Harold Varmus. At the Dakar meeting, he championed a sustained, internationally coordinated, multilateral malaria research effort. After the conference, nine sources-including NIH, EU, Institut Pasteur, MRC, Wellcome Trust, and WHO-jointly issued a request for letters of interest for proposals on collaborative projects, but no funding commitments have yet been made. In advance of any major increases in research dollars, the first goal of this newly formed Multilateral Research Initiative is to enhance collaboration among researchers around the globe, and particularly between those in developed countries and in Africa. Economic hardship, political turmoil, and poor communications networks have plagued researchers in developing countries, but African researchers also have been frustrated by the terms of previous collaborations. When African representatives at the meeting were asked about the obstacles to progress in collaborative malaria research, many complained that resources for such projects had been unfairly distributed between them and their colleagues in the U.S. and Europe, according to Lines. Several African scientists also reported that they had had little influence in decisions as to which research questions would be explored in collaborative projects. "Research is needed in Africa," agrees South African biochemist J.P. Dean Goldring of the University of Witwatersrand in Johannesburg, "but not a group of U.S. or European scientists coming in and doing their thing. Locals must be involved at all levels, and not just politically," contends Goldring, who has studied the disease in the U.S., the United Kingdom, and Malawi, as well as in South Africa. One collaborative project under way-an effort to plot the geographical incidence of malaria on the map of Africa-may provide a possible model for future joint research programs. Known as MARA (Mapping Malarial Risk in Africa), the project involves researchers from the U.S., Europe, and Africa and is funded by Canada's International Development Research Centre, WHO, and the Wellcome Trust. Similarly, WHO and the World Bank are studying the possible launch of a 30-year, multiagency program to control the disease. If approved, the project-known as the African Malaria Initiative-could commence around 2000. For the moment, Dakar conferees are pursuing two specific short-term objectives identified at the meeting: providing E-mail and Internet access for African research institutions and developing a pool of funds for multicenter malaria studies. These funds would be used to establish common protocols, materials, and databases for analyzing results from multiple sites. A follow-up to the Dakar conference is scheduled to take place in July in The Hague. "I'm actually quite optimistic that we can make a significant impact on malaria," Hall says. But, he warns, "it won't happen overnight." Number of clinical cases per year: 300 million to 500 million Number of deaths per year: 1.5 million to 2.7 million, about 4 percent to 5 percent of all fatalities Rank among major infectious diseases in mortality rates: 3rd (after pneumococcal acute respiratory infections and tuberculosis) Occurrence: 90 percent of all cases in sub-Saharan Africa; two-thirds of remaining cases in six countries: India, Brazil, Sri Lanka, Vietnam, Colombia, Solomon Islands (in descending order) Population affected: 2.4 billion people, about 40 percent of the world's population Estimated global annual direct and indirect costs (including lost labor) in 1995: $2 billion Estimated worldwide expenditure on malaria research, prevention, and treatment (1993): $84 million Estimated worldwide expenditure per malaria fatality (ca. 1990): $65; as compared with HIV/AIDS, $3,274 and asthma, $789 Sources: World Health Organization, Wellcome Trust National Institute of Allergy and Infectious Diseases Contact: Michael Gottlieb or Lee Hall Parasitology and International Programs Branch Solar Building/Room 3A12, Bethesda, Md. 20892-7630 Tel:(301) 496-2544 Fax: (301) 402-0659 E-mail: mg35s@nih.gov (Gottlieb) or bh24q@nih.gov (Hall) Web site: http://www.niaid.nih.gov UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) TDR Communications Ave Appia, 1211 Geneva 27, Switzerland Tel: 41 22 791 3725 Fax: 41 22 791 4854 E-mail: tdrnews@who.ch Web site: http://www.who.ch Burroughs Wellcome Fund 4709 Creekstone Dr., Suite 100, Durham, N.C. 27703 Tel: (919) 991-5100 Fax: (919) 941-5884 E-mail: mailback@bwfund.org Web Site: http://www.bwfund.org/bwfund The Malaria Foundation Mary R. Galinski, President 3 Washington Square Village, Suite 10F, New York, N.Y. 10012 Phone/Fax: (212) 979-7876 Email: MF@malaria.org Web Site: http://www.malaria.org Alison Mack is a freelance science and medical writer based in Wilmington, Del.

Collaborative Efforts Under Way To Combat Malaria

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