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EMBO reports 5, 9, 847–851 (2004)
doi:10.1038/sj.embor.7400244
Fighting malaria at the crossroads
The tools to battle the disease exist, but the lack of political will in developed nations jeopardizes their success
Andrea Rinaldi
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Every year, malaria kills between 1 and 3 million people—mostly children under five years of age and pregnant women—and newly infects 300 million to 500 million. But malaria is by no means a problem for developed countries, where it was defeated a long time ago. This is the main obstacle to the fight against the disease: as measures to curb malaria are predominantly financed by rich countries who are not affected by the disease, there is little incentive for them to provide sufficient attention and money towards finding effective solutions for treatment and prevention. In the meantime, the situation in poor countries is alarming, particularly in Africa where 90% of the global deaths and infections occur. Not only does malaria seize young lives, but it also cripples the economies of afflicted nations. The World Health Organization (WHO) estimates that malaria costs some 1.3% of the annual gross domestic product of the states in which the disease flourishes; their economies have been cut by more than 30% since 1960 as a result of decreases in fertility, population growth, saving and investment, and worker productivity, coupled with increases in absenteeism, premature mortality and medical costs. In some parts of Africa, families spend as much as 25% of their income on malaria treatments. Even worse, the burden of malaria continues to increase due to widespread parasite resistance to existing drugs, the geographic expansion of insecticide-resistant Anopheles mosquitoes (Fig 1) and a chronic infrastructural and organizational inability to tackle the problem. The Africa Malaria Report 2003 stated that in some parts of Africa the number of children killed by malaria doubled between the 1980s and 1990s (WHO & UNICEF, 2003). Thus, what was once thought to be a possible target for eradication is now considered to be an 'emerging disease'.
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What was once thought to be a possible target for eradication is now considered to be an 'emerging disease'
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Figure 1
An Anopheles stephensi mosquito, a known malaria vector, feeding. © Centers for Disease Control and Prevention, Atlanta, GA, USA/Dr William Collins
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Nevertheless, the blight finally seems back on the political agenda of developed nations and international institutions. Roll Back Malaria (RBM; http://www.rbm.who.int), a global partnership that includes the WHO and the United Nations, was launched in 1998, and endorsed two years later by African heads of state in Abuja, Nigeria, with a commitment to halve the number of deaths from malaria worldwide by 2010. The Geneva-based Global Fund to Fight AIDS, Tuberculosis and Malaria—financed by developed nations—now provides resources for a variety of malaria programmes, and even private donors are becoming aware of the problem: the Bill & Melinda Gates Foundation awarded US$168 million—to be used as grants for malaria initiatives—the biggest ever single donation for the disease. On the research front, the genomes of both the insect vector Anopheles gambiae and the parasite Plasmodium falciparum have been sequenced (Holt et al, 2002; Gardner et al, 2002), which will lead to a better understanding of host–parasite and vector–human interactions at the molecular level. At the same time, progress has been made over the past decade on other aspects of the disease, from drugs (Fidock et al, 2004; http://www.mmv.org) to vaccines (Webster & Hill, 2003; http://www.malariavaccine.org), and from transgenic approaches for mosquito control (Nirmala & James, 2003) to the development of new insecticides (Borovsky, 2003).
Research on the vector and parasite genomes suggests that blocking transmission in the mosquito could become an effective way to stop the disease. Fotis Kafatos's research group at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, has recently identified three mosquito genes that control the insect's immune response to Plasmodium (Osta et al, 2004). They showed that two insect C-type lectin (CTL) proteins protect the parasite from the Anopheles innate immune system as it develops in the mosquito gut, whereas a third leucine-rich repeat immune (LRIM) protein has the opposite effect. Selective gene silencing of CTLs resulted in the death of invading parasites in massive numbers, whereas inactivation of the LRIM gene led to a substantial increase in Plasmodium numbers. Thus, modulation of these proteins could expose the parasite to the mosquito's immune system, offering real options for fighting the disease in the insect before it is passed to humans, according to Kafatos. Another EMBL team led by Elena Levashina demonstrated that a mosquito glycoprotein, TEP1, binds to and mediates the killing of midgut stages of the parasite (Blandin et al, 2004). Taken together, TEP1 and LRIM studies show that it may be possible to block the parasite–mosquito cycle by enhancing the mosquito immune system, according to the TEP1 article's lead author Stephanie Blandin.
On another front, the quest for a malaria vaccine is still being actively pursued, although an effective jab has remained elusive for decades. One proponent of this approach, Stephen Hoffman, previously at Celera Genomics where he worked on sequencing the A. gambiae genome, has founded a company named Sanaria (Rockville, MD, USA) to "develop and commercialize a safe and effective malaria vaccine in seven years," and is obtaining funds from public and private sources. In fact, new results from his research are raising hopes. Based on the classic idea of using irradiated sporozoites—the parasite stage that infects the liver—Hoffman showed that up to 90% of human recipients were protected following bites from more than 1,000 irradiated, infected mosquitoes (Hoffman et al, 2002). His plan is to obtain attenuated sporozoites from infected and irradiated mosquitoes bred by the millions in the lab, and use them directly as a vaccine.
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... it may be possible to block the parasite–mosquito cycle by enhancing the mosquito immune system...
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However, Margaret Mackinnon and Andrew Read at the University of Edinburgh, UK, have recently shown that vaccines against malaria could cause the parasite to evolve into an even more deadly form (Mackinnon & Read, 2004). Performing an experimental evolution of the rodent malaria parasite, Plasmodium chabaudi, in immunized and naive mice, they found that parasites that evolved in immunized mice were more virulent than parasites that evolved in naive mice. If host immunity does indeed increase virulence in malaria pathogens, they fear all efforts devoted to vaccine development might be crippled. Read cautioned that vaccines should not be hailed as a magic bullet, and stressed that his and Mackinnon's observations reinforce the need to explore alternative strategies to eliminate malaria (Pearson, 2004).
"Antimalaria strategies must seek irreversible end-points, goals that will permit intervention coverage to be reduced. This is particularly critical in the case of malaria because immunity is 'disease-modifying' rather than 'sterilizing'," said Andrew Spielman from the School of Public Health and Center for International Development at Harvard University (Boston, MA, USA). "Where malaria is highly endemic, everyone is infected and relatively few residents are symptomatic. A transiently successful intervention, therefore, would eventually increase everyone's vulnerability to this disease. This implies that we should not expect too much from the use of drugs or insecticides because of resistance, and from vaccines," Spielman cautioned. "Fundamental improvement in the malaria situation probably will depend upon environmental management and home improvement." Mackinnon believes a better deployment of existing devices, which block transmission at the vector level and reduce the length of time that people are infectious to mosquitoes, should be attempted. "In the meantime, we should be examining the impact of any potential control measure on transmission, and on the parasite's evolutionary response to it," she said.
But although effective strategies exist, they are not used owing to a lack of political will. The outcry over this dismal situation was launched in the pages of the Lancet by Amir Attaran and colleagues of the Royal Institute of International Affairs in London (Attaran et al, 2004). "With nearly half the time to the 2010 deadline now past, progress on effective treatment is so inadequate that Roll Back Malaria is failing to reach its targets," they wrote. The main reason behind the increase in malaria deaths, they continued, is drug resistance in P. falciparum caused by the continuing use of outdated drugs, such as chloroquine and sulphadoxine-pyrimethamine, which are largely ineffective in most parts of Africa. This leaves only one possibility: artemisinin. This natural compound and its derivatives have proved to be very effective in treating different forms of the disease, killing parasites resistant to other drugs and avoiding the development of resistance in P. falciparum. A meta-analysis demonstrated the efficacy of artemisinin-class combination therapies (ACTs) by showing that 90% of patients could be successfully treated in just three days by adding artemisinin compounds to standard drug regimens (International Artemisinin Study Group, 2004). Another combination of an artemisinin with the recently released antimalarial chlorproguanil-dapsone (Lapdap) is now being investigated (Alloueche et al, 2004).
However, it is scandalous, accuse Attaran and his co-authors in the Lancet article, that although the WHO openly admits the failure of old drugs and recommends ACT as the therapy of choice in areas where malaria ravages, the organization and the Global Fund continue to finance African countries for the purchase of only chloroquine and/or sulphadoxine-pyrimethamine, while actively discouraging them from switching to artemisinins. The reason is the significant unit price difference between chloroquine (US$0.13), sulphadoxine-pyrimethamine (US$0.14) and ACT (US$1.00–3.00). Instead of signing the new cheque, major supporters of the WHO and Global Fund, such as the USA and UK, have pressured grant-receiving governments to avoid artemisinins (Butler, 2004).
Another critical strategy is the use of insecticide-impregnated bed nets, which are so effective in preventing infection and reducing childhood mortality from malaria that RBM has made it one of its key strategies, aiming to put 60% of those who need it under a treated net by 2005. But with little time remaining, only 2% of children sleep under these nets at present, signalling that current schemes for the distribution of nets to poor communities are not appropriate for achieving the targets agreed on in Abuja. A novel 'proactive pro-poor strategy' was proposed to link bed-net distribution to other existing disease-control programmes, which would reduce operational costs and at the same time offer additional health benefits (Molyneux & Nantulya, 2004).
An even more controversial issue is the use of dichloro-diphenyl-trichloroethane—commonly known as DDT—to control infected mosquitoes. DDT has a long history in Europe and North America (Figs 2, 3); it was widely used in agriculture as a pesticide and was instrumental in wiping out malaria in these continents and in large parts of Asia and Latin America. Now, several African countries are seriously reconsidering the use of DDT to control malaria in their most afflicted territories. What makes DDT so attractive is that it is much cheaper than the commonly used pyrethroid insecticides and it is very effective. Moreover, mosquito resistance to DDT has not yet been reported, whereas it is rapidly spreading for pyrethroids. But the problem with DDT—now banned almost worldwide—rests with its persistence in the ecosystem, where it accumulates along food chains and causes widespread environmental damage.
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Figure 2
A Stearman bi-plane spraying an insecticide during malaria control operations in Savannah, GA, USA. © Centers for Disease Control and Prevention, Atlanta, GA, USA. Year unknown.
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Figure 3
The National Malaria Eradication Program in the USA, starting in 1947, used DDT spraying to control mosquitoes. © Centers for Disease Control and Prevention, Atlanta, GA, USA. Year unknown.
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Building on past experience, this time DDT will be used more wisely, and only in small quantities for spraying homes to kill mosquitoes that rest on the walls and bite at night. This method has proved to be both remarkably safe for people—as it probably is for the environment—and effective in controlling the spread of infection. South Africa is leading the small patrol of nations that use DDT for routine malaria control, and the results speak for themselves. Malaria cases soared in the KwaZulu Natal province of South Africa after it stopped using DDT in 1996, and its reintroduction in 2000 brought the disease back under control. That is enough for other countries, such as Uganda and Kenya, to examine whether DDT could also work for them. The Ugandan Minister of Health, Jim Muhwezi, recently defended the plan to use DDT for indoor spraying in his country, emphasizing the need for a proactive rather than reactive strategy against malaria (Wendo, 2004).
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"DDT is a victim of its success, having so thoroughly eliminated malaria in wealthy nations that we forget why we once needed it."
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So why then is DDT not the weapon of choice to eradicate malaria? The answer is: simply because of its bad reputation in the USA and Europe. For this reason, major donors, such as the Global Fund and the US Agency for International Development, do not finance its use and the WHO dissuades poor countries from adopting it. This does not make any sense to some critics; for example Tina Rosenberg from the New York Times argues that environmental concerns about DDT in wealthy nations cripple African populations suffering from malaria (Rosenberg, 2004). "Given the malignant history of American companies employing dangerous drugs and pesticides overseas that they would not or could not use at home, it is understandable why Washington officials say it would be hypocritical to finance DDT in poor nations," Rosenberg wrote in her harshly critical article. "But children sick with malaria might perceive a more deadly hypocrisy in our failure to do so: America and Europe used DDT irresponsibly to wipe out malaria. Once we discovered it was harming the ecosystem, we made even its safe use impossible for far poorer and sicker nations." The moral of this story, remarked Rosenberg, is that "DDT is a victim of its success, having so thoroughly eliminated malaria in wealthy nations that we forget why we once needed it."
What is at risk is antimalarial action on a global scale. "The question now is whether the campaign can be saved," commented Gavin Yamey, assistant editor of BMJ Learning, on the looming failure of the RBM initiative (Yamey, 2004). "We have the three tools we need to curb malaria deaths: bed nets, effective combination treatment based on artemisinin, and insecticides. What we urgently need to do is make these tools much more widely available to affected communities, which are almost always too poor to pay for them themselves." Comparing it to AIDS activism that has brought affordable HIV therapy to some of the world's poorest countries, he argued for a similar 'malaria activism' to increase funding. Activism apparently has started: the Global Fund has decided to revise all malaria grants awarded to African countries to specify only artemisinin-based therapies and to stipulate their use in future funding (Butler, 2004). Furthermore, the agency is planning to finance some DDT spraying in Somalia (Rosenberg, 2004).
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"We have the three tools we need to curb malaria deaths: bed nets, effective combination treatment based on artemisinin, and insecticides. What we urgently need to do is make these tools much more widely available to affected communities..."
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On the basis of current research, 'high-tech' molecular approaches to fight malaria will probably be possible within 10–20 years. These will be based on vaccines, mosquitoes genetically modified to be resistant to parasitic infection and transmission, and new antimalarial drugs and insecticides. In the meantime, low-tech solutions are available that—if applied effectively—might save Africa from its tragic destiny. We are at the crossroads. While researchers follow the path towards scientific advances for malaria control, the path leading to the political and financial implementation of existing effective measures is still in the shadows.
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References
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