? Has malaria finally met its scientific match? Victoria Gill finds out whether a fresh round of research funding could put an end to the killer disease BENOIST CARPENTIER BENOIST

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0408CW-MALARIA.indd 50 18/03/2008 15:06:18 When John F Kennedy told the from the ‘massive public-private gambiae mosquito (see box p62) – world in 1961 that America would In short partnership’ that has already started has also developed its own resistance put a man on the Moon by the end  A surge of funding to bear fruit. to insecticides. of the decade, he triggered one of has rekindled the fight The traditional malaria medicine the biggest scientific and technical against malaria Achieving the impossible in Africa had been chloroquine projects in history. ‘That challenge  Public-private Malaria currently kills more than – a cheap, synthetic derivative of is one that we are willing to accept, partnerships are key one million people every year – and quinine, a natural product extracted one we are unwilling to postpone, – bringing public funding causes 500 million more to become from the bark of the South American and one which we intend to win,’ he and private resources severely ill. More than 90 per cent cinchona tree. promised in a speech the following to the design of new of deaths are in sub-Saharan Africa, Chloroquine blocks the parasite’s year. treatments for the where malaria kills a child every 30 ability to digest the host’s red Kennedy could easily have been disease and insecticides seconds. blood cells. As the parasite feeds, it talking about the fight against against the mosquito that The figures are daunting for breaks down the oxygen-carrying malaria. Shortly after the second carries it anyone hoping to combat the disease. molecule haemoglobin, releasing world war ended, global eradication  The first clinically Yet malaria has been eradicated the iron-based haem unit. This is of malaria had seemed to be a trialled before. From 1945 to 1970, it was toxic to the parasite, which normally realistic goal. Wartime use of DDT will enter Phase III trials driven out of large swathes of East polymerises it into harmless had been particularly effective, and this year Asia, America, as well as Eastern and haemozoin chains. But chloroquine policymakers believed that all it Mediterranean Europe. enters the digestive vacuole of would take to stamp out malaria was But during that period, the most the malaria parasite and caps the enough money to supply insecticides vulnerable people in countries haemozoin chains, preventing and medicine. worst affected by the disease often further polymerisation and causing It is no small irony that by 1969, had poor access to the drugs and a build-up of toxic haem that when Kennedy’s vision was finally prevention measures they needed, eventually kills the parasite. achieved, most officials while civil wars and patchy funding However, mutations in the had concluded that the fight to also helped to kill off the eradication parasite have gradually reduced eradicate malaria had largely failed. campaign. chloroquine’s ability to create this Indeed, in many regions it had The biggest problem, though, blockage – a single alteration to a actually strengthened the disease’s was the fact that the protein that transports chloroquine grip. falciparum parasite, responsible for into the parasite can render the drug But now there is a renewed sense the most common form of malaria, useless. of optimism and confidence among An optimistic 1960s can mutate rapidly to build up The new gold standard of the scientists, medics and politicians poster advocated the use resistance to medicines. What’s treatment is now based on another who make it their life’s work to of insecticide sprays more, the parasite’s favoured mode natural product found in Artemisia battle the disease. It is bolstered of transport – via the annua, the Chinese wormwood plant. by an enormous fundraising effort It has been used for over 2000 years from the Global Fund to fight Aids, in traditional Chinese medicine, and tuberculosis and malaria; the World its active ingredient –

NLM / NIH / NLM Bank; the President’s malaria – was originally extracted and initiative; and other partners, all developed into an anti-malarial of whom coordinate their efforts drug by the Chinese government to under the umbrella of the Roll Back protect soldiers during the Vietnam Malaria Partnership. war. This surge of funding (with Artemisinin also operates in the particularly heavy-duty support parasite’s food vacuole, breaking from the Bill and Melinda Gates open its characteristic endoperoxide Foundation) has been a catalyst bridge in a reaction with the iron for action, and success is emerging present in haem and haemozoin (see from its public-private research box p63). partnerships – including the first This reaction releases toxic haem clinically effective malaria vaccine and a burst of free radicals into the that will enter Phase III trials later parasite. This new mode of action, this year. bypassing changes that have allowed Confidence is so high that chloroquine resistance to develop, is Margaret Chan, director-general what makes artemisinin so powerful. of the World Health Organization Serious lessons have been learned (WHO), now dares to talk about from past reliance on chloroquine’s eradicating malaria, rather than single mode of action, and the WHO merely controlling it. On 14 February now endorses the use of artemisinin the UN appointed a special envoy combination therapies (ACTs) that for malaria, Ray Chambers, a incorporate several antimalarial businessman and philanthropist agents – hitting multiple targets in who founded US-based organisation the parasite and offsetting the risk Malaria No More. of one powerful genetic mutation He calls the previous lack of overcoming the action of a drug. emphasis on eradicating malaria a ‘Initially none of the big ‘genocide of apathy’ and has pledged pharmaceutical companies were to raise $8–10 billion (£4–5 billion) interested in artemisinin – there over the next four to five years was no financial incentive because

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of where in the world the disease new malaria treatments. Its key focus be aware of the danger of over-use was a threat,’ says Bob Laverty, vice for the immediate future is on new ‘Both the of artemisinin too – new drugs are president of communications for ACTs. parasite and always needed.’ Novartis – the Swiss pharmaceutical ‘We work in direct partnerships One joint project with GSK company that makes Coartem, the with drug companies both to develop the mosquito has discovered that an antibiotic, most widely-used ACT in Africa. ‘But new drugs and to get them out to that carries it triclosan, which blocks fatty acid in the 1990s one of the companies patients in the field,’ says Tim Wells, synthesis, a process essential for that merged to form Novartis MMV’s chief scientific officer. In evolve rapidly bacterial growth, can have the same approached the Chinese government early-stage discovery projects, MMV to evade effect in . and expressed an interest.’ has teamed up with companies In a separate project, GSK/MMV The initiative that Novartis has including GSK and Novartis chemical scientists have identified a group embarked on is one of the many to identify compounds in their attack’ of small molecules that inhibit the public-private partnerships that have pipelines that could be developed activity of proteins called falcipains, formed the most important part of into anti-malarials. which also have an essential role the global, combined effort against ‘ACTs are like anti-malarial in the breakdown of haemoglobin. the disease. The financial risk of grenades,’ says Wells. ‘Artemisinin- Wells says that the next generation of developing a drug with no significant based drugs are combined with anti-malarials could be available by market is removed by the funding, others that have an entirely different as early as 2015. and companies are gladly offering mode of action to hit the parasite at their best scientists and resources multiple targets.’ In Coartem, for On alert to anti-malarial drug development example, artemether is combined As new drugs are rolled out, schemes. with lumefantrine, which blocks accurate the haem polymerisation pathway. becomes essential in order to avoid The next generation Lumefantrine is much longer acting prescribing them incorrectly. The Medicines for Malaria Venture than artemether, and provides Prudence Hamade leads (which gets around 60 per cent of its a back-up – protecting against the malaria working group for funding from the Gates Foundation), resurgence of the disease. Switzerland-based Médecins Sans also based in Switzerland, is one of ‘We have four new ACTs coming Frontières (MSF). In Sierra Leone, the non-profit organisations that onto the market in the next couple she has been involved in MSF’s funds and manages research into of years,’ says Wells. ‘But we need to ‘total malaria response unit’ – a pilot Malaria life cycle

NIAID Female Anopheles mosquitoes carry malaria parasites in their saliva, which they inject when they bite humans – the saliva also contains an enzyme that prevents blood from clotting, and allows the insect to have a decent meal (1). Parasites travel to the human victim’s liver as tiny sporozoites, which invade liver cells (2). Here they grow and divide, until tens of thousands of daughter cells (merozoites) escape the liver and enter the bloodstream where they invade red blood cells (3). While some of the parasites break down the red blood cells (and are continually released in a cycle of reinvasion), some transform into sexual forms of the parasite, called gametocytes, which are able to reproduce (4). When a mosquito bites and takes a blood meal from an infected human, it ingests these gametocytes, which mature, reproduce and divide in the mosquito’s gut (5). The eventual products of this parasite reproduction are malaria sporozoites, which travel to the mosquito’s salivary glands to start the whole cycle of infection again (6).

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0408CW-MALARIA.indd 52 19/03/2008 08:43:34 later this year – enabling healthcare Malaria molecules workers to pick the most effective ones from hundreds on the market.

N HO O Prevention is cure O N N H O A key part of the battle that will take a N O big step this year is the development H O H of an effective malaria vaccine. Cl Joe Coen, vice-president of R&D N O chloroquine H on emerging diseases and HIV at quinine artemisinin GSK Biologicals in Belgium, has spent over a decade formulating the company’s candidate vaccine RTS,S. He calls it his baby. RTS,S CH2 Cl CH3 uses a section from a protein called H circumsprozoite (CSP), which is C CH3 H H3C CH2 produced by the malaria parasite and N N OO was identified as a vaccine candidate H3C Cl Cl over two decades ago. CH Fe O Mutation of the parasite is once HC H H H again a key problem in vaccine design N N O CH – it is tricky to get the body’s immune CH 3 H3C 3 O system to recognise something that is C H HO N constantly changing. But the portion H CH3 of CSP used in this vaccine appears HOOC COOH artemether to survive mutations, so the body can be trained to recognise it as the signal haem B for an enemy invasion. lumefantrine ‘The original idea was to link the Cl OH CSP proteins to hepatitis B viral antigen and express the fused genes O in yeast cells. They self-assemble into virus-like particles,’ explains Cl Cl Coen. These synthetic viral particles should fool the immune system into triclosan responding as if to an infection. ‘But the first attempt to develop a vaccine project that trains local people to use haemozoin chains – thus making in 1987 failed.’ diagnostic kits, supplies treatments the protein an excellent indicator Coen’s team finally managed free of charge and distributes of the parasite’s presence, requiring to stimulate an immune response insecticide-treated bed nets. nothing more than a drop of blood with a vital extra ingredient, known She points out that poorly- and a buffer solution to identify. as an adjuvant. Immunologic organised drug distribution has According to Hamade, the WHO The female Anopheles adjuvants have no effect on their already caused more long-term plans to publish a list of its tried, gambiae – an efficient own, but are used to enhance the problems than it has solved. tested and approved diagnostic tests malaria transporter effect of a vaccine – in this case the ‘Diagnosis is absolutely fundamental. Because the old anti-malarial drugs were so cheap, they were distributed very freely and administered whenever someone developed malaria symptoms. But the symptoms are so broadly indicative – a fever, headache, flu-like symptoms – that could be caused by a variety of other diseases, such as typhoid. The liberal use of chloroquine has now resulted in widespread drug resistance in the parasite.’ Hamade’s project uses simple diagnostic kits that provide a result within 15 minutes. The tests use a cellulose strip containing a band of antibodies that bind to a malaria biomarker called histidine-rich protein II. The malaria parasite uses this protein to convert the toxic haem produced as it feeds into harmless USDA-ARS www.chemistryworld.org Chemistry World | April 2008 | 53 Malaria

Tropical Medicine, UK explains that there are two kinds of resistance. ‘A mutation that changes the target site can disrupt, for example, the binding of the insecticide

agent,’ she says. But the PROJECT ATLAS MALARIA parasite can also develop metabolic resistance: ‘an up-regulation of the production of enzymes which allows the insect to metabolise the chemical’. Only four types of insecticide are approved by the WHO for indoor

Global malaria The first spatial map of global malaria risk to be produced in four decades shows that many of the people exposed to malaria are at a lower risk than previously thought. The (MAP) found1 that 2.37 billion people are at risk of contracting malaria from Plasmodium falciparum – but about 1 billion of them live under a much lower risk of infection than was assumed by previous historical maps. ‘This gives some hope of pursuing malaria elimination because the prevalence isn’t as universally high as many people suppose,’ says David Smith, a University of Florida associate professor of zoology and a co-author spraying: of the paper. DDT, pyrethroids, organophosphates 1 C A Guerra et al. PLoS Med, 2008, 5, e38. DOI:10.1371/journal.pmed.0050038 and carbamates (see box). All of these target specific proteins essential in the function of the insect’s addition of an aluminium salt made Pest control nervous system – either sodium all the difference, although the Where malaria has been successfully channel proteins at the membrane exact mechanism is unclear. ‘The eradicated, it has been insecticides between nerve and muscle, or the development of a better adjuvant rather than medicines that have acetylcholinesterase enzyme that system was the second part of the made the biggest impact. The breaks down a key neurotransmitter. project,’ says Coen. ‘We were able to distribution of insecticide-treated These proteins are sufficiently improve the vaccine and got our first bed nets and indoor spraying is a unique to the insect – distinguishable positive clinical result in 1996 – it was major preventative approach. In the from mammalian proteins – to allow a tremendous breakthrough.’ last three years, washable treated bed them to be used with a relatively low He praises the financial support, nets have become available. Rather risk of human nerve damage. particularly of the Gates foundation, than forming a temporary coating on Even so, human toxicity issues for reviving the project. And in Phase the outside of the net, the insecticide mean that of the four types, only II, results have been promising. is dispersed throughout the polymer pyrethroids can be used in the Importantly, the vaccine appears to fibres so that it gradually diffuses ‘There is light bed nets themselves. ‘You have to be effective in very young children, to the surface and is continuously at the end of assume that babies will be sucking who are most vulnerable to the replaced as the net is washed. the nets, whereas they’re unlikely disease. The GSK team is now poised But the mosquito, like the parasite the tunnel to be sucking the walls,’ says Tom for the make or break Phase III it carries, is not a willing victim – we have a McLean, senior executive officer trials. ‘I now see a light at the end of – it evolves rapidly to evade such of the Innovative vector control the tunnel – this is a potentially life- chemical weapons. Hilary Ranson potentially life- consortium (IVCC), who is also saving vaccine,’ says Coen. from the Liverpool School of saving vaccine’ based at the Liverpool School of 54 | Chemistry World | April 2008 www.chemistryworld.org

0408CW-MALARIA.indd 54 19/03/2008 08:44:43 Tropical Medicine. The IVCC was set up to address Supply and demand the lack of development of new insecticides against the malaria- One problem with artemisinin carrying mosquito, and received combination therapies (ACTs) a £50 million Gates Foundation is that their shelf life can be as grant in 2005. ‘Half of our grant will little as three years – a major be spent on information systems,’ concern when delivering drugs explains McLean. ‘We’re developing to remote regions lacking tools to tell researchers what the fundamental infrastructure is so insects are resistant to – databases difficult. of insecticides, where they are being One project based at the used and signs of resistance – so University of York in the UK has that insecticide exposure can be started to address the issue coordinated properly. We’ve also of artemisinin supply. The designed lab kits that are in field university’s Centre for Novel trials in Africa at the moment, and Agricultural Products (CNAP)

we will have early versions available received a $13.6 million (£7 ALAMY this year.’ The kits consist of specific million) grant from the Gates Artemesia annua reagents which highlight the DNA Foundation for a fast-track markers of resistance. breeding research programme are rapidly producing plants points out that a balance needs IVCC is also working with for the Artemisia annua plant. with bigger leaves and larger to be struck between supply and agrochemical companies, The goal is to optimise the plant leaf glands that contain the vital demand to make it sustainable. including Bayer and Syngenta, for high-yielding agricultural ingredient. ‘This glut will turn into a deficit to develop new insecticides. production, explains Elspeth There have been recent as more farmers turn away in ‘The public health market is Bartlet, a spokesperson from the concerns about overproduction favour of more profitable crops, not big enough to support the university. With a combination of of artemisinin threatening the such as biofuels. We need commercial development of genetic screening and selective industry (see Chemistry World, to make this crop [Artemisia a new insecticide – which breeding, the CNAP researchers January 2008, p6). But Bartlet annua] profitable.’ from bench to market takes 12–15 years and costs up to $250 million,’ says been carried out, in theory they could they are more accepting of them.’ McLean. ‘But if we can be brought onto the public health The offer of free bed nets is also used absorb the financial risks of market within five years. as an incentive to persuade families development, the companies and pregnant women to attend are more than happy to supply For the people treatment and infant vaccination the resources and do the work.’ Back in Africa, field workers like clinics. Wells points out that, for As well as developing new Hamade and Wells are acutely aware children, something as simple as insecticides from the bench, part of the gap between major innovative disguising the unpleasant taste of of this project involves scouring steps in scientific research, and the medicines can make a significant company pipelines for insecticides practicalities of life in a poverty- difference in how well they stick to that could be used against the stricken malaria region. their drug regimens – cherry flavour mosquitoes, and reviving their ‘People used to reject the bed nets works particularly well. development specifically for that because they found them too hot,’ It’s clear that every piece of this purpose. Since many of these says Hamade. ‘But many people are colossal jigsaw counts. Malaria was chemicals are already registered, and now finding that they can also help underestimated once, and the fight laborious toxicology work has already them to get a good night’s sleep, so against it failed, allowing an even more deadly disease to bounce back. Importantly, the current approach Approved insecticides incorporates research projects that will find out if prevention and treatment measures are actually compatible with people’s lives. The Global Fund’s project aims to halve deaths from tuberculosis and malaria by 2015, and the proof of their strategy will be in those DDT deltamethrin (a pyrethroid) disease’s stark mortality figures. But with a long-term commitment of resources in place, scientists can at least work to arm those on the front line with a fresh set of weapons against malaria. Further reading  Médecins Sans Frontières: www.doctorswith- outborders.org/news/malaria/index.cfm  Medicines for Malaria Venture: www.mmv.org bendiocarb (a carbamate) chlorpyrifos-methyl (an organophosphate)  Innovative Vector Control Consortium: www.ivcc.com  Roll Back Malaria: www.rbm.who.int

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