Female Anopheles mosquito sucking blood from a human. Credit: Shutterstock / Amir Ridhwan

Oxford and the mosquito

If world health chiefs don’t listen we’ll see a new pandemic, warns top Oxford malaria expert

By John Garth

The world’s number-one treatment for malaria is on the brink of failure because of a new strain of drug-resistant parasites — unless health policymakers take action. That’s the warning from the Oxford University scientist who first ushered the treatment onto the world stage.

Sir Nicholas White says that the mosquito-borne parasite responsible for severe malaria is now showing resistance to the prime treatment, Artemisinin Combination Therapy (ACT), across South-East Asia. If this resistance jumps to Africa, he warns, the tragedy will be on a massive scale.

Professor Sir Nicholas White

Darwinian evolution means the parasites that survive the encounter with ACT pass on their resistance, and their offspring will proliferate increasingly while their non-resistant cousins are killed off. One factor in the rise of resistance is the pernicious trade in fake medicines. At stake are not only the lives of millions now and in the near future, but also the possibility that malaria might be eradicated for good.

Worldwide, 15 years ago malaria was killing more than a million children a year — above 3,000 every day. ‘We don’t want to get back to those sorts of numbers,’ says Professor White.

When a leading Oxford expert on malaria such as White talks about the disease, it is worth listening. Oxford’s role in tackling malaria is both longstanding and truly outstanding. ‘Of all world universities Oxford is pretty much top for malaria research,’ says Professor Kevin Marsh, who headed its Kenya research unit for a quarter century. And among the many researchers in the University’s far-flung tropical disease network, Nick White stands tall. According to the Director of the Wellcome Unit for the History of Medicine, Professor Mark Harrison, he is ‘probably the premier clinical researcher in malaria’ in the world.

Of all world universities Oxford is pretty much top for malaria research

With fellow researchers White issued a paper in The Lancet Infectious Diseases in February [2017] warning about the new wave of resistance. But he fears policymakers are still not listening closely enough. ‘Whilst recognising this is a potentially serious situation, the true gravity has not been appreciated by the international organisations,’ he says.

‘There’s a lot that can be done but I’m not sure it will be done. Our role is to provide the scientific evidence, even if its unpalatable, but it’s the job of the international agencies and the national programmes to respond to that. Whether they will do that effectively to stop artemisinin resistance is very uncertain.’

In the field: Thai–Myanmar border

The name malaria, coined in the early 18th century, comes from the Italian for ‘bad air’, and the belief that some swampy miasma lay behind the disease. The role of the mosquito as a vector for tropical disease has been known since the 1870s. Malaria is passed on by the parasite Plasmodium, which is carried by the Anopheles genus of mosquito. The classic treatment was quinine, followed or accompanied by a generation of artificial treatments from the 1950s. But the Plasmodium parasite in its various forms is a protean and evasive enemy, and new treatments such as mefloquine, developed in the 1970s, could not long be entirely effective against it either.

The 1979 collaboration between Oxford’s Nuffield Department of Medicine in Oxford and Bangkok’s Mahidol University was to prove a vital step forward. Funded by the Wellcome Trust, the Mahidol Oxford Research Unit (MORU) has grown from just a handful of Oxford clinicians and Thai doctors. When Nick White — director until 2001 — stepped up in 1986 the unit began fieldwork in Thailand’s communities.

Professor Rose McGready works at one of the field stations established at that time — the Shoklo Malaria Research Unit in Mae Sot on the Thai–Myanmar border, about 500km north-west of Bangkok. It was set up by Professor François Nosten particularly to care for the marginalised populations of the region, notably the Karen people driven from Myanmar in decades of ethnic cleansing.

Professor Rose McGready

McGready, from Australia, originally came for a six-month stint after getting her tropical medicine diploma. She has been here for 23 years. ‘Working with the Karen, they needed someone who could do deliveries, so I never left.’

Staff had already begun to notice signs that the current malaria treatments were failing. ‘They were down to the very last remaining antimalarials,’ says McGready. ‘There wasn’t a drug left to offer for prevention.’

She vividly recalls her first sight of what the Plasmodium falciparum parasite can do to pregnant women. The Shoklo team realised a woman from one of the refugee camps needed bringing in for treatment. Wrapped in a blanket, she was carried on a bamboo stretcher on foot, by boat, on foot again, and then by four-wheel drive. ‘For 72 hours I didn’t sleep,’ says McGready. ‘She kept going unconscious. She was profoundly hypoglycaemic. We kept topping up her sugar and making sure she had enough fluids. This was my first case of severe malaria, so every now and then I’d get on the radio to say “help me” and just make sure I was doing all the right things.

‘She was seven months pregnant and had two small children and a husband. They had come to help take care of her, because in rural Asia we don’t really have nurses — it’s the family that provides that type of care. She woke up, she had a small meal. Then she developed a complication, which was awful because she was so very, very conscious by this stage.’ The Shoklo team gave her the appropriate treatment for her lung problem, a common feature in pregnancy with severe malaria, then transferred her to the better-resourced Thai hospital nearby.

‘But she didn’t survive. The worst thing was to send that father and the two children home without their mummy. It was the first time but it certainly hasn’t been the last. It was in the days of using quinine, not artemisinin — and maybe if we’d used artemisinin she’d still be alive.’

As yet, artemisinin was unknown. In the face of rising malaria mortality rates, Nick White and the Shoklo unit’s director, Professor François Nosten, established a frequent-screening programme, asking pregnant women to come for checks weekly if they could, and treating anyone who had malaria. It quickly cut the maternal mortality rate for malaria to a fifth of what it had been. But McGready and field researchers like her have plenty of other, equally harrowing memories from the dark days of surging drug resistance in the 1990s.

A new hope: Artemisinin Combination Therapy

The need for a replacement treatment had been clear for some time. Artemisinin Combination Therapy arrived via a momentous discovery by scientists in Mao’s China, which was only broken to the outside world through Nick White’s efforts with colleagues from Oxford and its partners in Asia and Africa.

By chance a Hong Kong contact had told the Bangkok unit in the early 1980s about a remarkable paper from mainland China on the qualities of qinghao su, an ancient herbal remedy extracted from Artemisia annua, sweet wormwood. ‘We were very excited,’ says White. A MORU delegation returned from China eager to take up the Chinese offer to supply what became known as artemisinin.

But now White encountered a new problem of resistance — not parasitic, but bureaucratic. The World Health Organisation said it judged the quality of the Chinese medicine too low. It promised an alternative, but none emerged.

In the end, frustrated national health organisations decided unilaterally to trial the Chinese medicine. Oxford’s tropical medicine teams conducted trials in Thailand and the Gambia, Africa. ‘If you have a radical approach you have to have the courage of your convictions and the support to carry it through,’ says White.

Thankfully Oxford has always given MORU great latitude to respond to local needs. ‘Work that’s generated and directed from a distant, temperate, wealthier country often isn’t quite appropriate for local circumstances and often doesn’t work very well,’ says White. ‘I often describe our unit as having a small placenta in Oxford with a very long umbilical cord. Our main collaborator is our host institution on site. Oxford didn’t interfere with those local relations. It supported them, cherished them.’

We haven’t had a death from malaria in pregnancy for close to ten years now

The trials of artemisinin fulfilled their promise, acting rapidly and better than anything seen before. MORU’s big innovation was to combine artemisinin with the already existing mefloquine. Where the failure rate for mefloquine had soared to 50 per cent, with this new Artemisinin Combination Therapy it plummeted to just two per cent. The combined drugs supported each other. If a parasite was resistant to one of the medications, the other would kill it.

Rose McGready had seen years of futile effort and experiment to prevent malaria in pregnancy on the Thai–Myanmar border — ‘big expensive studies, randomised control trials with bed nets, or with skin repellent. Mefloquine was trialled successfully but then resistance arrived so rapidly that it couldn’t be used. None of our fancy trials actually worked.’ She laughs grimly.

What made the difference was a rigorous screening system for pregnant woman leading to early diagnosis, and then from 1992 community-wide screening and the deployment of ACT. This worked better than trials of bed nets or skin repellents because it reduced malaria across the whole community. ‘It just had the most profound impact on falciparum malaria,’ says McGready. ‘We haven’t had a death from malaria in pregnancy for close to ten years now.’

The Shoklo unit’s meticulous record of more than 2,500 deliveries of babies every year since 1986 — effectively the largest-ever field study of malaria in pregnancy — helped to show artemisinins were safe for mother and child and to establish the optimum treatment regime.

But McGready adds: ‘It still takes a lot of convincing, even though we’ve been putting the evidence out there.’ Médecins Sans Frontières adopted ACT in 2002, treating tens of thousands of malaria sufferers per year. In 2006 the World Health Organisation began recommending ACT as the first-line treatment for falciparum malaria wherever it was endemic.

The fear that malaria inspires here on the Thai–Myanmar border is unabated since the last wave of drug resistance. ‘Even now, when we haven’t got as much malaria,’ says McGready, ‘mums are very agreeable to having their blood checked for malaria — they hold out their finger. Any fever in the child, they want that child checked. They know this disease.’

Resistance against resistance

Concerns had begun to emerge by 2005 that artemisinin was not working as it should, even while Artemisinin Combination Therapy was becoming the gold standard for treatment of severe malaria. It was Oxford’s MORU centre in Thailand that performed the first comparative tests to clearly show artemisinin resistance among Plasmodium falciparum parasites in western Cambodia. A 2009 report by MORU malaria research chief Professor Arjen Dondorp and others revealed resistance rates of 30% among falciparum parasites in western Cambodia, ten times what had been seen previously. With Artemisinin Combination Therapy estimated to have cut world malaria deaths by a quarter, this was very bad news indeed.

In the face of spreading resistance to antimalarial drugs, hope surely lies in the spread of collaboration. MORU in Thailand is just one of seventeen Oxford-run units in hospitals in South-East and South Asia, and in Africa too, that are involved in the UK-funded Tracking Resistance to Artemisinin Collaboration (TRAC). Since 2015, the collaboration has recruited 1,500 patients across eight countries to monitor their responsiveness to antimalarial drugs — an expensive and intensive process. Resistance is not an obvious problem to detect, so patients need to be followed up for a long time in order to establish a drug is not working.

The Worldwide Antimalarial Resistance Network (WWARN) was launched in 2009 to share data about drug efficacy, with Oxford as the base because of its academic resources and its track record on malaria, and with Nick White as chairman until last year.

The idea is to put all antimalarial drug resistance data in one accessible resource, to be an arena for cooperation not competition among researchers, and to expedite the delivery of research results to the health policymakers and practitioners. Co-founder Professor Philippe Guérin says, ‘Nine years ago data-sharing was a bad word. People were not convinced at all why they would do that.’ WWARN, funded by the Bill and Melinda Gates Foundation, the ExxonMobil Foundation and UKAID, seems to be changing that.

Professor Philippe Guérin

The tools developed by WWARN are proving so valuable in the battle against drug resistance that they are being applied to a whole range of other diseases in a vastly expanded organisation — the Infectious Diseases Data Observatory, or IDDO, of which WWARN is now just one facet.

Professor Paul Newton, director of an Oxford unit in Laos, heads WWARN’s investigations into medicine quality. The trade in fake medicines, deliberately counterfeited in the knowledge that patients may die as a result, prompted the World Health Organisation to launch a rapid alert system for national authorities in 2005, when it estimated 10% of all drugs sold globally — and up to 25% in developing countries — were counterfeit. Newton’s team also deals with the problem of substandard medicines, which can also kill. WHO tests in six sub-Saharan countries in Africa in 2011 found that 29% of antimalarials did not meet drug standards.

WWARN’s concern with drug quality springs from the fact that substandard drugs directly contribute to the spread of drug-resistant parasites. An antimalarial drug without sufficient active ingredients will kill fewer Plasmodium parasites, leaving more survivors to pass their resistant genes to their offspring.

Even if they contain no active ingredients, fake medicines can also indirectly foster parasitic resistance. That’s because fake medicines and substandard ones are frequently clustered in the same deprived areas. ‘If a patient takes an antimalarial that has no ingredient, they have a much higher chance of having very high parasite loads in their bodies,’ says Newton. If that same patient is then treated with a substandard antimalarial containing half the correct dosage of active ingredient, those extra parasite loads mean even more drug-resistant parasite survivors. ‘Nick White demonstrated by modelling that those are the key patients for engendering antimalarial resistance,’ says Newton.

A few years back at MORU, White was alerted to the circulation in Cambodia of unfeasibly cheap antimalarial drugs. With the help of Interpol and the World Health Organisation, the Chinese and Burmese authorities made arrests in the hope of shutting down one arm of the trade. But it has many tentacles. A single shipment of loudspeakers to Angola was found to contain 1.4 million packets of fake medicine, mostly artemisinin-based malaria tablets. ‘It’s a continual problem,’ says Newton, ‘Now a lot of our focus is in Africa.’

Endgame?

In 2015 World Health Organisation’s advisory committee on malaria policy called for massive measures to head off artemisinin resistance in South-East Asia. The risk of it spreading from there to Africa was ‘one of our prime concerns’, says Kevin Marsh, who chairs the committee. The proposal was hugely ambitious — to stamp out malaria completely in the Greater Mekong subregion — home to 300 million people in Cambodia, Myanmar, Thailand, Vietnam, and parts of China. Last November [2016], the WHO adopted the plan as policy, with a target date of 2030 for all malaria, and 2025 for falciparum malaria, the chief killer.

The obstacles are vast. There are the practicalities of extending and improving healthcare in vast and often impoverished areas, the political difficulties of cross-border cooperation and proper care for minorities, the technical challenges of tracking a multiform and mutating parasite. Military conflict can empty an area of healthpost workers who can diagnose and treat malaria. Above all, there is the problem that resistance to artemisinin can only increase. As the WHO policy document put it in November, ‘The quandary is that multidrug resistance is both an impediment to elimination and a reason for pursuing it.’

But the theory is that once the malaria parasites are reduced below a critical threshold, the disease can no longer propagate itself — there will be too few infected people or mosquitoes for the parasites to maintain their deadly cycle.

Early warning

At Oxford University’s Wellcome Trust Centre for Human Genetics, medical microbiologist Dr Climent Casals-Pascual has a dream that could transform the checking process: to create a rapid diagnostic test for malaria that virtually anyone can use. Through much of Africa or South-East Asia, when you fall ill the odds are that there will be no nurse or doctor to see. Even if there is a medical facility within travelling distance, who will take you, if other family members cannot be left unattended? So you will probably be diagnosed by someone with no medical training.

If we can achieve an effective rapid diagnostic tool I’ll die happy

Some severe forms of malaria look at first deceptively like pneumonia, with high fever, shortness of breath and aching muscles. The rapid diagnostic tests (RDTs) that currently exist do not distinguish between the two conditions, even though these require completely different treatments — antimalarials on one hand, antibiotics on the other. The mosquito bite that delivers the Plasmodium parasite may have been received seven days before symptoms appeared. By the time symptoms show, death will probably take less than 24 hours if left untreated.

A rapid diagnostic test to discriminate malaria and pneumonia should cost under $1, be easy to distribute and use, and deliver results within ten minutes, ideally five. The small research group Casals-Pascual formed in 2008 delivered proof of concept in 2013. They are working to identify which proteins must be measured to make the test as accurate as possible, while linking up with companies and writing up grants. ‘If we can achieve an effective rapid diagnostic tool I’ll die happy,’ says Casals-Pascual.

Mapping malaria

In the battle against tropical disease, tracking its reach is fundamental. On malaria, Oxford is taking this to new levels of precision. The world’s largest malaria datasets are gathered and maintained by the Malaria Atlas Project, set up 10 years ago when maps of malaria distribution provided little indication of risk areas below national level.

A lot of malaria prevalance is driven by how good the habitat is for mosquitoes... vegetation matters because although we see mosquitoes as bloodsuckers, in fact they are predominantly nectar feeders, and it is only the pregnant females that snack on us to get vital protein for their eggs

Foremost in its sights are the falciparum and vivax forms of Plasmodium. The first is prevalent in Africa. Vivax malaria causes fewer deaths but is subtly effective in spreading the disease, because it hibernates in the human liver and so can evade detection and most treatments. Increasingly fine data may help identify which areas can effectively be targeted in malaria elimination efforts.

Funded by the Gates Foundation and Medical Research Council, and working directly with Clinton Health Access Initiative, MAP researchers aim to be able to assess the effectiveness of various strategies against the disease — drugs, bed nets, insecticide in the home, and so on. Estimates fed back to the World Health Organisation and others may encourage sustained investment in the best programmes. ‘The driving force behind it is to make sure the funding agencies don’t take their eye off the ball — because there are still hundreds of millions of cases a year,’ says MAP’s Dr Dan Weiss.

With a US background in satellite-image processing, Weiss was brought in to provide data on temperature, moisture and vegetation cover for MAP’s models. ‘A lot of malaria prevalance is driven by how good the habitat is for mosquitoes,’ he says. Vegetation matters because although we see mosquitoes as bloodsuckers, in fact they are predominantly nectar feeders, and it is only the pregnant females that snack on us to get vital protein for their eggs.

Behind the project’s maps is ‘a tremendous amount of data and computation’ — and efficiency. ‘It’s not just being able to do it, but being able to do it quickly, that separates us from a lot of folks.’ A hugely diverse pool of ecologists, biologists, geologists and others — even an astrophysicist — already work with MAP.

Weiss’s colleague and fellow American Dr Katherine Battle, doing postdoctoral work on elimination mapping, was also drawn by ‘Oxford’s ability to attract’. As she points out, Dan and some of the other people on the team who run these statistical models could easily be in the City making big money. For Battle, the spur for going into malaria work was simple. ‘I did so specifically because it is most often fatal to children. That’s definitely an inspiration to make our work as robust and rigorous as possible.’

Kilifi, on the Kenyan coast, is a malaria-endemic area. Copyright © Oxford University Images / Alex Kamweru.

How to beat the mosquito

A complementary rationale took Kevin Marsh to Kenya in 1989. From his first arrival in Oxford as a molecular parasitologist specialising in malaria, he had dreamed of starting a research group in Africa. ‘I was really driven by a realisation that most of the work was being done not in Africa and not by African researchers, because African research at the time was quite underdeveloped.’

Professor Kevin Marsh

The unit was launched in 1989 at a small district hospital outside Mombasa. By the time Professor Marsh stepped down as director in 2014, the hospital and its KEMRI-Wellcome Trust Research Programme (KWTRP) had become a major international centre. Knowledge exchange is reciprocal, he stresses. ‘Everyone who goes out to work in Kenya or Thailand or Vietnam from Oxford would say — and not just out of some kind of political correctness — that they learn as much as they ever teach.’

Marsh is unabashed about Oxford’s contribution to the battle against malaria. ‘If you look at international and national policies for malaria, a very substantial number have been informed by research that’s come out of Oxford-associated groups.’ The Kenya programme itself can take credit for a landmark study showing that bed nets impregnated with insecticide can cut child malaria by up to 16%. They are now widely used across Africa and the globe. ‘We didn’t invent the bed net,’ says Marsh. ‘What was innovative was the set-up we established for long-term testing of interventions.’

In the longer term, it looks as though improvements to housing in Africa and elsewhere might provide similar defence against mosquito-borne disease. Dr Lucy Tusting of Oxford’s Malaria Atlas Project, in a collaboration with the London School of Hygiene & Tropical Medicine and the universities of Durham and Southampton, compared the prevalence of malaria in children living in improved housing compared with unimproved housing across 21 African countries.

Modern, improved housing was associated with up to a 14% reduction in infection, similar to the association between malaria and bed net use in the same children, she says. ‘I see huge potential for healthier housing in Africa and Asia. Many malaria endemic countries are undergoing tremendous economic and demographic change, creating demand for new and improved housing. This is a prime opportunity to incorporate features that help to protect against malaria and other vector-borne diseases.’

But bed nets and housing are less helpful where mosquitoes strike in the open air during the early and later parts of the day. Rose McGready and her colleagues at western Thailand’s Shoklo unit wanted an effective way of trialling skin repellent against mosquitoes. The Karen women wear use a cosmetic paste called thanaka. ‘It’s very visible — they make swirls and targets and cat whiskers,’ says McGready. The brainwave was to use this make-up as the base for DEET mosquito repellent. ‘It was the least absenteeism we’ve ever had.’

Further lessons may be drawn from malaria epidemics early in the last century. Mark Harrison, Director of the Wellcome Unit for the History of Medicine, is part of a small team studying the ‘invisible crises, neglected histories’ of malaria in Asia since 1900, and one of its particular interests is in the impact of ecological management efforts. Particularly effective was ‘flood and flush’, which used water from the monsoon-swollen Ganges in Bengal to clean out the stagnant paddy fields, normally a mosquito breeding ground.

But elsewhere there were notable failures when engineers ignored medical advice. Irrigation schemes boosted crop yield in formerly dry areas such as parts of the Indus valley, but also boosted malaria. The new irrigation canals and their stagnant run-off introduced the disease to areas where it had seldom been seen before, and where people had no acquired immunity. Harrison comments, ‘It produced some really quite horrific epidemics in the late Twenties which were entirely predictable — and predicted.’ The 19th-century precedents for such disasters make it a tragedy of mismanagement.

If the successful antimalarial strategies can be properly isolated from other contributory factors such as improvements in nutrition, Harrison suggests, they might be reintroduced to save lives now.

Mosquitoes versus mosquitoes: genetic modification

Against the mosquito some thoroughly 21st-century technologies are also being deployed. One is the smartphone app, which an Oxford research team hopes to tailor as an acoustic sensor that can detect and identify a mosquito, giving earlier warning of disease risk. [Find out more about the acoustic sensor]

Another highly modern weapon against the mosquito is the mosquito itself, genetically modified.

At the forefront is Oxitec, launched in 2002 as a spinout from Oxford, but now wholly owned by a US corporation. Oxitec founder Professor Luke Alphey, Reader in Genetics in Oxford’s Department of Zoology, has gone elsewhere to pursue further research, while Oxitec focuses on large-scale deployment of its ‘products’.

Closeup Aedes aegypti or common house mosquito. Credit: Shutterstock / nuwatphoto.

Oxitec has inserted an extra gene into the male Aedes aegypti mosquito, vector for dengue and Zika. Crucially, female mosquitoes only mate once; having done so with the GM males, they will only produce offspring genetically programmed to die as juveniles — too young to mate. Chief scientific officer Simon Warner claims that where pesticides can only reduce mosquito populations by 30% at best, Oxitec can slash them by 90% or more. With operations in Brazil, India and the Cayman Islands, Oxitec is looking at Florida too because of Zika.

Michael Bonsall, Professor of Mathematical Biology in Oxford’s Department of Zoology, models data for Oxitec on where the mosquitoes live, how they behave, and the environmental factors driving their population dynamics. Oxitec’s GM mosquito is what he calls a self-limiting technology — though it can produce offspring, they will die too young to do so themselves. Bonsall predicts that the alternative, self-sustaining approach won’t be viable for another decade. Gene-editing could theoretically produce an Anopheles mosquito unable to carry the malaria pathogen but able to pass on its immunity to viable offspring.

If Oxitec is right about the 90% population drop it can achieve, its GM strategy could cut mosquito numbers so deeply that there are simply not enough of the insects left to pick up the pathogen and pass it back to humans. ‘It’s just a numbers game,’ says Bonsall.

Genetic modification raises concerns, especially when the released populations are self-sustaining. In the words of Julian Savulescu, Director of the Oxford Uehiro Centre for Practical Ethics, ‘The public are worried that you don’t know what will happen once genes enter the real world and start to be modified and move around among mosquitoes. Life is tenacious, and some mosquitoes will escape that genetic modification in some way and then repopulate. And we don’t know what that population of mosquitoes will be like.’ However, Savulescu believes that such concerns are ones ‘that science today can quite reasonably address’.

Bonsall himself believes vital GM innovation is being stifled by legislation which was built on concerns about GM crops rather than insects, and which has fallen far behind such technologies as CRISPR ‘cut-and-paste’ gene-editing. Most legislative approaches preclude consideration of benefits, while providing risk information which policymakers generally misconstrue. Obtaining consensus across a hydra-headed organisation like the EU is ‘an absolute nightmare’.

Bonsall was specialist advisor for the House of Lords Science and Technology Committee’s 2015–16 report on genetically modified insects. It urges that there is a moral imperative to use technologies which work, and that the onus is on scientists, governments and health organisations to consult widely and openly with the people potentially affected.

‘I don’t have a beef with mosquitoes,’ says Bonsall. ‘I just have a beef with the fact that there are so many sick people in the world. A kid under the age of five dies every minute from malaria. Half the world’s population are at risk of these diseases and we have the capacity to do something about that.’

Challenges

Eliminating malaria in humans involves not only practical and technological challenges but also ethical and political ones.

Treating patients with Artemisinin Combination Therapy is not enough to stop transmission, because ACT does not kill the gametocytes, the sexual form of the Plasmodium parasite in the blood. ‘The patient, now cured of their malaria, can still be infectious to a mosquito, which can then go and infect another person,’ says Professor Nick Day, director of Oxford’s MORU unit in Bangkok since 2002. Another drug, primaquine, does kill the gametocytes and can stop the cycle. But in patients with G6PD-deficiency — a genetic condition very common in malarial areas — primaquine can cause anaemia.

So the conundrum for practitioners is whether it is ethical to give primaquine to individuals for the sake of the wider community. The patient, already cured of malarial symptoms, gains no personal benefit — but the community may well do so. MORU staff take a cautious approach, giving such a low dose of primaquine that the risk of anaemia may theoretically be zero. They monitor it carefully nonetheless.

Mass drug administration to remove the malaria parasite from its human reservoir needs exceptionally broad coverage to work. The Oxford Martin School Programme on Collective Responsibility for Infectious Disease is a cross-disciplinary collaboration which, in the words of co-director Julian Savulescu, aims ‘to understand what sort of norms we should be constructing to solve problems like collective responsibility and how people can be encouraged to conform to those norms’. He says, ‘You can force people to take antimalarials, or you can use incentives, or you can appeal to their rational nature. You need ethics to evaluate which of those are permissible.’

Savulescu believes that as a species we are ill-suited to global challenges like eliminating malaria. Though we are uniquely advanced in intellect, technology and power, our moral evolution is stuck in hunter-gatherer mode. The tit-for-tat emotions we evolved for cooperation in small groups during the vast majority of the past 200,000 years — gratitude, anger, pride, shame and so on — are little use or even counterproductive in solving global problems like antimalarial resistance.

The programme’s other co-director, Mark Harrison, outlines some of the failures of collective responsibility in the battle against malaria. He sees one as overuse of medications, leading to resistance to successive treatments up to and including ACT. Another is failure by nations to share intelligence — a problem the Malaria Atlas Project is seeking to remedy. Harrison points out that Bangladesh — an important gateway for the disease — is vulnerable on its eastern border due to political issues. Neglect or outright repression of minorities, such as the Karen or the Muslim Rohingya in Myanmar, is generally accompanied by lack of scrutiny, and all of this opens the gateway wider.

‘A lot of things are passing under the radar at the moment,’ warns Harrison. ‘If the drug-resistant strains of malaria do spread to Africa, a lot of the progress which has been made there could be undone. One of my big concerns is with Bangladesh, because so many Bangladeshi troops are sent on peacekeeping operations in Africa for the UN. It’s only a matter of time before the military is affected, because there are large numbers of military around the border.’ Malaria has travelled across the globe with humans since prehistory. [Find out more about how prehistoric humans spread malaria across the globe]

The spreading threat

Fake antimalaria medicines turning up in Angola, drug-resistant malaria parasites massing in Bangladesh… With the history of how resistance has spread from the Greater Mekong region, experts’ fears for Africa look terrifyingly well founded.

Kenya harbours plenty of other mosquito-borne diseases, such as lymphatic filariasis, a cause of elephantiasis. ‘But in terms of overall impact and deaths, historically malaria has been always the big one,’ says Kevin Marsh, the man who established Oxford’s KWTRP research unit there.

‘Historically, drug resistance for malaria has been a big issue. When we moved to Kenya, the drug used all around the world had been chloroquine — very cheap, very effective. Resistance began in South-East Asia, spread, and eventually became worldwide.

‘Resistance to the drugs which followed also tended to begin in South-East Asia and spread to Africa. And because of the massive numbers of people involved in Africa — its sheer size and scale — it means that that has a massive impact.’

In 2003, before Artemisinin Combination Therapy became an established treatment, Médecins Sans Frontières reported that globally there were upward of 300 million malaria cases a year, 90% of them in Africa; and up to two million deaths annually, mostly in Africa. The disease accounted for up to half of all hospital admissions in Africa, and was the main child killer. As Nick White says, ‘We don’t want to get back to those sorts of numbers.’

Can the World Health Organisation’s ambitious plan to eliminate malaria in the Greater Mekong actually work? The February Lancet report by Nick White and others says the parasite resistance to artemisinin and one of its ACT partner drugs, piperaquine, ‘is now spreading quickly throughout Cambodia’. Parasites resistant to multiple antimalarial drugs are showing an alarming ability to spread themselves, and have been found throughout neighbouring regions of Cambodia, Laos, and Thailand. What looked at first like an odd cluster of incidents has taken the shape of ‘a more familiar scenario’ in which highly drug-resistant malaria parasites ‘spread and threaten malaria control and elimination throughout the region and beyond’.

Will resistance to Artemisinin Combination Therapy ultimately make the jump to Africa? ‘We’re not sure,’ says Kevin Marsh. ‘There are many things that govern that. But we’re really concerned about it. We’re very aware of the danger.’


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