Will efforts to eradicate the killer disease overcome technical, finanicial and political obstacles?

The global death toll from malaria has dropped dramatically in just over a decade – more than 25 per cent overall and 33 per cent in hard-hit sub-Saharan Africa, according to the World Health Organization. Yet the WHO reckons that malaria still kills more than 625,000 people a year – roughly equal to the population of Vancouver – and some estimates, including one published two years ago by The Lancet, suggests that the WHO’s figures reflect only about half the actual total. As well, country-by-country statistics make clear that progress in combating this killer disease is both fragile and spotty. For example, while the number of deaths reported in Tanzania plummeted from more than 20,000 in 2005 to just 840 in 2009, next door in the Democratic Republic of Congo the toll soared from fewer than 15,000 to well over 20,000 in the same period.

Today malaria is almost exclusively a tropical disease, but until a century ago or even less, it was also found in much of Europe and North America. Variants of the anopheles mosquito, which carries the parasite that causes malaria, are still common across Canada and in most temperate countries, but good public health measures have extirpated the parasite. Thus the disease is no longer endemic in any developed country, though imported cases crop up from time to time.

But while the rich places – southern Europe, Washington, D.C., the U.S. South, Ottawa – eliminated it years ago, malaria doesn’t strike only the poor. In the fall of 2013 I set out on a round-the-world trip (supported by my employer, the Vancouver Sun, and funded by a grant from the Canadian Institutes of Health Research) to investigate all aspects of malaria. Most malaria workers I interviewed, even professionals in malaria-endemic parts of the world who are well paid by their countries’ standards, had had bouts of it themselves and had seen it in their families.

In addition to the death toll, the economic cost of malaria is huge. Hundreds of millions of working days are lost in scores of countries when workers fall ill or stay away from their fields or off the job to care for sick children. And health is inextricably connected to education and economic progress. “In a village where malaria is endemic, life expectancy goes down,” says Sir Fazle Abed, the founder and head of BRAC, a multifaceted Bangladesh-based NGO that has grown into one of the largest development agencies on earth. “If half the time I’m sick, my productivity will go down, and I’ll always be a poor person. All kinds of other deprivations will happen because of my poverty, and each deprivation will mean I can never get out.”

Rosemin Kassam, an associate professor in the University of British Columbia’s School of Population and Public Health who has worked on malaria-related issues in Uganda and elsewhere, says the early impact of malaria on children can drag them down for life: “Even if they don’t die, they’re likely to be left with some kind of morbidity. It can be significant – paralysis, brain damage and retardation, a lot of negative consequences. Even just carrying the parasite can create anemia, which can make it difficult to sit in school and concentrate.”

The international effort

Successes to date in controlling malaria are due to many factors – billions of dollars from governments and private donors, better and better-targeted insecticides, effective environmental management, easy and cheap diagnosis, new medicines, education on preventing malaria and seeking appropriate treatment, community organization to ensure that people get the prophylactics and the care they need. But it will take at least as large an arsenal – accompanied by luck and bolstered by a promising new vaccine – if the fight is to be finished.

The catalyst and guiding hand for much of the progress – and no doubt a vital player going forward – is the Global Fund to Fight AIDS, Tuberculosis and Malaria. It has not only funded billions of dollars worth of work on several fronts around the world since it made its first grants in April 2002, but has also marshalled political will in both rich countries and poor, focused prevention and treatment initiatives, and broken down silos and coordinated research to a degree not seen before in the annals of medical history.

The Global Fund’s role was one of my interests in my global investigation. At every major stop – the funding and research hubs of Washington and Geneva and the fieldwork centres in northern Liberia, northern Namibia, western Kenya, the Indian border region of Bangladesh and the remote hills of the off-the-beaten-path Philippine island of Palawan – the depth and breadth of its influence became ever more apparent.

The impact of the Global Fund’s involvement goes well beyond paying for prevention, diagnosis and treatment in countries too poor to cover the costs themselves, says Kishor Wasan, who until his recent move to the University of Saskatchewan was dean of pharmacy research at UBC, where he founded the university’s Neglected Global Diseases Institute. It has also enticed researchers out of their ivory towers by funding only multidisciplinary research.

“The range of work on our campus alone is exciting,” Wasan said in an interview in late 2013. “It’s all the way from drug discovery and development to implementation and understanding the barriers to getting a product from a bench in the lab to the patient on the ground. We’re touching business, chemistry, community geography. Fifteen years ago these researchers would never even have talked to each other.”

The Global Fund’s financial support for research is substantial, and its prevention and treatment initiatives cost much, much more. So much of its success is thanks to the support of donor governments, which have given or pledged more than $30 billion since the fund’s inception, and from private sector partners, most notably the Bill and Melinda Gates Foundation, who have added hundreds of millions of dollars more.

Yet individual interventions are cheap. The international benchmark for health program cost-effectiveness is US$150 per year of healthy life, and a British study estimates that with malaria this cost is between $8 and $110 (depending on the location and distribution complexities) for insecticide-treated bed nets, or $89 for drugs to treat diagnosed cases.

Mosquitoes and parasites

Mosquitoes are usually blamed for spreading malaria, but humans are also complicit, and our forebears helped turn the disease into the scourge it is today. Although the parasite that causes it, a protozoan called plasmodium, has existed for at least 50 millennia, it didn’t become common until the dawn of agriculture about 10,000 years ago, when people started living in larger and more settled groups. Such good-sized pools of human hosts, with our nourishing blood and livers, are vital to the parasite’s lifecycle. The one-celled plasmodium can reproduce only in a human body, and mosquitoes can’t infect new victims unless they first bite people who already have plasmodia in their blood.

Most variants of parasite-bearing mosquitoes are nighttime or early-morning biters that can be foiled – or killed – by insecticide-treated bed nets. The parasite has several variants too, the most lethal being plasmodium falciparum. All are tiny, too small to be seen with the naked eye, but when their manic reproductive cycle takes hold inside a human body, the results can be catastrophic. Infected people get sick – chills, fever, sweats, fatigue. Without treatment, especially if victims are small children with yet-to-develop immune systems, many die.

The fight to control malaria plays out differently in various parts of the world. But every malaria control program shares three key elements.

Cheapest and best is prevention. This may include low-tech environmental measures – things such as clearing brush around water sources where mosquitoes breed or homes where potential victims sleep. But the most effective component is insecticide-treated bed nets, often accompanied by regular spraying of the walls in rooms used for sleeping. Various insecticides are used, even highly effective DDT in a handful of countries that haven’t banned it yet. Treated nets and sprayed walls provide double-barrelled protection. The obvious benefit is preventing sleeping people from being bitten. The not-so-obvious plus is that, even if a mosquito doesn’t die until after it bites someone, at least it won’t live long enough to bite again. This is significant because mosquitoes don’t carry the parasite unless they bite somebody who has it. So a mosquito that dies after biting once is an irritant, but not a danger.

The second essential element is diagnosis, which has become much easier and more reliable than in the past. The Global Fund’s promotion and widespread distribution of new rapid diagnostic tests – strips that react to a drop of a patient’s blood – mean even minimally trained volunteers can get accurate results. This is a major advance. Previously, every fever was assumed to be malaria, which meant expensive treatments were often wasted on people who needed different interventions. And these same patients did not, of course, get the treatment they actually needed.

The final step is treatment. This, too, has become simpler thanks to new combination drugs. Precise combinations vary from region to region and are changed as necessary to combat any resistance that develops in the parasite. Significantly, treatment loops back to prevention to complete a virtuous circle. Because mosquitoes don’t carry the parasite unless they bite an infected human, sick people are essential to the parasite’s lifecycle. So the more who are cured quickly, the more the reservoir shrinks.

But both insecticides and drugs face moving targets. Mosquitoes develop resistance to sprays and parasites become drug-resistant in alarmingly short order. The parasites, in particular, are genetically primed to adapt, says Chris Ockenhouse, senior research scientist with the PATH Malaria Vaccine Initiative in Washington, D.C. He notes that while viruses typically comprise a couple of dozen proteins, the complex malaria parasite has 5,000. Its lifecycle includes six unique environments – three inside mosquito carriers and three in a human host – so it’s inherently adaptable. Thus, widely used medicines rapidly lose their punch as new generations of parasites become immune.

Vaccines, drugs and money

16_IMG_3110_cayo_1For researchers pursuing the holy grail of an effective vaccine, the question is whether this adaptability will shorten the useful life of what they come up with. It may not, Ockenhouse said, because drugs and vaccines work differently. Drugs attack the infecting agents, so any parasite not killed will propagate its drug resistance. Vaccines, however, stimulate the body’s immune system to protect itself and don’t interact with the invader. So if parasites survive, it’s because of the person’s weak immune response, not the parasite’s genetic resistance.

Several potential vaccines are under development, but only one – a GlaxoSmithKline product targeting early stages of a malarial infection – has undergone somewhat successful trials and is seeking regulatory approval. The most recent trials ran at 11 sites in seven African countries and focused on young children – six to 12 weeks in some cases, and five to 17 months in others. The best results were for the older children, who enjoyed roughly 50 per cent protection for at least 18 months. This doesn’t mean half the vaccinated kids never get malaria. Rather, they experience only half as many bouts of malaria as the unvaccinated – perhaps an average of two a year instead of four.

These results fall well below the performance of vaccines for most diseases, but for Walter Otieno of the Kombewa Clinical Research Centre near Kisumu, Kenya, they’re heartening. For one thing, vaccination halves the risk of a protected child’s death or disability. For another, like every preventive measure, it shrinks the reservoir of human carriers who can infect mosquitoes that will in turn infect other humans. So, Otieno thinks the vaccine should be rolled out for general use, and soon.

Yet 50 per cent efficacy doesn’t look so good to many drug researchers working to refine artemisinin-based combination therapies (ACTs), which cure virtually all cases if the victims receive treatment in time. Viollaine Dallenback, the Geneva-based communications coordinator for the international Drugs for Neglected Diseases Initiative, is more concerned with the push to find drug combinations that stay a step ahead of the parasite’s ability to adapt. Another key goal is a one-pill therapy to replace the current three- to 24-pill treatments, which tempt patients to take fewer than they need so they can hoard the rest for a possible subsequent bout.

Dallenback’s colleague Bernard Pecoul notes that keeping the cost down is also vital. And cost control is a tough challenge. For one thing, both malaria medications and vaccines are unusual in that they’re being developed primarily for poor people. In the past, the poor have had to wait a long time – often a couple of decades – to get access to new preventatives or treatments. This meant that by the time they got the drugs, paying customers in the developed world had largely covered the drug companies’ high overhead and research costs.

16_IMG_5779_Bangladesh testing_CayoAs well, says Chris Orvig, a UBC professor of chemistry and pharmaceutical science, new therapies will probably be costly. Old, cheap, plant-based medicines have mostly become ineffective, he said, and new drugs tend to involve synthetic molecules: “If you have to do multiple synthetic steps to put together a molecule, it requires a bunch of PhDs, and laboratories that have safety standards, and chemicals that have to be approved. So it’s inherently expensive.”

Similar cost considerations will no doubt influence decisions on whether or how to roll out malaria vaccine. This issue is complicated by the fact that the cost per shot will depend on how big the rollout is. Drug and vaccine costs drop substantially when massive distribution programs generate huge economies of scale.

If the Global Fund or other funders have decided what combination of cost and efficacy they require to move ahead or what scale of distribution they favour, they aren’t saying. But three main scenarios are possible. One is to roll it out everywhere it’s needed, as Otienio advocates. Another is to wait until the vaccine is refined and results improve. A third is to use it soon in large-scale pilot programs in the worst-hit areas – an approach that fits well with current thinking about strategies for the future.

For more than a decade, the goal has been to “shrink the malaria map” – to eradicate the disease inward from the edges of its range and gradually reduce the percentage of the world that’s affected. This has worked, but with limitations. The problem is that as long as malaria remains highly endemic in the core – more than half the population carries the parasite in some regions – the disease keeps getting reintroduced in areas outside the core. These areas might be malaria-free if no one travelled back and forth. But people now travel more than ever, even in the poorest countries.

So some researchers advocate massive intervention in core areas because fewer infected people would mean fewer parasites carried out. A partially effective vaccine could be part of this strategy, as could various proposals to mass-treat everyone in the worst areas regardless of whether they’re sick.

Of course, whether dealing with the vaccine or a new drug, the question of cost complicates any decision about when to start using a new product and on what scale. Massive rollouts may be cheaper per dose but, as Pecoul noted, they may also trigger resistance in the parasite. And cost, ironically, becomes a bigger issue as countries or regions get closer to eliminating the disease.

In highly endemic places such as the jungle villages of Liberia, the biggest challenge isn’t figuring out who’s ill or what to do about it. Even before the Ebola outbreak threw the medical system throughout the country into chaos, it was a challenge to lay hands on drugs to treat the disease in a place where the fragile supply chain is often disrupted by dishonesty or incompetence. So the lucky would get three pills to take – usually all they would need – and the unlucky would be left to suffer or die.

By contrast, on the dusty plains of northern Namibia, where after a decade-plus of progress authorities dare to hope they’re on the cusp of eliminating the disease, a now-rare episode of malaria triggers a substantial response. First, the victim gets prompt and supervised treatment. Then a team moves in to trace the source of the infection, and to test and, if necessary, treat all family members and close neighbours who may also have been exposed. “So getting close to elimination is expensive,” said Chris Lourenco, who heads the Clinton Health Access Initiative’s malaria program in Namibia. “When you find a problem, you have to carpet-bomb it.”

Cross-border politics and worse

Namibia faces another challenge – sadly, one that’s far from unique – in what in other circumstances might be a straightforward march to eradication of what is now a well-controlled disease. It’s how to clean up the neighbourhood when the neighbours don’t do their part. Northern Namibia’s malaria-prone strip borders southern Angola, where the disease remains rampant. With several thousand people crossing the border every day, travelling Namibians may pick up the parasite in Angola, or visiting Angolans may bring it across. So people with parasites in their blood continue to infect Namibia’s mosquitoes.

Namibia maintains a network of hospitals in its towns, supplemented by stand-alone rural clinics. The clinics, scattered here and there on the scrubby plain that stretches in every direction, are placed to be reasonably accessible to the people living in tiny homesteads, often spaced a kilometre or more from one another. But because health care is free and is seen to be better here than in Angola, many patients come from across the border. So on one hand this network shrinks the reservoir of parasites living in human bloodstreams, and on the other it lures more infected people into Namibia.

Cross-border problems aren’t confined to Namibia – they’re found wherever countries with unequal levels of infection share a common border. In Bangladesh – also close, though not close enough, to eradication – the two parts of the country where malaria stubbornly lingers are the southeast, near the Myanmar border, and the north, next to the Indian state of Assam.

In both Assam and the border area of Myanmar, which is home to the persecuted Rohingya minority, insurgency has strained relations with central governments. “As a result, these parts of both countries have been neglected by their governments,” says Fazle Abed, whose organization, BRAC, is not only the lead agency in Bangladesh’s malaria programs but is also trying to establish similar ones in Myanmar. “At this point, I don’t think there’s any cooperation across the borders.”

But there is a lot of cross-border traffic. Be-Nazir Ahmed, director of Bangladesh Communicable Disease Control, notes that people living on both sides of the line share “the same colour, the same language, the same religion. We have a very close cultural connection.” And with the clashes with the Buddhist majority making life difficult for the Muslim Rohingyas, millions of refugees are flowing into Bangladesh. “We feel very close to them,” Ahmed said. “But they’re a risk.”

This risk is not just that Myanmar abuts the Chittagong Hill Tracts, the worst area for malaria in Bangladesh. This less-developed neighbour is also seeing increasing incidents of drug-resistant malaria parasites, which are slowly moving out from Cambodia and Thailand, where they’ve been a scourge for years. “Without international cooperation to stop it, this will be a nightmare,” says Abul Faiz, a professor of medicine and a prominent Bangladeshi malaria researcher.

The onset of drug resistance in the parasite has been traced to the Vietnam war when American troops used massive monotherapies as a malaria preventative, said Pecoul. Victims of drug-resistant parasites can still be treated, but only at great cost and not with the readily accessible and affordable medications that are generally so effective. As well, the development of drug-resistant strains has made the medical community leery of overusing monotherapies – it’s the reason today’s widely used ACTs are combination drugs, and the combination is occasionally changed. And, because malaria medications appear to have a finite useful lifespan, they’re reluctant to start using new ones until the existing ones have become ineffective,

The cross-border issue doesn’t affect every malaria-endemic country – islands like the Philippines, Zanzibar or Madagascar can run more or less self-contained programs because they don’t butt up against any neighbouring countries. But the issue does complicate the job in most countries to the point where Carl Lowenberger, a biology professor at Simon Fraser University who has worked in malaria control for more than 30 years, is pessimistic about ever seeing the disease disappear. “It has to be a regional, multicountry approach,” he said. “So who’s going to run it, especially in places with tribal tensions? In Africa, for example, you’d have to have 30-some countries coordinating their efforts. I don’t see that happening.”

Difficult as cross-border politics may be, an even more worrisome challenge looms on the horizon, says former British Columbia NDP MP Svend Robinson, who now works from Geneva to coordinate Global Fund relations with governments around the world. It’s to keep both donor countries and recipients focused on – and financially committed to – finishing the job rather than using early successes as an excuse to ease off.

Another former British Columbia MP, Liberal Keith Martin, who now heads the Washington-based Consortium of Universities for Global Health, agrees that maintaining the will to defeat the disease will be key to any future success. “We know how to prevent malaria deaths and disability,” he said. “Yet we still have 650,000 people a year dying from malaria. If we know what to do, why are they dying?”