Night lands with a thud in the tropics, sounding another round of inevitable hostilities. In the fast-gathering gloom of equatorial malaria country, humanity’s most dangerous adversary is on the move.
The lowlands of Papua New Guinea’s north coast have been a flashpoint in the shattering contest of mosquito versus human throughout history. Here people don’t so much die from malaria as endure it, morbidity outstripping mortality. Debilitating sickness reverberates through genetics, culture, prosperity and aspiration.
Only in the past few years have locals dared to hope it might not be ever thus, offering their blood and that of their children to the research scientists who come to this front line in their quest to find a vaccine to prevent infection, or better drugs to treat the casualties.
There is good reason for hope. Fighting malaria has been a global health success story. Since 2000, malaria incidence has fallen by 37% in populations at risk. Fatalities have dived by 60%. This means more than 6 million lives have been saved – most of them African children.
In PNG, control measures – in particular the rollout of long-lasting, insecticide-treated bed nets – have resulted in the prevalence of malaria declining by more than 80% across the country since 2009. Cases reported at four sentinel sites have dropped from 205 to 48 per 1,000, surpassing all expectations.
Encouraged by this success, PNG – in common with many other countries – has ramped up its ambitions from controlling malaria to eliminating it. It’s an exciting time, but one tempered by the risks of overconfidence and complacency. Because we’ve been here before.
A global eradication campaign beginning in the 1950s, mainly using insecticides, had malaria eliminated in some locations and on the run in many more by the 1970s. But then the disease bounced back. Now, as the world again pursues what it hopes will be the defining end-game against the disease, the lessons of the past weigh heavily.
The greatest lesson of all is that the fight against malaria cannot be won by a shock and awe campaign but through a comprehensive hearts-and-minds campaign, aligned with dogged jungle warfare.
At the vanguard of the battle are the field teams of the Papua New Guinea Institute of Medical Research (PNGIMR). They trawl the lowlands of Madang and Sepik provinces for the morsels of intelligence required to further advance the assault on malaria, working alongside locals, enlisting vials, swabs, needles, slides and the stories and observations of communities. The teams are defining a textbook model of the grassroots research required in the long march to eradication.
“No corner of our understanding of malaria today is untouched by research findings from Papua New Guinea,” said John Reeder, a former director of PNGIMR who now leads the Word Health Organisation’s special program for research and training on tropical diseases, at the time of the institute’s 40th anniversary last year: “While some other parts of the world were subjected to ‘commando research’, the PNGIMR program was built on the solid foundation of community participation.”
Leanne Robinson’s regular morning begins on the fractured roads of downtown Madang, a sweltering gridlock of battered buses and trucks piled with people and cargo. The port town was once said to be the prettiest in the Pacific, and there are still glimpses of that place. War, neglect, industry and exploding population have dulled its charms, but not its potential as a strategic hub for desperately needed trade, research and investment.
Driving from Madang to the laboratories of the PNGIMR about 10 km south takes Robinson into a more postcard tropical idyll, though tangled lush forest and past palm-thatched hamlets. She has driven this route most working days for the past eight years. Navigating around chickens, children, potholes and the odd creek crossing, she deftly works the gears of her 4WD. Locals wave her along. Many know her by sight; those who don’t, know where she’s from. One way or another they are all touched by the programs she oversees. Robinson has been head of the institute’s Vector Borne Disease Unit since 2013. Infections carried by mosquitoes are her business, and this stretch of country is mozzie paradise.
Malaria is particularly and powerfully entrenched in the communities here on PNG’s north coast and through the surrounding lowlands, where it has afflicted and shaped generations throughout history, a story written into their DNA.
Despite the gains of the past 15 years, malaria continues to take a heavy toll throughout PNG. Nearly 95% of the population lives in areas where malaria is a high risk, with more than 1 million presumed and confirmed cases in 2013 (the most recent year for which figures are available from the Asia Pacific Malaria Elimination Network). Countless more go undiagnosed and untreated.
This represents the highest malarial burden in the Western Pacific region, and among the highest burdens outside Africa. But the fixes applied in Africa won’t always work in PNG, which hosts a different suite of mosquito species and parasites.
Not all mosquitoes transmit malaria. The culprits are certain species of the genus Anopheles, the unwitting air transport service enlisted by a diabolical biological passenger, Plasmodium. The parasite slips into the bloodstream when a pregnant female mosquito takes her meal.
There are four main types of human malaria. By far the most notorious and deadliest is Plasmodium falciparum, the biggest killer globally and the main strain in sub-Saharan Africa. By contrast, PNG has the world’s highest prevalence of P. vivax, which is difficult to control because it lingers in the body and relapses. PNG is also host to low undercurrents of P.ovale (also relapsing) and P. malariae.
Beating malaria in PNG therefore requires a bespoke campaign of tools and tactics. Identifying, trialing and tracking effective countermeasures has been the preoccupation of scientists and researchers at the PNGIMR throughout its 40-year history.
The institute’s work, which is funded by the PNG and Australian governments as well as grants from a wide collection of international NGOs and institutions, helps inform a national strategy that has made encouraging progress across the country. Intensive control efforts have slashed the number of annual deaths from about 20,000 in 2000 to about 300 today.
Rates of sickness, however, remain high, and it’s common for the same person to be infected multiple times. They suffer terrible headache, nausea, shaking chills, raging fever, fatigue, body ache. The toll on children’s health and education, and on households when parents get sick, is shattering. The debilitating disease is a major health and economic burden on the country.
Maddening questions remain about the local malarial parasites’ persistence and idiosyncrasies. What is it about the particular strains here that makes it more likely for children to get sick than die? How can the cycle of infection and re-infection be broken? These and other enigmas are the questions preoccupying Robinson and her team.
Robinson pulls up in the shade near a constellation of weary shacks that house the PNGIMR laboratories. Mouldering in the tropical heat but functional, jammed to the sagging rafters with equipment, personnel and archives, the facilities are stoic testimony to the resolve of the researchers who have worked here since the lab was built in 1977.
Over those years they have had some remarkable achievements. They include conducting, in 1985, one of the first field trials of insecticide-treated mosquito nets, now a critical tool in the global antimalarial arsenal. At one point they even came tantalisingly close to realising the dream of a vaccine, progressing to field trials of a therapy that ultimately proved unsuccessful. An effective vaccine for the dominant strain of malaria in this part of the world (P. vivax) has so far eluded everyone. The most promising vaccine to date, RTS,S, now undergoing testing in pilots in Africa, targets P. falciparum, so it doesn’t work against the parasite most widespread in the Asia Pacific.
Robinson and her colleagues continue in the tradition of a long line of scientists who have come to this coast determined to make some contribution to beating the disease. It was the scourge of the German colonialists. In 1899, they imported their celebrated countryman Robert Koch, the scientist who unveiled the tuberculosis bacterium some years earlier, to try to find some solution to malaria. Despite two years’ work, it defeated him.
In 1977, another storied scientist arrived in Madang. Australian researcher Michael Alpers had already spent years working in remote areas of the country, playing a central part in cracking the baffling case of killer “kuru” disease, helping discover prions and a whole new ball game of infectious disease.
Taking up his position as director of the fledgling PNGIMR, Alpers was convinced the time was ripe for a concerted effort to develop a vaccine against malaria. He set to work immediately to make Madang the permanent field headquarters of the research mission, recruiting specialists, scrounging funds, and negotiating to set up shop in a cluster of disused buildings at a bush hospital in the nearby village of Yagaum.
Alpers’ researchers also went on the hunt for other strategies and interventions that might curtail – even quash – spread of the disease. By then experience had taught them about the resilience of their foe. Almost a decade had passed since massive insecticide spraying campaigns using DDT – the weapon of choice in the first war on malaria, the Global Malaria Eradication Program (GMEP, 1955-1969) – had rolled out across PNG and the rest of the world.
Despite being successful in many locations internationally, for a complex mess of reasons the program was abandoned: it couldn’t work as a lone strategy in less developed nations; funding fell short; complacency about other control measures grew; mosquitos developed resistance; environmental safety concerns brewed.
Malaria bounced back with a vengeance in many countries – including PNG, where an elimination campaign had reached about 70% of the population by the early 1970s.
The moral of the story? There can be no weakening of the effort against malaria. As the World Health Organisation’s director general, Margaret Chan, warned in 2015 at the launch of a joint WHO-UNICEF report on the success of antimalarial programs since 2000: “With a disease like malaria you can never tread water. You either surge ahead or you sink.”
That year Papua New Guinea signed on to efforts to eliminate malaria from the Asia Pacific by 2030. “It is a big shift in the mindset of a country, and the decision makers, that elimination is even on the agenda,” Robinson says. But the welcome ambition is not without its own hazards: “The risk of committing to such an ambitious goal is the potential that attention is diverted away from the need to maintain control, and that is the worst thing that could possibly happen, because it will backslide and we will be back to square one.”
Complicating the campaign, and adding to its urgency, is concern around increasing resistance to artemisinin, a powerfully effective component of many treatment drugs. It has already been confirmed in five countries in South East Asia, and there is a real risk that strains of disease resistant to most available antimalarial medicines will soon emerge elsewhere in the region.
The challenge for Robinson and her colleagues now is to generate more insights and tools to stay one step ahead of the wily, masterful survivor, Plasmodium, which has so successfully exploited humans and mosquitoes to its advantage throughout history.
“Know the enemy, and know yourself” – this oft-quoted rule of war reflects the core of the research efforts in the PNGIMR laboratories and its far-flung field sites.
The strain of malaria which looms most dangerously in PNG, P. vivax, has too often been overlooked and underestimated in malaria research efforts because it’s less deadly than P. falciparum. But debilitating sickness has a shattering and enduring impact on individuals and communities when its victims can’t work or go to school or care for their families.
The powerful trick of vivax and the other local player, ovale, is their ability to lurk, dormant, in the liver of human hosts. Over the ages these parasites have ensconced themselves as liver-stage hypnozoites deep in the collective body of the populations of north coast PNG, carried about and nurtured by often healthy, unwitting men, women and children. The enemy is within.
Sometimes the hypnozoites rouse to inflict relapsing illness on their carriers. This is the malaria tale familiar to so many travellers and soldiers who have returned from the tropics to find themselves mysteriously floored by bouts of illness for years afterwards.
Often the hypnozoites lurk entirely under the radar. Individuals hosting them rarely if ever experience any of the classic symptoms of malaria. The hypnozoite does not show itself on any presently available diagnostic blood test. Even when awakened the infection in the blood can sometimes also lie low, produce few if any symptoms and be difficult to detect by standard methods.
But, explains Robinson, “if you screen people with something more sensitive, you often find they come up positive, and potentially have the parasite stage that is transmissible back to the mosquito”.
If an uninfected mosquito feeds on a Plasmodium-infected human, the parasite might seize the opportunity to climb aboard the mosquito. When the now-infected mosquito next takes a meal of human blood, injecting saliva down into its meal to stop it clotting, the parasite slides in as well.
The system makes for a kind of parasitic magic pudding. The blood running in the veins of human populations in endemic malaria country serves as a replenishing reservoir for the parasite. “Tackling this,” Robinson says, “is a major challenge.”
Robinson was lead investigator of a landmark 2015 study that revealed four out of five cases of P. vivax malaria infections, and at least three out of every five P. ovale cases in PNG children, come from relapses rather than fresh bites. The study provided a critical insight into the dynamics of the disease, and what it would take to get on top of it. Interrupting the transmission cycle, the researchers concluded, requires mass treatment campaigns combining blood and liver stage treatments. Whatever measures might be taken to eliminate or control the parasite’s spread in the outside world – bed nets, insecticide spraying – would be undermined so long as the parasite could revive itself from the liver stage.
The capacity to roll out treatments that can knock the parasite out of the liver is hampered by limitations around available drugs. Right now the only drug licensed to clear the hypnozoite liver stage is primaquine. But for individuals who lack a gene that is important for normal red blood cell function, primaquine can be toxic, so all patients need to be carefully screened and monitored.
Finding ways to overcome these obstacles is just one of a broad sweep of investigations underway in the PNGIMR laboratories, drawing on work across a range of communities and field sites, many of them enlisting cohorts of hundreds, sometimes thousands, of local people.
“For me, understanding malaria, and ways that we might possibly intervene against malaria, is all about the people,” Robinson says. “Working closely with communities to identify who is infected, who is most at risk and how that is changing. Understanding the dynamic interplay between host, parasite and vector, so that we know what interventions will be effective and have a sustained impact.”
One of the communities where Robinson, her institute colleagues and their international partners have been engaged for the past decade, collecting intelligence and blood samples and rolling out trials, is the old mission settlement of Mugil, about an hour’s rough driving north from Madang up the coast of the Bismarck Sea. She parks her 4WD under the trees at the busy health centre, where about two dozen people – many heavily pregnant women, or women with young babies – wait their turn to see a nurse. Robinson chats easily, mother to mother, in a mix of English and Tok Pisin.
It’s something of a treat these days for Robinson to get out of the office but she plainly revels in field work, connecting easily and warmly with locals. Seduced into global health during a stint volunteering in Ghana, she first came to PNG a decade ago as a 27-year-old, doing fieldwork for her PhD in malaria immunology at Melbourne’s Walter and Eliza Hall Institute (WEHI). She lived for months at a stretch in one of PNGIMR’s field outposts at Maprik, in East Sepik Province (north-west of Madang), famous for its wild rivers, crocodiles, carvings, culture, and off-the-chart malaria rates.
Her interest was in studying the natural immune responses in children living in endemic malarial zones, and her research drew on samples and data collected by PNGIMR teams.
Having fallen a bit in love with PNG, she leapt at the opportunity in 2009 to work at the institute full-time – initially on secondment from WEHI, and these days working in affiliation with the Burnet Institute, also based in Melbourne. When she and her husband made the move to Madang, they planned to stay for two years, but they stayed for eight years and two babies of their own.
Though the Mugil facilities are tired, they are better resourced and staffed than many others in PNG. In a tiny room tucked under a wide veranda, Sr Mary Salib examines a miserable-looking seven-year-old boy brought to the clinic by his mother because he has “skin i hat”– fever. Although based at the health centre and pitching in on general duties, Salib is also on PNGIMR’s payroll, attending to any patients suspected of having malaria.
She pricks the boy’s finger and squeezes a drop of blood onto a white dipstick. A few minutes later a rapid diagnostic test, which has revolutionised malaria treatment in recent years, comes up positive for P. vivax malaria.
Salib explains to the boy’s mother he will be given artemether-lumefantrine tablets and primaquine (PNG’s first-line standard treatment for uncomplicated malaria) and should begin to feel much better within a week or so. Sickness, though, might linger for a month, its severity compounded by common factors like sepsis, bacterial meningitis and, most significantly, malnutrition.
Salib also works through a consent protocol with the boy’s mother to enrol him in one of the ongoing studies being conducted at Mugil that range from routine surveillance to long-haul tracking of hundreds of children.
With this information, Robinson and her colleagues can begin to untangle questions around children’s immunity as well as the activity of the various parasite species in PNG – which ones are active in which locations and what sicknesses in addition to malaria are they causing.
Nationwide, there has been a progressive decline in the prevalence of both P. falciparum and P. vivax, Robinson says, but the story varies between different parts of the country, and is dynamic. Inland, transmission has declined and stayed low, with bed nets having made a big impact on reducing cases. But in coastal areas and lowlands – like the Madang province – the suspicion is that rates have popped back up a little bit.
Whether this is indeed happening and, if so, whether these are new infections or coming out of the hypnozoite “reservoir”, is soon to be the subject of a major investigation by Robinson and colleague Moses Laman, who has a central role in a suite of international studies now underway.
Laman, a paediatrician turned researcher, is himself a survivor of severe malaria he contracted as a child growing up on the Sepik River. His research tries to unpick some of the intriguing genetic factors at play in malaria scenarios in PNG. There is a lot of evidence in the literature that mortality in Melanesian children with severe malaria is lower. Laman’s work investigates why, when they get the disease, they don’t die like African children.
One of the key projects at the Mugil centre investigates the potential “kick in the tail” of successfully preventing malaria in children aged under five – historically the cohort most likely to die. The current hypothesis is that as exposure to the malaria parasites becomes less frequent, children won’t develop strong protective immune responses when they are very young. Which means they may become sick as older children or adolescents.
“So we need to consider that in the next 10 years the vulnerable age group might shift upwards,” Robinson says, “and what impact this will have in terms of transmission and control.”
To defeat malaria requires capturing not just human data, but the enemy. To that end, the PNGIMR deploys some creative and sometimes crude, albeit effective, strategies.
An example is the “human landing catch”. Valiant teams of researchers are sent into villages at dusk. They bare their ankles, tantalising the mosquitos. When the insects land, the trick is to suck them up in lengths of plastic and imprison them in vials before they take their meal.
Another technique is to hoist plastic barriers up on stilts to catch passing mosquito traffic. This provides the institute’s entomology laboratory with specimens that have already sated their thirst for blood. That blood meal is analysed, yielding insight into which creatures, human or pig or otherwise, are preferred by different species.
The surveyors also compose data sheets of mosquito behavior. There is evidence that some species are evolving countermeasures to bed nets. Denied access to warm, sleeping bodies, they change strategy. Late-night biters strike earlier; indoor biters feed outdoors. This gift for adaptation – the secret of the Anopheles mosquito’s superlative evolutionary performance – will have profound implications for control measures into the future.
Overseeing this cornucopia of programs makes for a richly rewarding scientific life, Robinson says. While some research is long haul, other programs can have immediate translation and impact on the ground. For instance, earlier IMR work investigating and demonstrating the efficacy of new antimalarial drugs underwrote the shift to artemether-lumefantrine as an effective first-line treatment. And trials of new prevention regimes in pregnancy and infancy substantially improved the health of mothers and babies involved, reinforcing policy on intermittent preventative treatment for malaria during pregnancy – that is, giving pregnant women a full course of antimalarial medicine at routine antenatal checkups, whether the woman has malaria or not.
Currently the institute is running a world-first trial of a novel drug regime for the control and elimination of another disease spread by mosquitoes, lymphatic filariasis. Commonly known as elephantiasis, this neglected tropical disease impairs the lymphatic system and leads to gross swelling, disability and stigma. This trial is set to change WHO policy and accelerate elimination of the disease worldwide.
Robinson is passionate about nurturing home-grown talent. “One of the most rewarding parts of being here this length of time is being able to see people go from being clinicians or science graduates straight out of university coming into research for the first time, learning how research is done, to getting a PhD, coming back as experienced and independent researchers,” she enthuses.
“We are seeing the development of a cohort of Papua New Guineans in leadership positions in this institute, addressing the questions that are really important for PNG; and that is an incredibly satisfying difference to when I arrived in 2009.”
What PNG and its people have taught Robinson, she says, is immeasurable.
“When I came up here I was very focused on the research questions I was wanting to ask, the projects I was working on, and probably had a narrow and fairly naïve view of how that work fitted into the overall context of malaria in PNG, and even globally,” she says.
She has also learnt how to communicate science and negotiate informed consent with teams operating in 70 languages and vastly differing cultural systems, to locate individuals in far-flung jungle villages, to reconcile the ritual demands of modern medicine and ancient superstitions and not run afoul of complex local politics. And, not least, how to pilot that 4WD across rivers, mountains, and broken roads.
