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Science 8 November 2013:
Vol. 342 no. 6159 pp. 684-687
- News Focus
The Forgotten Malaria
Long considered "benign," the malaria parasite Plasmodium vivax threatens billions while eluding control measures. Now, scientists are going on the offensive.
It has plagued english kings and as many as eight U.S. presidents—including George Washington and Abraham Lincoln—and may have helped kill Genghis Khan. It causes wracking fever and chills, headaches and muscle pain, and can lead to severe anemia. After you think you have beaten it, it can return again, months or even years later, starting the same cycle of misery. Roughly one-third of the world's population is thought to be at risk, mostly in Asia and Latin America. And almost no one has ever heard of it.
It is Plasmodium vivax, one of the five Plasmodium species that infect humans and cause malaria (see table, p. 685). For many years, vivax malaria was officially called "benign" malaria, in contrast to the "malignant" variety caused by its cousin Plasmodium falciparum. Falciparum malaria is undeniably deadly, killing more than 650,000 people each year—mostly children in sub-Saharan Africa—and accounting for more than 90% of global malaria deaths. Because it is so lethal, it has received most of the attention—and funding—in the global fight against the disease.
In contrast, vivax malaria has long been an afterthought in both public health plans and in research funding. But that is beginning to change, in part because the global campaign against malaria is starting to pay off. Since the wide-scale introduction of bed nets and new drugs, malaria rates have fallen dramatically across the globe. There is even talk about eventually eradicating the disease (Science, 7 December 2007, p. 1544). But vivax malaria can evade some of the standard malaria-fighting tools, so as overall rates of malaria fall in a region, the proportion of cases that are caused by P. vivax increases. And although vivax malaria kills fewer people, it is decidedly not benign. "The saying used to go: Vivax malaria doesn't kill you, but you feel like it will," says Robert Newman, director of the Global Malaria Programme at the World Health Organization (WHO) in Geneva, Switzerland.
Now, as public health leaders intensify their push to eliminate the disease from more and more regions, they are also starting to give P. vivax special attention. For the first time, Newman says, WHO is drawing up a specific plan to address vivax malaria as part of its updated global malaria-fighting strategy, due out in 2015. The plan is likely to include, for example, better diagnosis of parasite species in patients and updated treatment guidelines. "We have recognized the deficiencies of always making vivax an afterthought," he says. The fight against vivax may also benefit from a new drug to overcome the parasite's best defense: its ability to lie dormant in the human liver.
Richard Feachem, the director of the Global Health Group at the University of California, San Francisco, who has long warned about the threat of vivax malaria, argues that such strategies will be crucial to defeating malaria. "The final battle against malaria is a battle against vivax."
A formidable foeIn several ways, Plasmodium vivax is even more exquisitely adapted to its human host than P. falciparum is. Unlike P. falciparum, P. vivax can populate the bloodstream with sexual-stage parasites—the form picked up by mosquitoes on their way to the next victim—even before a patient shows symptoms. That means treating symptomatic patients promptly doesn't necessarily help stop an outbreak, as it does with falciparum malaria, in which fevers occur at the same time as sexual stages develop. When the debilitating symptoms do set in, they make the human host miserable but are usually not fatal—at least in the short term—which allows the parasite to continue multiplying. And when vivax hides out in the liver, it causes no symptoms and is undetectable in blood tests, only to reappear weeks or even many months later, once again tormenting the human host and ready, again, to infect new mosquitoes."Falciparum kills you quickly. Vivax kills you slowly," says malaria researcher Ric Price of the University of Oxford in the United Kingdom and the Menzies School of Health Research in Darwin, Australia. At first glance, clinical cases of both vivax and falciparum malaria look similar. Both cause the classic symptoms of alternating fever, chills, and sweats. Both kinds of malaria invade the blood. But whereas P. falciparum attacks red blood cells of all ages, P. vivax targets reticulocytes, immature red blood cells that are relatively rare, which can make vivax infections hard to diagnose. When P. falciparum invades red blood cells, it makes them rigid, which is thought to lead to blocked capillaries, a factor in the deadly cerebral malaria. Blood cells infected with P. vivax seem to remain pliable, which might explain why it isn't quite as lethal.How and why P. vivax causes severe malaria is unclear, but recurrent episodes leave people chronically anemic—children are especially vulnerable, Price notes. A single infectious bite can trigger six or more relapses a year, as the dormant parasites in the liver activate and cause a new bout of disease. Fighting off those episodes can leave people more vulnerable to other diseases—and to poverty and malnutrition, because they can't work while ill. Other infectious diseases, including falciparum malaria, also exacerbate the disease because they seem to trigger relapses. "It's a cofactor in a lot of people's deaths," says Simon Hay, an epidemiologist at the University of Oxford.As researchers delve into vivax malaria, it is becoming apparent just how little is known about the parasite. Much of the research on it was done more than half a century ago, when the parasite was endemic across North America and northern Europe. (Tens of thousands of people were infected in outbreaks across the Netherlands and northern Germany after World War II.) In a strange twist, P. vivax was even used from the 1920s until the 1940s as a radical treatment for end-stage syphilis (see sidebar, p. 686). The "malariotherapy" practitioners recorded and published clinical data on hundreds of patients, documenting the behavior of different strains and the clinical course of the disease. Vivax malaria "is one of the only diseases or infectious agents that we've forgotten more about than we've learned in recent years," says Nick White, a professor of tropical medicine at Mahidol University in Bangkok and the University of Oxford."We have a vivax research deficit," Feachem says. Although scientists discovered in the 1970s how to grow P. falciparum in the lab, there is still no system for culturing P. vivax for more than a few weeks. It has even been unclear just how many people P. vivax sickens and where the toll is the highest. Malaria cases are notoriously hard to count, because they occur overwhelmingly in regions where health care—and health care records—are lacking (Science, 15 June 2012, p. 1372). And not all diagnostic tests distinguish whether a patient is suffering from vivax or falciparum malaria.To help fill the gap, the Malaria Atlas Project, which Hay coordinates, has used geographic, population, and epidemiological information to estimate the number of people at risk of contracting P. vivax (Science, 6 August 2010, p. 618). Their latest analysis concluded that 2.5 billion people are at risk, which means they are living in places where the parasite has been reported and where mosquitoes can transmit it.Most of those are in Asia and Latin America. Although P. vivax used to be entrenched in Europe and the United States, it disappeared as countries became wealthier and housing conditions improved. (One of the most effective, though expensive, antimalaria measures is mosquito-proof housing with screens on the windows and doors.) Now, it is a plague of low- and middle-income countries, except those in sub-Saharan Africa, where the P. vivax map has a conspicuous hole. There, most of the population lacks the Duffy antigen, a protein on the surface of red blood cells that P. vivax uses to invade the cells. The parasite can't spread effectively in populations in which most people are "Duffy-negative."P. vivax is carried by at least 71 species of mosquitoes, which gives it another edge over P. falciparum. Many vivax vectors live happily in temperate climates—as far north as Finland. Some even prefer to bite outdoors or during the daytime, so in some regions indoor insecticide spraying and bed nets are less effective at preventing the disease. Several key vector species haven't ever been grown in the lab for closer study, and it's also unclear how widespread insecticide resistance might be.One bright spot is that, like falciparum malaria, vivax malaria is treatable. In fact, P. vivax has so far developed less resistance to common drugs. Chloroquine, which has lost most of its potency against P. falciparum, can still effectively treat acute infections of P. vivax in most regions.But those treatments are powerless against the parasite's nastiest trick: its ability to lurk in the liver, making it much harder to cure than P. falciparum. Both parasites, when they are transmitted from mosquito to human host, go first to the liver. But unlike P. falciparum parasites, which undergo asexual reproduction in the liver and then burst out to infect red blood cells, some vivax parasites simply go into hiding. They form what are called hypnozoites (the name derives from "sleeping parasites"), an especially small form that nestles inside a liver cell. There they remain for weeks, months, or even years, waiting until chances are good that a recipient mosquito will be available to pass sexual stages on to the next victim. In fact, it is the hypnozoites that allow the parasite to survive in more temperate zones, where mosquitoes bite only part of the year. The parasite can bide its time for 9 months or even longer—enough time to wait out the winter and allow new vectors to hatch. (Another parasite, Plasmodium ovale, can also form hypnozoites, but it is much rarer than P. vivax.)Hypnozoites can't be detected by blood tests, so the best strategy to eliminate the parasite from a region would be to mass-treat populations with a drug that could kill the sleeping pathogens. One drug can do that: Called primaquine, it was developed in the 1940s and early 1950s. It has two major drawbacks, however. The standard dose requires people to take a daily pill for 14 days—not an easy thing to enforce in people who don't feel ill. And in people who have a genetic condition called G6PD deficiency, the drug causes red blood cells to burst open. In severe cases, the reaction, called hemolysis, can be fatal.G6PD stands for glucose-6-phosphate dehydrogenase, an enzyme that is especially important in red blood cell metabolism. There is no cheap, easy field test for G6PD traits, so any mass treatment campaign risks severe side effects in some people. The variant also seems to confer some protection against vivax malaria, so that regions in which the parasite is common tend to have more people with the trait.Another complication is that the drug itself is not well understood. No one knows how the body processes it or how it attacks the hypnozoite. The standard 2-week dose stems from the 14 days it took to ship malaria-infected soldiers home from the Korean War. Studies have shown that people treated with the drug have fewer relapses, but there is little definitive data on dosage, efficacy, or resistance.
Hopeful glimmersAn improved, if imperfect, alternative is raising hopes. At the annual meeting of the American Society of Tropical Medicine and Hygiene in Washington, D.C., next week, researchers are scheduled to present results from a long-awaited trial of what could be the first new drug to target liver-stage parasites in half a century, tafenoquine. Its main advantage: A single dose, instead of a 14-day course, seems to be sufficient. That "would be a game-changer," Newman says.Tafenoquine was developed by researchers at the Walter Reed Army Institute of Research in the 1970s and tested, decades ago, in safety trials in thousands of healthy volunteers. It languished, however, until the push for malaria elimination sparked new interest in alternatives for primaquine, says Tim Wells, chief scientific officer of the Geneva-based nonprofit Medicines for Malaria Venture (MMV), which is helping coordinate the trial with the pharmaceutical company GlaxoSmithKline (GSK). In 2011, the partners launched the trial testing the effectiveness of a single dose of tafenoquine compared to a standard course of primaquine in 320 malaria patients in Brazil, India, Thailand, and Peru. (The drugs were combined with a standard 3-day course of chloroquine to treat blood-stage parasites.)Although GSK scientists can't talk about the study before the meeting, initial trial results posted on the company website indicate that 90% of patients who received a single 300- or 600-mg dose of the drug were relapse-free 6 months later. Among patients who received primaquine, 24% relapsed within 6 months. "The data are absolutely spectacular," Wells says. Ideally, he says, researchers will be able to combine the safety data from the Army's earlier trials with the new study in a submission to the U.S. Food and Drug Administration for approval.Tafenoquine is chemically similar to primaquine, so it still causes hemolysis in people who are G6PD deficient. Wells says GSK will apply for its approval only in combination with a test for G6PD deficiency. That could limit its use in some regions. Still, Newman says, a single dose is a huge improvement over a 14-day course of drugs. If the results hold up, he says, "tafenoquine will fix a lot of things."Although other antihypnozoite drug candidates are sparse, the search for alternatives is gaining momentum. In 2008, the first P. vivax genome was sequenced. Since then, several more strains have been added to the databases, allowing researchers to identify new potential weak spots. Primate models and new ways to grow the parasite in vitro are also helping researchers search for new compounds that can target the parasite's liver stages.Sangeeta Bhatia, a bioengineer at the Massachusetts Institute of Technology in Cambridge, has developed a way to grow human "microlivers," liver cells growing together with supporting cells that can live in the lab for 4 to 6 weeks. In July, Bhatia and her colleagues described in Cell Host & Microbe how they were able to grow liver stages of both P. falciparum and P. vivax. The researchers saw miniature forms of the parasite in some of their vivax cultures, which may be hypnozoites. The scientists did not see any of the small forms reactivate, Bhatia says, so they haven't yet proven that they have cultured hypnozoites, but she and others think it is likely. "We have a glimpse of the organism for the first time in vitro," she says.Despite the challenges, Feachem says he is optimistic that with new attention to P. vivax, the parasite can ultimately be defeated, even in tropical regions where it seems hardest to tackle. He points to Taiwan, Singapore, and the Maldives as places that, with sufficient investment, managed to eliminate the parasite with existing tools.A century ago, malaria "was a global disease. It was endemic in every country … including regions north of the Arctic Circle," Feachem says. More than 100 countries have eliminated malaria in the past century, he says; all of them overcame vivax. To be sure, he says, many of those victories were closely linked to economic development. Still, he says, "we've won this war 100 times in the past 100 years. It's not like we can't do it."