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Malaria Mosquitoes Gain Ground as Search for New Defenses Intensifies

Companies and public health agencies are trying to develop low-toxic and inexpensive—yet powerful and long-lasting—new insecticides
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Flickr/Muhammad Mahdi Karim

KARATU, Tanzania – Dr. Frank Artress is loath to get into an arms race with mosquitoes. “You hate to drag out all the heavy poisons,” he says, standing in front of the medical clinic he and his wife built in this rural town. But to fend off the voracious insects and their payload of malaria parasites, he knows there are few other choices.

Artress, a physician from California, frowns as he looks out over the tiny earthen houses straggled across the flank of the Ngorongoro Crater. Their screenless windows and doors, open to damp forest and red, puddle-pocked fields, are bullseyes for mosquitoes. Like many communities in sub-Saharan Africa, Karatu is reliant on house nets laced with insecticides called pyrethroids to keep malaria at bay.

But a decade of blanketing Africa with pyrethroids has fueled resistance to this front-line chemical weapon. Now pyrethroid-immune mosquitoes are spreading quickly throughout the continent.

“At some level, to really control the mosquitoes,” Artress says, “they’re going to have to do more.”

What that “more” is, however, is uncertain. Because of a lack of research, no new chemicals for killing malaria-infected mosquitoes have emerged in more than 40 years.

Now pesticide companies and public health agencies are trying to develop low-toxic and inexpensive – yet powerful and long-lasting – new insecticides. Other researchers are working on novel approaches such as genetically modifying mosquitoes so they can’t harbor parasites.

It's likely to be years before new tools are widely available. In the meantime, health officials say, pyrethroid failure could trigger a malaria resurgence that kills hundreds of thousands of people worldwide.

To fill the void, some are turning to “green” methods, such as botanical oils or other plants that keep mosquitoes away. Others are practicing mosquito birth control by draining ditches where they breed and stocking ponds with larvae-eating fish or larvae-killing bacteria.

However, for a growing number of communities battling malaria, the controversial pesticide DDT, banned in most of the world, may become a more frequent weapon of choice.

A disease of poverty, environment and race
The need for new safe and sustainable malaria-fighting tools is resounding throughout the world’s neediest regions, where the disease sickens an estimated 219 million people and threatens more than 3 billion.

Mosquitoes that are invulnerable to one or more approved indoor insecticides are already active in two-thirds of malaria-ridden countries, according to the World Health Organization. And that figure is probably a “gross underestimate,” said Abraham Mnzava, coordinator of malaria vector control for the World Health Organization’s Global Malaria Programme.

Sub-Saharan Africa and India are hit hardest, but resistant mosquitoes have turned up as far away as Bolivia, Turkey and China. The problem is compounded by the recent emergence of malaria parasites that are immune to the leading medication, artemisinin.

worldwide malaria exposure mapRoughly half the world is at risk for malaria exposure.
Map: US Centers for Disease Control

A disease of poverty, environment and race, malaria kills an estimated 660,000 people – mainly children – every year.

Once prevalent worldwide, malaria was quashed in affluent nations decades ago, largely due to efficient insect control and housing improvements. But as of last year, 104 countries were still plagued by virulent species of parasitic Plasmodium protozoa that live inside female Anopheles mosquitoes and invade human bloodstreams when the insects feed. Half the world’s population remains at risk for malaria, according to the WHO.

Making matters worse, warming temperatures, coupled with deforestation, crop irrigation and other man-made environmental changes, are driving mosquitoes to new grounds across the globe. In sub-Saharan Africa, malaria is now reaching higher altitudes than ever before.

Karatu is one such place. When Artress and his wife moved there seven years ago, they were told “no mosquitoes, you’re above the malaria line,” he said. But “apparently with global warming, there are actually a lot of mosquitoes.”

For communities first encountering the disease, the results can be devastating.

“The appearance of malaria mosquitoes in the African highlands is real,” Mnzava said. “These areas are now prone to malaria epidemics with severe consequences to local populations due to their lack of immunity.”

Pyrethroids losing effectiveness
Developed in the 1970s, pyrethroids are the last new class of pesticides produced for public health uses in nearly half a century.

These synthetic compounds, based on a natural substance found in chrysanthemums, are considered "safe," according to the Environmental Protection Agency. Animal studies, however, have found that pyrethroids alter developing brains, and there have been virtually no studies of their potential effects on human health.

“Given uncertainty about the existence of long-term health effects of exposure to pyrethroids, particularly under realistic scenarios, we should be cautious when promoting pyrethroid products as safe methods for pest control,” a group of environmental health scientists in Canada recently advised.

Nonetheless, pyrethroids are the backbone of all major malaria-control programs. Pyrethroid treatments, provided in a massive, decade-long campaign by U.S. and international aid organizations, have made significant inroads against the disease in recent years. The insecticide saved more than a million lives between 2000 and 2010, according to the WHO.

But reliance on pyrethroids, the only insecticide permitted for mosquito nets and the main ingredient in most indoor sprays, has allowed insects with a gene conferring immunity to flourish. That immunity now threatens to roll back those gains.

The surge of resistance to antimalarial weapons is analogous to today’s spate of “superbugs” that are invulnerable to antibiotics. Both were set off by unsustainable use of chemicals.

“Attacking malaria around the world and using a lot of drugs will generate drug-resistant parasites. And attacking mosquitoes around the world and using a lot of insecticides will generate insecticide-resistant mosquitoes,” said Sir Richard Feachem, former executive director of the Global Fund to Fight AIDS, Tuberculosis and Malaria and current director of the Global Health Group at the University of California, San Francisco.

“We always knew that – no fundamental surprise here – we always knew it would happen,” he said. “What we didn’t know was how quickly it would happen.”

The potential impact is huge. If resistance renders pyrethroids in mosquito nets and sprays useless, the toll could be 120,000 malaria deaths and as many as 26 million new cases a year, according to the WHO.

“It’s a serious problem,” said Bruce Hammock, professor of entomology at the University of California, Davis, and member of the UC Malaria Research and Control Group.

Malaria kills an estimated 660,000 people – mainly children – every year.
Image:  US Embassy

“Sadly it started building up in the 1950s, before there were even pyrethroids,” he said.

The culprit was DDT, the big gun in the first global war on malaria. Begun in 1955, widespread and massive spraying had remarkable initial success, with nearly 40 nations, primarily in Europe and the Americas, eradicating the disease.

But the pesticide’s ubiquity – it was also widely applied to crops – unleashed resistant mosquitoes, and by the 1970s, deaths in the remaining malarial countries rebounded to the same or even higher levels than before. Three decades later, as campaigns to eradicate malaria with pyrethroids ramped up, the trigger for resistance had already been pulled.

“Many of the resistance mechanisms to DDT cross over to pyrethroids,” Hammock explained. With cross-resistance, immunity acquired to one pesticide can transfer to a completely different chemical if the two have the same mode of action. DDT and pyrethroids both target the insect nervous system.

“So when we started using pyrethroids widely, we began to see resistance immediately because we’d already selected for it with DDT,” he said.

DDT use may rise
Ironically, with pyrethroids fading, DDT now stands as the primary chemical alternative. Earlier this month, the African Union's Heads of State and Government passed a resolution endorsing DDT for malaria control throughout its 54 member nations.

One of the original “dirty dozen” persistent organic pollutants, the compound was banned under a United Nations treaty except for limited use to control insect-borne disease. That exception was intended to be temporary: four years ago, the United Nation’s Environment Programme (UNEP) announced its goal of a 30 percent drop in DDT use by 2014, with total phase-out by the early 2020s. Now, rising pyrethroid resistance will likely derail that plan.

High levels of DDT can accumulate in people in sprayed homes, such as this home in a Mozambique village.
Image: Flickr/Gates Foundation

DDT and its metabolites are all-but indestructible; they accumulate in the Arctic and concentrate atop food chains. Traces are still found in the breast milk of women worldwide. The chemical thins eggshells, causing near-extinctions of eagles and other birds in the 1960s and ‘70s. In humans, a growing body of evidence links it to miscarriages, abnormal brain development, hypertension, diabetes and cancer.

In Africa, seven countries – South Africa, Mozambique, Eritrea, Swaziland, Mauritius, Zambia and Gambia – report using DDT in the past few years, and the number of nations is likely to increase in response to the African leaders’ recent decision.

Statistics are spotty, but according to UNEP, an average of 3,716 tons of the chemical are produced each year. India is the biggest user, followed by South Africa.

Although mosquitoes are resistant in some regions, DDT remains an effective weapon. “It turns out that it’s a better repellant than a killer,” Hammock said. “DDT can be very useful in malaria control today. If we can keep the mosquitoes out of the house, we could do a lot to break the malaria cycle. We don’t have to kill every mosquito… but we can break the zoonosis [disease spreading from animals to people] and control 90 percent of malaria.

“This will undoubtedly get me thrown out of the Sierra Club [but] if we were using DDT to coat walls [in Africa] or coat mosquito nets, we could…dramatically reduce human suffering," Hammock said.

Yet people in Africa can be exposed to extremely high doses because it is sprayed on walls inside homes. The DDT concentrations in the breast milk and blood of South African villagers exceed those found in Americans and Europeans decades ago. The few health studies that have been conducted in these villages have yielded some disturbing results: DDT has been linked to low sperm counts and semen quality in highly exposed South African men, and to urogenital defects in baby boys.

Concerned about these high exposures, a panel of 15 U.S. and South African health scientists issued a statement in 2009 saying that DDT should be used only as a last resort. They also urged the monitoring of people in homes where DDT is sprayed.

Malaria is transmitted through the saliva of the female Anopheles mosquito.
Image: Public Health England

That same year, UNEP executive director Achim Steiner called DDT “a simplistic option of a previous age” and promised “innovative solutions” and “sustainable choices.”

But last spring, UNEP’S DDT expert group approved the pesticide’s ongoing use for disease control, citing the “lack of new active ingredients with new modes of action and long lasting efficacy to replace DDT.”

The only other chemicals approved for indoor mosquito control – carbamates and organophosphates – are deemed too expensive and wear off too quickly to be used where the need is greatest.

“If we stop using it [DDT], we are sentencing our people to death,” the South African representative declared at the recent African leaders’ meeting, according to the Nigerian newspaper, Premium Times. “Every other continent used DDT to eradicate malaria, so why is our turn different in Africa?”

Mnzava of WHO said “it is a wrong approach to talk about phasing out DDT without making provision for its alternatives. Until cost-effective and sustainable formulations are available, DDT will continue to be one of the insecticides for malaria control broadly and for the management of insecticide resistance in particular.”

Searching for safe, cheap pesticides
The pesticide industry is now searching for replacements that cost only a couple of dollars per application, yet are lethal to insects, slow to degrade and safe for humans, especially children.

“It’s a matter of great urgency,” said Jed Stone, head of access and advocacy for the Innovative Vector Control Consortium, a non-profit collaboration between public health institutions and agrochemical companies working to create new insecticides.

For decades, there was little research into insecticides designed to protect public health. “The whole field just went dead,” said Feachem. Instead, efforts focused exclusively on agriculture.

These women are carrying bed nets treated with pyrethroids. Mosquitoes are becoming resistant to the insecticide, sparking fears of a malaria resurgence.
Image: Flickr/Gates Foundation

“From the ‘70s onwards, there’ve been eight new classes of chemistries for agriculture and none for public health,” said John Lucas, business development manager for global vector control at Sumitomo Chemical, one of the companies now working with the consortium. “To be honest, the market is huge in ag and relatively tiny in public health,” Lucas said.

What’s more, the two markets have greatly different needs. For crops, pesticides must be short-lived to avoid contaminating food, while for public health uses such as mosquito nets, they need to last as long as possible. “So that’s why there’s no real supply of molecules in that [latter] area,” Lucas said.

Malaria mosquitoes breed in standing water, such as these rock pools along the Niger River.
Image: M. Fodde and M. Coluzzi, NIH

The industry consortium aims to produce at least three new insecticides, as well as repurposing agricultural pesticides for indoor use.

Stone is optimistic about the “healthy and robust pipeline of new active ingredients and formulations,” now in progress.

The challenge, Lucas said, is that “many times, you find that the ones that work really well against insects happen to kill mammals as well. And it’s the skill of the chemist to find a compound that has low mammalian toxicity and high insecticidal activity.”

Now, with a rapid screen called the “one mouse test,” they can rule out anything that shows signs of toxicity right off the bat. Advances in entomology have also revealed many more insect target sites, opening the door for new active ingredients with totally different modes of action.

“Instead of just looking at straight kill effects, you’re looking at subtle effects, behavioral effects, long-term effects,” Lucas said. “In the old days you sprayed an insect and if it wasn’t dead in a day you’d say the product is useless.”

But the emergence of new products is hindered by the expense and burden of safety and efficiency trials needed for gaining a WHO recommendation, which major aid organizations require.

“These trials take time, they take a huge amount of money,” Lucas said.

Gaining approval for reformulations of existing pesticides takes at least a couple years and around $1 million. And that path is streamlined compared to the process for completely new chemicals, which can cost “certainly $100 million to bring a new product to market," he said.

As a result, new insecticides will probably not be available for malaria control programs until around 2022, Lucas said.

The WHO is aware of the bottleneck and has created an advisory group to examine new vector control paradigms, Mnzava said.

“This will also help in shortening the process to review new products,” he said.

Some public health scientists, however, say new insecticides should be thoroughly studied before they are approved. Citing the example of pyrethroids, University of California, Berkeley epidemiologist Brenda Eskenazi, a pesticide expert, said “virtually nothing is known about the human health effects… I’m astounded that there’s been very little human research.”

"Green" ways to kill mosquitoes
To many malariologists, this latest round of resistance gives proof that the long-standing reliance on synthetic chemicals to fight malaria can’t continue.

“The agencies hate to hear this… the nets are still effective, but I think the handwriting is on the wall,” said Gregory Lanzaro, a medical entomologist at UC-Davis and expert in the genetics of malaria-transmitting mosquitoes. “Nobody’s pooh-poohing the idea of using bed nets. They’ve saved many, many lives. They’ve worked very well. But the thing is, they’re not sustainable. They’re going to have to be replaced by something else.”

New insecticides are not the answer, Lanzaro and others say, because the mosquitoes will just adapt again.

“It’s a living system and if you poke it, it responds,” Lanzaro said. “We need completely new strategies.”

One approach researchers are working on is genetically engineering mosquitoes to be impervious to the malaria parasite. Another is infecting mosquitoes with bacteria that fight off invading protozoa. While promising, these methods are still in the experimental stage.

“Green” environmental management tactics are proving very successful in some areas.

Draining ditches and removing weeds to eliminate places for mosquitoes to breed – traditional practices largely abandoned with the advent of DDT – helped cut malaria cases by more than half in Mexico and Central America in recent years. Some Mexican states control mosquitoes that breed in algae-covered ponds by skimming the water once a week. Other places, including many parts of the U.S. and Europe, treat breeding sites with biological agents that kill insect larvae.

Image: Courtesy of National Institutes of Health

UNEP and other international health agencies have several projects underway to test non-chemical approaches such as mosquito-repellent trees and larvae-eating fish.

The projects are promising, said Heidelore Fiedler, senior scientific affairs officer with the UNEP Chemicals Branch, “but implementation on the ground moves only slowly… One measure does not fit all.”

Back in Karatu, Artress is trying to put off dragging out the heavy poisons like DDT. A cardiac anesthesiologist who traded his lucrative practice in Modesto, Calif., for bush medicine after a near-death experience climbing Mt. Kilimanjaro, Artress is teaching villagers sustainable practices, such as eliminating standing water around their homes.

On a nearby hillside, meanwhile, Karatu naturalist Paskali Gwandu scouts an alternative in the form of a shrubby plant with spires of yellow flowers. Smoke from the bush, cassia (senna) didymobotrya, called qarerei by the local Iraqw tribe, contains a natural repellent, according to Gwandu.

“We put [the leaves] on the fire in our tribe,” he says, describing how the plants are burned in braziers to fumigate homes.

“When you use cassia,” Gwandu says, “you don't need mosquito net.”

Graph: Roll Back Malaria, World Health Organization

This article originally ran at Environmental Health News, a news source published by Environmental Health Sciences, a nonprofit media company.

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