When Janet Hemingway started her career in mosquito research in 1977, a child was dying of malaria every 10 seconds. Yet the disease, and the mosquitoes that carry it, were low on the global health priority list.
Today, the landscape has been transformed. Scientists at the prestigious Liverpool School of Tropical Medicine (LSTM) in the United Kingdom, which Hemingway now heads, and elsewhere have sequenced the genomes of at least 23 mosquito species, looking for clues that might help them conquer the disease. And malaria has surged to the top of the global agenda. Thanks to a bolus of new funds, deaths have been halved. And halved again.
But one thing hasn't changed. The world still relies on the same class of insecticides, known as pyrethroids, as it did in 1977. Now, in part because of that neglect, these compounds may be nearing the end of their useful lives as mosquitoes develop resistance to them at alarming rates, and there is little in the pipeline to replace them. "If we don't do something about this very quickly, we have a public health catastrophe on our hands," Hemingway says.
Pyrethroids have played an outsize role in the global fight against malaria in the last decades. They are the main compounds used to spray the inside walls of homes—so-called indoor residual spraying, or IRS—to kill the Anopheles mosquitoes that transmit the disease. And they are the only insecticides that can be used on bed nets. Much of the global success in fighting malaria has come from these two interventions. In a Nature paper last year, a group led by Simon Hay at the University of Oxford in the United Kingdom estimated that between 2000 and 2015, some 633 million malaria deaths were averted, with 68% of that decline due to insecticide-treated bed nets and 10% to IRS. (Treating people with antimalarial drugs accounted for the remaining 22%.) Pyrethroids have also played a role in the fight against Aedes aegypti, the main mosquito transmitting the yellow fever, dengue, and Zika viruses, even though bed nets are less effective against A. aegypti because it predominantly bites people outdoors and during the day.
Pyrethroids have several distinct advantages: They kill mosquitoes efficiently, act rapidly, and, although toxic, are safer for humans than the alternatives. But when the massive rollout of insecticide-treated bed nets began in Africa in the early 2000s—more than a billion have been distributed—little thought was given to resistance, says Maureen Coetzee, director of the Wits Research Institute for Malaria at the University of the Witwatersrand in Johannesburg, South Africa. "Nobody dreamt that insecticide resistance would spread the way it has spread throughout Africa."
Scientists shouldn't have been surprised, however. An earlier insecticide, DDT, played a major role in driving down malaria cases starting in the 1940s. But in many places, resistance reversed those gains. In Sri Lanka, for instance, malaria was all but wiped out with the help of DDT, but by the end of the 1960s, when resistance was widespread, cases surged to more than half a million a year. By that time, Rachel Carson had highlighted the toxic effects of DDT in Silent Spring, and many nations banned its use.
Nor has there been much incentive for companies to develop new mosquito-killing insecticides, which could be used in tandem with existing ones to slow the development of resistance. Most R&D has focused on agricultural chemicals, a far more lucrative market. "No publicly traded company is going to spend the money required to discover and develop and take to the market an insecticide for public health," says Nick Hamon, who heads the Innovative Vector Control Consortium (IVCC) in Liverpool. "These companies are looking for $100 million in sales every year to have any chance of recouping the money for a new compound."
First detected in Ivory Coast in 1993, resistance to pyrethroids was relatively rare until about 10 years ago, when it began racing across the continent (see map above). "Some countries are seeing an increase in malaria transmission, and resistance is one of the probable causes," Coetzee says. It's hard to be sure, she says, because drug shortages or cutbacks of control programs may also be taking a toll. But Hilary Ranson of LSTM thinks the problem is real and will only get worse. "I think insecticide resistance is a time bomb."
Many scientists have their hopes pinned on new approaches to vector control that would be less likely to run into resistance or prove toxic, such as mosquitoes genetically modified to die young, traps that lure the insects to their death, or insecticidal bacteria or fungi. "We need to diversify in terms of the kind of tools that we use to control mosquitoes and not focus it entirely on chemical control," says Willem Takken, a medical entomologist at Wageningen University & Research in the Netherlands. But Hemingway and other scientists caution that even if these new tools prove their mettle, they are years away at best. The first priority, Hemingway says, is to preserve and improve the tools we know work. And to her, that means insecticides.
That's why, in 2005, Hemingway started IVCC, a public-private partnership that aims to develop entirely new classes of insecticides and get them on the market in 5 to 8 years. Since IVCC's inception, the Bill & Melinda Gates Foundation has kicked in more than $200 million, and the U.S. Agency for International Development, the Wellcome Trust, and others have each contributed millions. In the meantime, IVCC is scrambling to help scientists find smarter ways to use existing insecticides or combine them with other interventions in a way that keeps resistance at bay.
With IRS, one option is to switch to an insecticide from one of the other available classes: organochlorides, carbamates, and organophosphates. South Africa went back to using DDT, an organochloride, after an epidemic of malaria transmitted by pyrethroid-resistant mosquitoes in 1999 and 2000. But many other countries avoid the insecticide—and not just for environmental reasons. DDT and pyrethroids also work through a very similar mechanism, so some mosquitoes resistant to pyrethroids are also resistant to DDT.
Some countries have switched from pyrethroids to an organophosphate insecticide called actellic. But actellic is four times as expensive, Hemingway says. "Fewer houses are getting sprayed, because the money available hasn't increased fourfold." And with many countries switching to the same compound, there is a danger that resistance will emerge to it as well.
Two new mosquito killers could be on the market as soon as 2017: SumiShield, developed by Japanese company Sumitomo Chemical, and chlorfenapyr, an insecticide mostly used to control cat fleas, developed by BASF. But both are seen as stopgap measures. Although they are new to public health, these compounds have been used in agriculture for years, so some mosquitoes may be resistant already. And SumiShield is a neonicotinoid, a class of compounds that faces public opposition because it has been implicated in the mass die-off of pollinators.
Finding replacement insecticides for bed nets is far trickier. Any insecticide used in a bed net "has to be safe enough that a child can put it in their mouth," says Ranson, and only pyrethroids fit the bill. Pyrethroids also have a trait scientists call excito-repellency: They stimulate mosquitoes to leave the net. Neither SumiShield nor chlorfenapyr does that.
Not only are bed nets the best weapon in the fight against malaria-carrying mosquitoes, in many countries they are the only one. "Some countries still don't have IRS as part of their program. They view it as too expensive and difficult to implement," Ranson says.
From 2011 to 2016, Ranson headed an EU-funded project called AvecNet to evaluate new weapons to fight mosquitoes and take one through a clinical trial. The researchers eventually chose a net that combines pyrethroids with a compound called pyriproxyfen, which prevents mosquitoes from producing fertile eggs. "The idea is that if the mosquitoes are fully susceptible they will be killed by the insecticide, and if they are resistant they will pick up a dose of the sterilizing agent and the population will crash as well," Ranson says. The group began testing the nets in 40 clusters of villages in Burkina Faso in 2014; results of the trial should be known in a few weeks. "There is a lot riding on this," Ranson says. "If it doesn't show any improvement, then I doubt there will be any further clinical trials of it."
Another combination net is already on the market, but it's not widely used because its efficacy is still in doubt. The net combines pyrethroids with a chemical called piperonyl butoxide (PBO). PBO blocks enzymes that help resistant mosquitoes break down pyrethroids, so, in theory, the mosquitoes should become susceptible again. Small-scale studies have suggested that the nets do work, but there haven't been any large-scale clinical trials.
To find new compounds for spraying and nets, IVCC has partnered with several large chemical companies including BASF, Syngenta, and Sumitomo to screen more than 4 million compounds in their libraries. Over the next few months they will choose three to go into large-scale toxicology testing, Hamon says. Any candidates for bed nets will have to pass other demanding tests: In addition to being safe, they will have to survive at least 20 washes and perform well for 3 years. "We were just very lucky with the pyrethroid insecticides in the '70s and '80s," Hamon says.
Luck may not run out quite as fast as many fear. Although resistance to pyrethroids is widespread, its impact on public health is still unclear. Even though a mosquito may survive a dose of an insecticide, the chemical may weaken it in some way. And the genes needed for resistance may take their own toll, perhaps by shortening a mosquito's life span. If the insect survives for fewer than 14 days, the malaria parasites won't have enough time to mature to the stage where they can infect humans, says Matthew Thomas, an entomologist at Pennsylvania State University, University Park. "There is some evidence to show that things like that can happen," Thomas says.
Insecticide resistance is going to matter at a certain point, he says—"What we don't know is whether we are just approaching that point, whether it is 1 year away, or five or 10." Defeating diseases like malaria may depend not only on finding chemicals to kill mosquitoes, but also on understanding how the insects manage to survive them.