A Pivotal Mosquito Experiment Could Not Have Gone Better
An extremely common microbe can stop the insects from spreading the virus that causes dengue fever.
Adi Utarini had her first of two bouts of dengue fever in 1986, when she was still a medical student. Within a few hours, she spiked a temperature of 104 degrees Fahrenheit and couldn’t stand up, because her knee was shaking so badly. Within a few days, she was in the hospital. That experience is common in Utarini’s home city of Yogyakarta, Indonesia: It has one of the highest rates of dengue in the country, which itself has one of the highest rates of dengue in the world. “Here, when you ask people if they know someone who’s had dengue, they can always name someone,” says Utarini, now a public-health professor at Gadjah Mada University.
Thanks to her work, that might soon change.
Dengue fever is caused by a virus that infects an estimated 390 million people every year, and kills about 25,000; the World Health Organization has described it as one of the top 10 threats to global health. It spreads through the bites of mosquitoes, particularly the species Aedes aegypti. Utarini and her colleagues have spent the past decade turning these insects from highways of dengue into cul-de-sacs. They’ve loaded the mosquitoes with a bacterium called Wolbachia, which prevents them from being infected by dengue viruses. Wolbachia spreads very quickly: If a small number of carrier mosquitoes are released into a neighborhood, almost all of the local insects should be dengue-free within a few months. It’s as if Utarini’s team vaccinated a few individuals against a disease, and soon after the whole population had herd immunity.
The World Mosquito Program (WMP), a nonprofit that pioneered this technique, had run small pilot studies in Australia that suggested it could work. Utarini, who co-leads WMP Yogyakarta, has now shown conclusively that it does. Her team released Wolbachia-carrying mosquitoes in parts of Yogyakarta as part of a randomized controlled trial. The results, which were unveiled last year and have now been published, showed that Wolbachia rapidly spread among the local mosquitoes, and reduced the incidence of dengue by 77 percent. “That provides the gold standard of evidence that Wolbachia is a highly effective intervention against dengue,” says Oliver Brady, a dengue expert at the London School of Hygiene and Tropical Medicine, who was not involved in the study. “It has the potential to revolutionize mosquito control.”
The trial’s results were so encouraging that the researchers have since released Wolbachia-carrying mosquitoes over all of central Yogyakarta—a 32-square-kilometer zone that’s home to more than 400,000 people. They’re now expanding into the densest surrounding provinces, aiming to protect 4 million people by the end of 2022. If they succeed, they should be able to prevent more than 10,000 dengue infections every year, Katherine Anders of the WMP told me. And the team is optimistic enough that it’s daring to think about an even grander goal: eliminating dengue from the city altogether.
“Dengue is a particularly challenging virus,” Natalie Dean, a statistician at the University of Florida, told me. It comes in four distinct versions, or “serotypes.” People who recover from one serotype can still be infected by the other three; if that happens, they’re more likely to develop severe and potentially lethal symptoms. For that reason, the only existing dengue vaccine also increases the risk of severe dengue in people who’ve never been infected, and is recommended only for people who’ve already encountered the disease.
Then there’s the mosquito. Aedes aegypti was once a forest insect confined to sub-Saharan Africa, where it drank blood from a wide variety of animals. But at some point, one lineage evolved into an urban creature that prefers towns over forests, and humans over other animals. Carried around the world aboard slave ships, Aedes aegypti has thrived. It is now arguably the most effective human-hunter on the planet, its senses acutely attuned to the carbon dioxide in our breath, the warmth of our bodies, and the odors of our skin. The viruses it carries have also thrived, including those responsible for Zika, chikungunya, yellow fever, and dengue. (Malaria, the deadliest mosquito disease, is caused by a parasite that’s spread by a different mosquito species.) “Dengue is one of the few infectious diseases that has increased year-on-year over the past few decades,” Brady told me. Aedes aegypti can be poisoned with insecticides, but quickly evolves resistance. The standing water in which it breeds can be removed, but the mosquitoes always come back. The world needed something new.
Wolbachia was first discovered in 1924, in a different species of mosquito. At first, it seemed so unremarkable that scientists ignored it for decades. But starting in the 1980s, they realized that it has an extraordinary knack for spreading. It passes down mainly from insect mothers to their children, and it uses many tricks to ensure that infected individuals are better at reproducing than uninfected ones. To date, it exists in at least 40 percent of all insect species, making it one of the most successful microbes on the planet.
But Aedes aegypti isn’t one of Wolbachia’s natural hosts. Scott O’Neill, the founder of the WMP, spent decades trying to get the latter to stably infect the former, and his team finally succeeded in 2006. Five years later, it released 300,000 of its special mosquitoes into two suburbs of Cairns, Australia. Within four months, 80 to 90 percent of the local mosquitoes were full of Wolbachia. Dengue cases fell, but it was hard to say if that was due to the mosquitoes or some other factor. To prove that Wolbachia could really make a dent in dengue, the team needed to set up a randomized controlled trial. It did so in Yogyakarta.
First, WMP’s Indonesian chapter spent years earning public trust. The Wolbachia approach is unorthodox, and involves releasing live mosquitoes into people’s backyards. Beyond setting up community meetings and WhatsApp hotlines, “we opened up our entomology lab for people to see the technology for themselves,” Utarini told me. By the time the researchers started their trial in 2017, their surveys showed that the endeavor had support from 88 percent of the public. The team divided a large portion of the city into 24 zones and released Wolbachia-infected mosquitoes in half of them. Almost 10,000 volunteers helped distribute egg-filled containers to local backyards. Within a year, about 95 percent of the Aedes mosquitoes in the 12 release zones harbored Wolbachia.
From January 2018 onward, the team checked on people in the city who showed up to primary-care clinics with a fever, and tested them for dengue. This continued until March 2020, when the pandemic brought the trial to a premature end—but fortunately not before it had enough participants. The team found that just 2.3 percent of feverish people who lived in the Wolbachia release zones had dengue, compared with 9.4 percent in the control areas. Wolbachia also seemed to work against all four dengue serotypes, and reduced the number of dengue hospitalizations by 86 percent.
Even then, these already remarkable numbers are likely to be underestimates. The mosquitoes moved around, carrying Wolbachia into the 12 control zones where no mosquitoes were released. And people also move: They might live in a Wolbachia release zone but be bitten and infected with dengue elsewhere. Both of these factors would have worked against the trial, weakening its results. That those results exist, let alone that they are so impressive, is surprising. “We don’t have strong evidence of how effective most [dengue] interventions are,” says Gonzalo Vazquez-Prokopec of Emory University, who studies vector-borne diseases. “When you see trucks spraying insecticides, we don’t know how many dengue cases that prevents.”
The Wolbachia method does have a few limitations. The bacterium takes months to establish itself, so it can’t be “deployed to contain an outbreak today,” Vazquez-Prokopec told me. As the Yogyakarta trial showed, it works only when Wolbachia reaches a prevalence of at least 80 percent, which requires a lot of work and strong community support. And the dengue viruses could eventually evolve some way of resisting Wolbachia. Still, Wolbachia seems to block dengue infections in a variety of ways. It outcompetes the viruses for the nutrients they need to reproduce, and also boosts the mosquito’s immune system. That should make it harder for the viruses to get around the Wolbachia blockade.
The method has other benefits too. It is self-amplifying and self-perpetuating: If enough Wolbachia-infected mosquitoes are released initially, the bacterium should naturally come to dominate the local population, and stay that way. Unlike insecticides, Wolbachia isn’t toxic, it doesn’t kill beneficial insects (or even mosquitoes), and it doesn’t need to be reapplied, which makes it very cost-effective. An analysis by Brady’s team showed that it actually saves money by preventing infections.
“There’s no reason to think that the public-health benefits we’re seeing in Yogyakarta would not accrue elsewhere,” Anders said. “The science is there.” The WMP is now working in 11 countries and territories. So far, 7 million people live under the protective blanket of Wolbachia, and the organization’s goal is to cover at least 75 million by 2025, and at least half a billion by 2030. Those people won’t be protected against just dengue. Wolbachia also seems to work against the other diseases that Aedes aegypti carries, including Zika and yellow fever. It could transform this mosquito from one of the most dangerous species to humans into just another biting nuisance.