A plate of Wolbachia-infected mosquitoes, which were released in an Indonesian city.Credit: World Mosquito Program
Epidemiologists typically speak in qualified and maintained language. But newly released results from a trial of a biological technology aimed at stopping the spread of mosquito-borne diseases, they have come up with terms such as “staggering” and “epochal”. The study, conducted in a city in Indonesia, showed that the release of mosquitoes is adapted to carry a named bacterium Wolbachia, which stops the insects from transmitting some viruses, leads to a steep decline in cases of dengue fever. The findings provide the strongest evidence yet that the technology, in development since the 1990s, could free the world from some of these deadly diseases, researchers say.
The trial in Yogyakarta released Wolbachia-infected mosquitoes in randomly designated parts of the metropolis. Rates of dengue in these places were 77% lower, several years, compared to areas that did not get the mosquitoes. The results were reported in press releases on August 26, but the full details of the figures have yet to be published.
It will be important to examine the full data, but “a 77% reduction is really extraordinary”, says Philipp McCall, a vector biologist at the Liverpool School of Tropical Medicine, UK. “This has a great promise.”
The study has been running since 2016 and ended several months early due to COVID-19. But scientists say the results should support the implementation of the technology worldwide. The trial was coordinated by the nonprofit World Mosquito Program (WMP), which hopes to deploy mosquitoes in dengue endemic areas around the world.
“This is a real breakthrough, a new hope for us, for the people and hopefully for the program,” said Adi Utarini, a public health researcher at the University of Gadjah Mada in Indonesia, who co-led the trial.
Stop transfer
The approach proven in the Yogyakarta trial was pioneered by a team led by Scott O’Neill, a microbiologist at Monash University in Melbourne, Australia, and director of the WMP. About 60% of the insect species carry it Wolbachia pipientis, but the bacteria do not naturally infect the Aedes aegypti mosquito species that transmit dengue, Zika and numerous other viruses. Beginning in the 1990s, O’Neill’s team developed laboratory populations of infected A. aegypti and showed these insects do not transmit viruses including dengue.
The team first began releasing mosquitoes in parts of northeastern Australia that experienced periodic outbreaks of dengue – a disease that infects nearly 400 million people annually and kills 25,000, mostly in low- and middle-income countries in Asia, the Pacific Ocean and Latin America. The bacteria tend to spread quickly through local mosquito populations, and a 2018 study from a release program in Townsville found that dengue rates dropped after 4 million mosquitoes were released in several weeks. But the study did not include control areas that did not have mosquito repellent. Australian outbreaks of dengue are also smaller and less common than those affecting cities in Southeast Asia and Latin America, where the virus is endemic.
Lab staff prepared examples of Wolbachia-infected mosquitoes.Credit: World Mosquito Program
The WMP launched the Yogyakarta process to fill those gaps. Utarini and her colleagues divided the city of nearly 400,000 people into 24 clusters, randomly selecting 12 for mosquito release and 12 to serve as controls. Working with clinics spread across Yogyakarta, the researchers identified 400 confirmed cases of dengue among thousands of people who appeared with acute fever. They then compared where people with dengue – who were mostly children – had been in the previous two weeks, to determine if they were in an area where mosquitoes were released or not.
The trial data were unblinded in June – a few months earlier than planned, due to emerging coronavirus cases in Indonesia. But they were “pretty surprising,” said Nicholas Jewell, a biostatistician at the London School of Hygiene and Tropical Medicine (LSHTM) and the University of California, Berkeley, who co-led the study. The 77% reduction in dengue cases in areas receiving Wolbachia mosquitoes tell them that humans are 4 times less likely to develop the disease.
“I’ve never been so successfully involved in a study,” says Jewell, who has been studying infectious disease interventions since the beginning of the HIV epidemic in the 1980s. ‘We’ve never had such a thing before. Condoms provide this level of protection, ”he adds. Jewell thinks her estimate for the reduction in dengue cases is conservative, as many people are likely to have moved between areas with Wolbachia mosquitoes and without. (Now that the trial is done, the WMP will release modified mosquitoes all over the city. “That is our obligation,” Utarini says.)
With the underlying data unpublished, McCall says many questions remain unanswered, such as how the level of protection varies between different areas, and how this relates to the prevalence of Wolbachia in local populations. “All we have is that golden number. We need to hear much more about it, ”he says.
The fall in dengue rates “provides strong evidence for the use of Wolbachia,” says Neal Alexander, an epidemiologist at LSHTM. Looking at how mobility of people between treated and untreated areas affects protection should help determine how generalizing the releases are elsewhere.
Next decades
“Scaling up” is what O’Neill plans to do next. The WMP hopes to release Wolbachia mosquitoes in areas that cover 75 million people at risk of dengue in the next 5 years and reach half a billion people in a decade. The releases have been done with regulatory approval and extensive local consultation, which will also be scaled up. One obstacle will be the adoption of the World Health Organization, which guides public health decisions in many countries.
Another will be funding. Charities such as the Bill & Melinda Gates Foundation in Seattle, Washington (of which WMP is a part), Wellcome in London and the Indian Tahija Foundation have so far supported trials. But O’Neill says funding from governments and agencies such as the World Bank and the Inter-American Development Bank is needed to help fund large-scale releases. Work by independent economists has suggested that the mosquito nets, which are estimated to cost between US $ 12 to $ 21 per covered person, pay for themselves within a few years by reducing healthcare costs, lost income and other tolls of dengue.
The WHO typically requests data from two separate trials to recommend an intervention, says Immo Kleinshmidt, an epidemiologist at LSHTM who was part of an independent board that followed the trial. “But I suspect that the demand for this intervention from dengue endemic countries will result in widespread introduction of this method, with a good prospect of eventually eliminating the disease,” he says. “The significance of this result is epochal.”
