Modified Mosquitoes Suppress Dengue in Field Trial

Distributing mosquitoes artificially infected with Wolbachia parasites in one Indonesian city slashed confirmed dengue virus illnesses in the targeted areas, researchers reported.

Three years after a cluster-randomized trial began in Yogyakarta, Indonesia, rates of virologically confirmed dengue cases were 9.4% in untreated zones versus 2.3% in zones where the altered Aedes aegypti mosquitoes were deployed, said Katherine Anders, MSc, PhD, of Monash University in Clayton, Australia.

That represented a reduction of 77.1% (95% CI 65.3%-84.9%) in confirmed cases -- the study's primary endpoint -- in treated versus untreated areas, she told attendees in a virtual presentation at the American Society of Tropical Medicine and Hygiene's annual meeting.

A key secondary outcome also clearly favored the intervention: dengue cases requiring hospitalization were lower by 86.2% in treated zones (95% CI 66.2%-94.3%). Absolute rates for this measure were 0.4% in the intervention areas versus 3.0% elsewhere.

Among other things, Wolbachia prevents mosquitoes from transmitting the dengue virus.

Anders said the interzone differences may actually underestimate the program's effectiveness, insofar as the zone assignments were a patchwork -- almost every intervention zone was contiguous with two or more control zones, such that altered mosquitoes eventually turned up in control areas in significant numbers.

Trapping studies showed that, by the end of the 3-year trial, at least 40% of mosquito populations were Wolbachia-infected in most control zones.

Investigators in the so-called AWED trial hoped to see 50% efficacy for the primary endpoint, Anders said, so the 77% reduction in cases was a welcome surprise. Another encouraging result was that it appeared to be effective against all major dengue virus serotypes.

And, because the infected mosquitoes produce infected offspring and enjoy a reproductive advantage over wild-type A. aegypti, "the intervention is self-sustaining and resilient," Anders said.

It's also equitable because the mosquitoes do not discriminate between affluent and poor neighborhoods and can be deployed cheaply.

Anders said deployment is now occurring across the entire city of Yogyakarta and could easily be expanded to other urban areas.

Study Details

Yogyakarta, with a population of about 400,000, is located in central Java about 320 miles east of the capital of Jakarta. Anders's group divided the city into 24 zones, randomizing them 1:1 to receive infected mosquitoes or not.

Wolbachia, Anders explained, is a parasitic organism that naturally infects about 60% of insect species, but not A. aegypti. In other species, it has a range of effects including alterations in reproductive biology.

But while it won't infect mosquitoes naturally, it can be artificially transfected into them, such that succeeding generations are also infected. The advantage as a public health intervention is that infected females can mate with either infected or uninfected males to produce offspring, all of which are infected; but when uninfected females mate with infected males, they cannot lay viable eggs at all, thanks to a phenomenon called cytoplasmic incompatibility.

Thus, infected mosquitoes out-breed the wild-type insects and eventually dominate the population.

In the trial, transfected A. aegypti eggs were put out in buckets in the 12 assigned zones. This was repeated every 2 weeks over a period of several months in 2017. In the intervention zones, infected mosquitoes quickly took over, constituting more than 90% of local populations by early 2018.

Anders and colleagues then monitored 18 clinics in Yogyakarta for patients presenting with fever, testing them for dengue infection and correlating the confirmed cases with their primary residence. Some 54,000 febrile patients came to these clinics. Criteria for dengue testing included 1-4 days of fever, ages 3-45 years, and no other specific diagnosis.

Most patients didn't meet these criteria. Of the 8,144 who did, median patient age was about 12 and about 45% lived in intervention zones. All but 385 tested negative for dengue; 115 confirmed cases required hospitalization. Median age and sex distributions were similar irrespective of diagnosis.

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