Modified mosquitoes suppress dengue in subject trials

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The spread of mosquitoes artificially infected with Wolbachia parasites in an Indonesian city has slashed confirmed dengue virus diseases in the targeted areas, researchers reported.

Three years after starting a cluster-randomized study in Yogyakarta, Indonesia, the rate of virologically confirmed dengue cases in untreated areas was 9.4% versus 2.3% in areas where Aedes aegypti’s modified mosquitoes were used, said Katherine Anders, MSc, PhD, from Monash University in Clayton, Australia.

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

An important secondary result also clearly spoke in favor of the intervention: Dengue cases that required hospitalization were 86.2% lower in the treated zones (95% CI 66.2% -94.3%). The absolute rates for this measure were 0.4% in the intervention areas compared to 3.0% in other countries.

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

Anders said that the differences between the zones could actually underestimate the effectiveness of the program, as the zone assignments were a patchwork of patches – almost every intervention zone bordered two or more control zones, so altered mosquitoes eventually showed up in significant numbers in control areas.

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

The investigators of the so-called AWED study hoped for an effectiveness of 50% for the primary endpoint, so Anders. The 77% reduction in cases is therefore 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 have a reproductive advantage over wild-type A. aegypti, “the intervention is self-supporting and resilient,” said Anders.

It is also fair because the mosquitoes cannot differentiate between affluent and poor areas and can be used cheaply.

Anders said the operation is now taking place across the 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 Jakarta. Anders’ group divided the city into 24 zones and randomized them 1: 1 to get infected mosquitos or not.

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

Although it does not naturally infect mosquitoes, it can be artificially transmitted into them, infecting future generations too. The benefit of public health intervention is that infected women can mate with either infected or uninfected men to produce offspring, all of which are infected. When uninfected women mate with infected men, they are unable to lay viable eggs at all thanks to a phenomenon known as cytoplasmic incompatibility.

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

In the experiment, transfected A. aegypti eggs were dispensed in buckets in the 12 assigned zones. This was repeated every 2 weeks in 2017 over a period of several months. In the intervention zones, infected mosquitoes quickly took over, which by early 2018 made up more than 90% of the local population.

Anders and colleagues then monitored 18 clinics in Yogyakarta for patients with a fever, tested them for dengue infection and correlated the confirmed cases with their main residence. Around 54,000 febrile patients came to these clinics. Criteria for dengue testing included 1 to 4 days of fever between ages 3 and 45 and no other specific diagnosis.

Most of the patients did not meet these criteria. Of the 8,144 patients, the mean patient age was about 12 years and about 45% lived in intervention zones. All but 385 tested negative for dengue; 115 confirmed cases required hospitalization. The mean age and sex distribution were similar regardless of diagnosis.

Disclosure

The AWED study was funded primarily through government and private foundation grants. Investigators did not report any relevant financial interests.

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