Reduced dengue incidence following deployments of Wolbachia-infected Aedes aegypti in Yogyakarta, Indonesia: a quasi-experimental trial using controlled interrupted time series analysis

Abstract

Background: Ae. aegypti mosquitoes stably transfected with the intracellular bacterium Wolbachia pipientis ( wMel strain) have been deployed for biocontrol of dengue and related arboviral diseases in multiple countries. Field releases in northern Australia have previously demonstrated near elimination of local dengue transmission from Wolbachia-treated communities, and pilot studies in Indonesia have demonstrated the feasibility and acceptability of the method. We conducted a quasi-experimental trial to evaluate the impact of scaled Wolbachia releases on dengue incidence in an endemic setting in Indonesia. Methods: In Yogyakarta City, Indonesia, following extensive community engagement, wMel Wolbachia-carrying mosquitoes were released every two weeks for 13-15 rounds over seven months in 2016-17, in a contiguous 5 km ² area (population 65,000). A 3 km ² area (population 34,000) on the opposite side of the city was selected a priori as an untreated control area. Passive surveillance data on notified hospitalised dengue patients was used to evaluate the epidemiological impact of Wolbachia deployments, using controlled interrupted time-series analysis. Results: Rapid and sustained introgression of wMel Wolbachia into local Ae. aegypti populations was achieved. Thirty-four dengue cases were notified from the intervention area and 53 from the control area (incidence 26 vs 79 per 100,000 person-years) during 24 months following Wolbachia deployment. This corresponded in the regression model to a 73% reduction in dengue incidence (95% confidence interval 49%,86%) associated with the Wolbachia intervention. Exploratory analysis including 6 months additional post-intervention observations showed a small strengthening of this effect (30 vs 115 per 100,000 person-years; 76% reduction in incidence, 95%CI 60%,86%). Conclusions: We demonstrate a significant reduction in dengue incidence following successful introgression of Wolbachia into local Ae. aegypti populations in an endemic setting in Indonesia. These findings are consistent with previous field trials in northern Australia, and support the effectiveness of this novel approach for dengue control.

Keywords: Aedes aegypti; Indonesia; Wolbachia; World Mosquito Program; dengue; interrupted time series analysis; mosquito release; quasi-experimental study; vector-borne disease.

Figure 1.. Map of intervention and control areas in the Yogyakarta quasi-experimental study (QES).

The study area for the ‘Applying Wolbachia to Eliminate Dengue (AWED)’ cluster randomised controlled trial (CRCT), ongoing until late 2020, is also indicated.

Figure 2.. Insecticide susceptibility of the wMel Ae. aegypti colony and wild-type Ae. aegypti collected from the quasi-experimental study intervention area.

Bars show mean (st. dev.) % mortality across four replicate tests, each with 20 – 28 mosquitoes tested against each insecticide.

Figure 3.. Power estimation.

Power to detect a Wolbachia-associated reduction in dengue incidence using interrupted time series analysis was calculated as the proportion of significant results out of 1,000 simulations for varying post-intervention observation periods and relative risks.

Figure 4.. Wolbachia infection prevalence in local Aedes aegypti mosquito populations.

Lines show the percentage of Aedes aegypti collected from intervention areas (closed circles; solid line) and untreated control areas (open circles; dashed line) that were Wolbachia infected, each week since the start of deployments until September 2019. For the intervention areas, week 0 is the week in which deployment commenced (between 15 August and 18 September 2016, see Table 2). For the control areas, week 0 is the week in which the first deployments commenced in the intervention area (15 August 2016). Shaded area indicates release period.

Figure 5.. Dengue incidence in intervention and control areas, before and after the Wolbachia intervention.

Monthly notified dengue case incidence (per 100,000 population) in the intervention (solid line) and control (dashed line) areas before and after Wolbachia deployments, January 2006 - September 2019. Blue shading indicates the Wolbachia infection prevalence in Ae. aegypti collected from the intervention area.

Figure 6.. Laboratory-confirmed dengue cases in intervention and control areas, before and after the Wolbachia intervention.

Dengue rapid diagnostic test results for patients presenting to primary care clinics in the intervention ( A) and control ( B) areas. Standard Diagnostics Dengue Duo rapid diagnostic kits for the detection of dengue virus NS1 antigen and IgM/IgG antibody were available in primary care clinics throughout Yogyakarta city from March 2016, and were used at the discretion of clinic staff as part of routine clinical care. Monthly counts of positive and negative results for DENV NS1 antigen, as recorded by clinic staff, were aggregated for all patients resident in the intervention area or control area. The blue dashed line indicates the completion of Wolbachia releases in the intervention area in March 2017.