Efficacy of Wolbachia-Infected Mosquito Deployments for the Control of Dengue

Abstract

Background: Aedes aegypti mosquitoes infected with the wMel strain of Wolbachia pipientis are less susceptible than wild-type A. aegypti to dengue virus infection.

Methods: We conducted a cluster-randomized trial involving releases of wMel-infected A. aegypti mosquitoes for the control of dengue in Yogyakarta, Indonesia. We randomly assigned 12 geographic clusters to receive deployments of wMel-infected A. aegypti (intervention clusters) and 12 clusters to receive no deployments (control clusters). All clusters practiced local mosquito-control measures as usual. A test-negative design was used to assess the efficacy of the intervention. Patients with acute undifferentiated fever who presented to local primary care clinics and were 3 to 45 years of age were recruited. Laboratory testing was used to identify participants who had virologically confirmed dengue (VCD) and those who were test-negative controls. The primary end point was symptomatic VCD of any severity caused by any dengue virus serotype.

Results: After successful introgression of wMel into the intervention clusters, 8144 participants were enrolled; 3721 lived in intervention clusters, and 4423 lived in control clusters. In the intention-to-treat analysis, VCD occurred in 67 of 2905 participants (2.3%) in the intervention clusters and in 318 of 3401 (9.4%) in the control clusters (aggregate odds ratio for VCD, 0.23; 95% confidence interval [CI], 0.15 to 0.35; P = 0.004). The protective efficacy of the intervention was 77.1% (95% CI, 65.3 to 84.9) and was similar against the four dengue virus serotypes. The incidence of hospitalization for VCD was lower among participants who lived in intervention clusters (13 of 2905 participants [0.4%]) than among those who lived in control clusters (102 of 3401 [3.0%]) (protective efficacy, 86.2%; 95% CI, 66.2 to 94.3).

Conclusions: Introgression of wMel into A. aegypti populations was effective in reducing the incidence of symptomatic dengue and resulted in fewer hospitalizations for dengue among the participants. (Funded by the Tahija Foundation and others; AWED ClinicalTrials.gov number, NCT03055585; Indonesia Registry number, INA-A7OB6TW.).

Figure 1:. Map of study location.

In panel A, the map of Indonesia is shown with the Special Region of Yogyakarta shaded blue. In panel B, the map of Yogyakarta City (plus a small region of neighbouring Bantul District) is shown with wMel intervention clusters (shaded blue) and untreated clusters (shaded grey) indicated. The locations of primary care clinics (red crosses) where enrolment occurred are also shown.

Figure 2:. wMel introgression into local Aedes aegypti mosquito populations.

Lines show the percentage of Ae. aegypti collected from intervention clusters (A) and untreated clusters (B) that were wMel infected, each month from the start of deployments (March 2017) to the end of participant enrolment (March 2020). The shaded area indicates the period from the first release in the first cluster (March 2017) to the last release in the last cluster (December 2017). There were between 9 and 14 fortnightly release rounds per cluster.

Figure 2:. wMel introgression into local Aedes aegypti mosquito populations.

Lines show the percentage of Ae. aegypti collected from intervention clusters (A) and untreated clusters (B) that were wMel infected, each month from the start of deployments (March 2017) to the end of participant enrolment (March 2020). The shaded area indicates the period from the first release in the first cluster (March 2017) to the last release in the last cluster (December 2017). There were between 9 and 14 fortnightly release rounds per cluster.

Figure 3:. Cluster randomisation, participant enrolment, inclusion in analysis dataset, and follow-up of safety endpoints.

The commonest reasons for exclusion from the analysis dataset were enrolment before the predefined time point of Wolbachia establishment (8^th January 2018), enrolment in a calendar month without any VCD cases (September 2018) or having positive or equivocal dengue IgM or IgG serology at enrolment that precluded classification as a test-negative control.

Figure 4:. Intention-to-treat efficacy.

Shown is the protective efficacy (expressed as 100×(1−OR)) of wMel-infected Aedes aegypti deployments against virologically-confirmed dengue of any serotype (All VCDs), by infecting DENV serotype, and against hospitalised VCD. VCDs with ‘Unknown serotype’ were test-negative by DENV RT-PCR and test-positive for DENV NS1 antigen. Seven participants had two DENV serotypes detected during the same febrile episode: four with serotypes 1 and 2, two with serotypes 1 and 4, and one with serotypes 2 and 4.

Figure 5:. Cluster-level proportions of virologically-confirmed dengue cases.

VCD cases as a proportion of all participants in Wolbachia-treated (closed circles) and untreated (open circles) clusters. Circle size is proportionate to the total number of participants in the cluster. Circles are labelled with their respective cluster number. Horizontal bars show the mean VCD proportion in intervention and untreated clusters; the relative risk and P-value are derived from a comparison of these mean proportions (see Methods).