Li Yun Tan

Background: Wild-type female Aedes aegypti which mates with male Wolbachia-infected Aedes aegypti mosquito produces infertile offspring due to cytoplasmic incompatibility. Sustained releases of Wolbachia-infected males can potentially suppress wild-type mosquito populations. Methods: We conducted a large-scale cluster-randomised trial using Wolbachia-mediated incompatible insect technique-sterile insect technique (IIT-SIT) for the control of dengue in Singapore. This involved releases of male wAlbB-infected Ae. aegypti mosquitoes which were irradiated prior to releases to sterilise residual females to avoid an establishment of wAlbB-infected Ae. aegypti mosquitoes in the field. Fifteen clusters, comprising an estimated 730,328 residents, were randomised into two arms: 8 clusters received deployments of male wAlbB-infected Ae. aegypti (intervention clusters) and 7 clusters received no deployments (control clusters). All clusters practised baseline vector control measures. We assessed the impact of Wolbachia releases on Ae. aegypti and Ae. albopictus abundance using a differences-in-differences framework. The interaction-weighted estimator was used to account for the staggered adoption setting and the dynamic effect of releasing male wAlbB-infected Ae. aegypti on wild-type Ae. aegypti and Ae. albopictus abundance. Results: Intervention clusters which received male wAlbB-infected Ae. aegypti had increasing reductions in Ae. aegypti abundance when subject to longer periods of intervention. In the 0–25 weeks following release, intervention efficacies (IE) were moderate (0-12 weeks: 29.15% [21.80%, 35.24%], 13-25 weeks: 60.35% [50.85%, 66.77%]). Whereas one year post intervention, reductions in Ae. aegypti abundance in intervention clusters were sustained at around 90% (52-103 weeks range: 90.20%–91.26%). Concomitantly, 78-weeks post intervention to the end of intervention, there was an increase in Ae. albopictus abundance in intervention clusters (78-103 weeks range: -32.43% – -63.10%). However, the average weekly increase in the Ae. albopictus abundance due to male wAlbB-infected Ae. aegypti releases was low and estimated to range between 0.0103 – 0.0482. Conclusion: Our results demonstrate the high efficacy of Wolbachia-mediated IIT-SIT in reducing Ae. aegypti abundance.

Matings between male Aedes aegypti mosquitoes infected with wAlbB strain of Wolbachia and wildtype females yield non-viable eggs. We evaluated the efficacy of releasing wAlbB-infected Ae. aegypti male mosquitoes to suppress dengue. We specified the protocol of a two-arm cluster-randomized test-negative controlled trial (cRCT) and emulated it using a nationally representative test-negative/positive database of individuals reporting for febrile illness to any public hospital, general practitioner or polyclinic. We retrospectively built a cohort of individuals who reside in Wolbachia locations vs a comparator control group who do not reside in Wolbachia locations, using a nationally representative database of all individuals whom report for febrile illness and were tested for dengue at the Environmental Health Institute/hospital laboratories/commercial diagnostic laboratories, through general practitioner clinic, polyclinic or public/private hospital from epidemiological week (EW) 1 2019 to EW26 2022. We emulated a constrained randomization protocol used in cRCTs to balance dengue risk between intervention and control arms in the pre-intervention period. We used the inverse probability weighting approach to further balance the intervention and control groups using a battery of algorithmically selected sociodemographic, environmental and anthropogenic variables. Intention-to-treat analyses were conducted to estimate the risk reduction of dengue given Wolbachia exposure. Intention-to-treat analyses revealed that, compared with controls, Wolbachia releases for 3, 6 and ≥12 months was associated to 47% (95% confidence interval: 25–69%), 44% (33–77%) and 61% (38–78%) protective efficacy against dengue, respectively. When exposed to ≥12 months of Wolbachia releases, protective efficacies ranged from 49% (13–72%) to 77% (60–94%) across years. The proportion of virologically confirmed dengue cases was lower overall in the intervention arm. Protective efficacies were found across all years, age and sex subgroups, with higher durations of Wolbachia exposure associated to greater risk reductions of dengue. Results demonstrated that Wolbachia-mediated sterility can strengthen dengue control in tropical cities, where dengue burden is the greatest.