Efficacy ofWolbachia-mediated sterility for control of dengue: emulation of a cluster randomized target trial

Abstract

BackgroundMatings between maleAedes aegyptimosquitoes infected withwAlbB strain ofWolbachiaand wildtype females yield non-viable eggs. We evaluated the efficacy of releasingwAlbB-infectedAe. aegyptimale mosquitoes to suppress dengue.MethodsWe specified the protocol of a two-arm cluster-randomised 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 built a cohort of individuals who reside inWolbachialocations versus a comparator control group who do not reside inWolbachialocations. We emulated a constrained randomisation 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 was conducted to estimate the risk reduction of dengue givenWolbachiaexposure.FindingsThe final cohort consisted of 7,049 individuals residing in areas treated byWolbachiainterventions for at least 3 months and 69,216 individuals residing in non-treated areas in the same time period. Intention-to-treat analyses revealed that, compared with controls,Wolbachiareleases for 3, 6, 12 or more months was associated to a 47% (Odds ratio (OR): 0.53 [0.45-0.62]), 47% (OR: 0.53 [0.50-0.65]) and 59% (OR: 0.41 [0.39-0.50]) protective efficacy against dengue respectively. When exposed to 12 or more months ofWolbachiareleases, protective efficacy ranged from 36% (OR: 0.64 [0.58-0.96]) to 77% (OR: 0.23 [0.22-0.33]) dependent on township, and from 48% (OR: 0.52 [0.48-0.7]) to 78% (OR: 0.22 [0.09-0.32]) across years. The proportion of virologically confirmed dengue cases was lower overall in the intervention arm, and across each subgroup. Protective efficacies were found across all townships, years, age and sex subgroups, with higher durations ofWolbachiaexposure similarly associated to greater risk reductions of dengue.InterpretationOur results demonstrated the potential ofWolbachia-mediated sterility for strengthening dengue control in tropical cities, where dengue burden is the greatest.FundingThis study was supported by funding from Singapore’s Ministry of Finance, Ministry of Sustainability and the Environment, National Environment Agency, and National Robotics Program. JTL is supported by the Ministry of Education (MOE), Singapore Start-up Grant. SB is supported by an MOE Tier 2 grant.

Wolbachiaincompatible insect technique program optimization over large spatial scales using a process-based model of mosquito metapopulation dynamics

“…When male insects infected with Wolbachia mate with females that either lack Wolbachia or have different Wolbachia strains, cytoplasmic incompatibility can cause the offspring to die during the early stages of embryonic development (Engelstädter & Telschow, 2009). Wolbachia- mediated cytoplasmic incompatibility has been tested in field trials in China, the USA, and Singapore through the incompatible insect technique (IIT), where only male mosquitoes with the Wolbachia infection are released, and has been found to effectively suppress the mosquito population (Zeng et al, 2022; Crawford et al, 2020; The Project Wolbachia - Singapore Consortium & Ng, 2021; Bansal et al, 2023) and consequently reduce dengue incidence (Lim et al, 2023; Lim et al, 2024). A cluster-randomized controlled trial is also underway in Singapore to provide gold-standard evidence of the technology’s epidemiological efficacy (Ong et al, 2022).…”