Assessing the efficacy of male Wolbachia-infected mosquito deployments to reduce dengue incidence in Singapore: study protocol for a cluster-randomized controlled trial

Abstract

Background Dengue is a severe environmental public health challenge in tropical and subtropical regions. In Singapore, decreasing seroprevalence and herd immunity due to successful vector control has paradoxically led to increased transmission potential of the dengue virus. We have previously demonstrated that incompatible insect technique coupled with sterile insect technique (IIT-SIT), which involves the release of X-ray-irradiated male Wolbachia-infected mosquitoes, reduced the Aedes aegypti population by 98% and dengue incidence by 88%. This novel vector control tool is expected to be able to complement current vector control to mitigate the increasing threat of dengue on a larger scale. We propose a multi-site protocol to study the efficacy of IIT-SIT at reducing dengue incidence. Methods/design The study is designed as a parallel, two-arm, non-blinded cluster-randomized (CR) controlled trial to be conducted in high-rise public housing estates in Singapore, an equatorial city-state. The aim is to determine whether large-scale deployment of male Wolbachia-infected Ae. aegypti mosquitoes can significantly reduce dengue incidence in intervention clusters. We will use the CR design, with the study area comprising 15 clusters with a total area of 10.9 km2, covering approximately 722,204 residents in 1713 apartment blocks. Eight clusters will be randomly selected to receive the intervention, while the other seven will serve as non-intervention clusters. Intervention efficacy will be estimated through two primary endpoints: (1) odds ratio of Wolbachia exposure distribution (i.e., probability of living in an intervention cluster) among laboratory-confirmed reported dengue cases compared to test-negative controls and (2) laboratory-confirmed reported dengue counts normalized by population size in intervention versus non-intervention clusters. Discussion This study will provide evidence from a multi-site, randomized controlled trial for the efficacy of IIT-SIT in reducing dengue incidence. The trial will provide valuable information to estimate intervention efficacy for this novel vector control approach and guide plans for integration into national vector control programs in dengue-endemic settings. Trial registration ClinicalTrials.gov, identifier: NCT05505682. Registered on 16 August 2022. Retrospectively registered.

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

“…We emulated a cluster-randomised test-negative controlled target trial in this study, which has been employed to study the epidemiological efficacy of field interventions, such as Wolbachia 4,11 . By employing a large and representative cohort of patients who have suspect dengue illness and were tested for dengue, across all major diagnostic laboratories through public hospitals, general practitioner clinics and polyclinics, we were able to emulate a cluster randomized controlled target trial and incorporate key study characteristics, such as ( 1 ) constrained randomisation, which enabled intervention and control arms to have balanced dengue risk in the pre-intervention period, ( 2 ) the use of a test-positive and test-negative comparator groups, to avoid selection bias at the point of testing and enable detection of virologically confirmed dengue cases and thereby ( 3 ) enabling casual identification of the protective efficacy of Wolbachia on dengue.…”

“…Towns were demarcated planning areas used by government ministries and departments for administrative purposes. While four long-term Wolbachia field trial townships were not randomly pre-selected, we emulated constrained randomisation protocols for cluster-randomised trials by randomly selecting a set of 12 control townships, such that the historical dengue incidence of the intervention arm is similar to that of the control arm in the pre-intervention period 4,11 .This further prevents chance-imbalance in baseline dengue risk due to the small number of intervention (n=4) locations considered (See Supplementary Information). All locations practiced the same baseline dengue control protocol in the pre- and post-intervention periods 2,3 .…”

“…In Singapore, 133,821 individuals reported for febrile illness and were tested for dengue at the Environmental Health Institute, hospital laboratories and commercial diagnostic laboratories, through general practitioner clinic, polyclinic or public/private hospital from EW1 2019 – EW 26 2022. All dengue-suspect patients were tested using either using an internally controlled RT-qPCR assay, dengue non-structural protein 1 (NS1) or IgM as diagnostic assays to detect dengue virus in serum samples 3,11 . We excluded individuals who were tested on more than one occasion in 4 weeks, individuals who had more than one residential address in different control or intervention townships and individuals who had been tested at different labs with conflicting dengue results.…”

Wolbachia Infection through Hybridization to Enhance an Incompatible Insect Technique-Based Suppression of Aedes albopictus in Eastern Spain

“…albopictus and Ae. aegypti in different areas of the world, either alone [ 31 , 36 , 37 , 38 , 39 , 40 , 41 ] or in combination with SIT [ 42 , 43 ], gradually increasing the record of successes achieved.…”

Efficacy ofWolbachia-mediated sterility to suppress adultAedes aegyptipopulations

“…aegypti have been ongoing in Singapore since 2016. As of Epidemiological Week (EW) 26 2022 21,22 , these field trials cover a total area of 10.35 km 2 and a population of 607,872. Past phases of the field trials have already delineated the behaviour, efficacy to induce cytoplasmic incompatibility, competitiveness and fitness of wAlbB-SG, a localized Ae.…”