Abstract
BACKGROUND: Dengue remains a global health challenge with limited treatment options, highlighting the need for effective vector control strategies. The introduction of Wolbachia pipientis into Aedes aegypti populations has shown success in reducing dengue transmission across global field trials. However, the spillover effectiveness of the technology on untreated areas is not well-known. This study estimates the spillover protective effectiveness (PE) of Wolbachia-mediated introgression on dengue. METHODS: We used the synthetic control method (SCM) under assumption of partial interference to evaluate the direct and spillover PEs of Wolbachia-mediated introgression in a long-running operational trial of the intervention in Malaysia. Synthetic controls (SCs), which comprise of a weighted sum of non-spillover controls, were constructed for each directly-treated and spillover site in the pre-intervention period to account for historical imbalances in dengue risk and risk trajectories. SCs were compared to directly/spillover-treated sites to estimate the impact of Wolbachia-introgression on dengue incidence across each site, calendar year and intervention time. Robustness checks, including visual inspections, root-mean-square error (RMSE) calculations, in-space and in-time placebo checks, and permutation tests, were used to inspect the model's ability in attributing dengue incidence reductions to the Wolbachia interventions. FINDINGS: The direct and spillover PEs of Wolbachia on dengue incidence were expressed as a percentage reduction of dengue incidence, or the absolute case reductions, by comparing SCs to actual intervention/spillover sites. Findings indicate a direct reduction in dengue incidence by 64.35% (95% CI: 63.50-66.71, p < 0.05 using permutation tests) in directly treated areas, corresponding to 1802 (95% CI: 1768-1932) cases averted. Meanwhile, spillover effects contributed to a 37.69% (95% CI: 36.45-38.49, p < 0.05) reduction in adjacent non-intervention areas, accounting for 115 (95% CI: 104-132) absolute cases averted. Tracking PEs by intervention time revealed a dose-response relationship, where PEs increased concomitantly with Wolbachia frequency. Model checks confirmed the robustness of these results, and ascertained that these PEs were not an artefact of poor control selection, pre-trends in dengue incidence or poor predictive ability of the fitted SCs. INTERPRETATION: Wolbachia-introgression effectively diminished dengue incidence in directly-treated and surrounding spillover regions. This dual effectiveness highlights the potential of Wolbachia-infected mosquitoes as a sustainable, cost-effective strategy against dengue. FUNDING: This research is hosted by CNRS@CREATE and supported by the National Research Foundation, Prime Minister's Office, Singapore, under its Campus for Research Excellence and Technological Enterprise (CREATE) program, and is funded by the Lee Kong Chian School of Medicine-Ministry of Education Start-Up Grant. The original Hoffmann et al. (2024) study was funded by the Wellcome Trust Awards 226166, 108508, 202888 and the Ministry of Health Malaysia NMRR-16-297-28898.