Ignoring transmission dynamics leads to underestimation of the impact of a novel intervention against mosquito-borne disease

New vector-control technologies to fight mosquito-borne diseases are urgently needed, the adoption of which depends on efficacy estimates from large-scale cluster-randomized trials (CRTs). The release of Wolbachia -infected mosquitoes is one promising strategy to curb dengue virus (DENV) transmission, and a recent CRT reported impressive reductions in dengue incidence following the release of these mosquitoes. Such trials can be affected by multiple sources of bias, however. We used mathematical models of DENV transmission during a CRT of Wolbachia -infected mosquitoes to explore three such biases: human movement, mosquito movement, and coupled transmission dynamics between trial arms. We show that failure to account for each of these biases would lead to underestimated efficacy, and that the majority of this underestimation is due to a heretofore unrecognized bias caused by transmission coupling. Taken together, our findings suggest that Wolbachia -infected mosquitoes could be even more promising than the recent CRT suggested. By emphasizing the importance of accounting for transmission coupling between arms, which requires a mathematical model, our results highlight the key role that models can play in interpreting and extrapolating the results from trials of vector control interventions. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by the NIH National Institute of General Medical Sciences R35 MIRA program (R35GM143029). John Huber was additionally supported by an NSF Graduate Research Fellowship. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All model parameter estimates came from published studies. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All model code is available at https://github.com/scavany/awed\_trial\_modeling