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.