Author summary Using realistic simulation of dengue in the state of Yucatn, Mexico, we show high coverage indoor residual spraying (IRS) interventions can largely eliminate transmission for a few years, when applied proactively. However, initial success relies on population-level immunity, which declines with reduced infection rates, so simulated IRS campaigns stabilize at much lower effectiveness than initially observed. Moreover, if a campaign then suddenly stops, the model predicts large outbreaks until population immunity recovers. These results suggest that mosquito control could enable elimination in endemic settings, but that natural infections must be replaced, e.g. with vaccination, to achieve that end. Regardless, early campaign years' performance cannot be assumed representative of longterm benefit, and campaign cost estimates must account for increasing population susceptibility.
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