Background: Routine vaccination supplemented by planned campaigns occurring at 2–5 y intervals is the core of current measles control and elimination efforts. Yet, large, unexpected outbreaks still occur, even when control measures appear effective. Supplementing these activities with mass vaccination campaigns triggered when low levels of measles immunity are observed in a sample of the population (i.e., serosurveys) or incident measles cases occur may provide a way to limit the size of outbreaks. Methods and Findings: Measles incidence was simulated using stochastic age-structured epidemic models in settings conducive to high or low measles incidence, roughly reflecting demographic contexts and measles vaccination coverage of four heterogeneous countries: Nepal, Niger, Yemen, and Zambia. Uncertainty in underlying vaccination rates was modeled. Scenarios with case- or serosurvey-triggered campaigns reaching 20% of the susceptible population were compared to scenarios without triggered campaigns. The best performing of the tested case-triggered campaigns prevent an average of 28,613 (95% CI 25,722–31,505) cases over 15 y in our highest incidence setting and 599 (95% CI 464–735) cases in the lowest incidence setting. Serosurvey-triggered campaigns can prevent 89,173 (95% CI, 86,768–91,577) and 744 (612–876) cases, respectively, but are triggered yearly in high-incidence settings. Triggered campaigns reduce the highest cumulative incidence seen in simulations by up to 80%. While the scenarios considered in this strategic modeling exercise are reflective of real populations, the exact quantitative interpretation of the results is limited by the simplifications in country structure, vaccination policy, and surveillance system performance. Careful investigation into the cost-effectiveness in different contexts would be essential before moving forward with implementation. Conclusions: Serologically triggered campaigns could help prevent severe epidemics in the face of epidemiological and vaccination uncertainty. Hence, small-scale serology may serve as the basis for effective adaptive public health strategies, although, in high-incidence settings, case-triggered approaches are likely more efficient.
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