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Background: The spread of airborne infectious diseases such as measles is a critical public health concern. The U.S. was certified measles-free in 2000, but the number of measles cases has increased in recent years breaking the record of the nationwide annual number of cases since 1992. Although the characteristics of schools have made them one of the most vulnerable environments during infection outbreaks, the transmission risk of measles among students is not completely understood. We aimed to evaluate how three factors influence measles transmission in schools: personal (vaccination), social (compartmentalizing), and building systems (ventilation, purification, and filtration).Methods: We used a combination of a newly developed multi-zone transient Wells-Riley approach, a nationwide representative School Building Archetype (SBA) model, and a Monte-Carlo simulation to estimate measles risk among U.S. students. We compared our risk results with the range of reported transmission rates of measles in school outbreaks to validate the risk model. We also investigated the effectiveness of vaccination and ten supplemental infection control scenarios for reducing the risk of measles transmission among students.Results: Our best nationwide estimate of measles transmission risk in U.S. schools were 3.5 and 32% among all (both unvaccinated and immunized) and unvaccinated students, respectively. The results showed the transmission risk of measles among unvaccinated students is > 70 times higher than properly immunized ones. We also demonstrated that the transmission risk of measles in primary schools (assuming teacher self-contained classrooms) is less than secondary schools (assuming departmentalized systems). For building-level interventions, schools with ductless-with-air-filter and ductless-without-air-filter systems have the lowest and highest transmission risks of measles, respectively. Finally, our simulation showed that infection control strategies could cut the average number of infected cases among all students in half when a combination of advanced air filtration, ventilation, and purification was adopted in the modeled schools.Conclusions: Our results highlight the primary importance of vaccination for reducing the risk of measles transmission among students. Yet, additional and significant risk reduction can be achieved through compartmentalizing students and enhancing building ventilation and filtration systems. [ABSTRACT FROM AUTHOR]