PROJECT SUMMARY/ABSTRACT There is a fundamental gap in understanding the extent to which the school environment contributes to respiratory virus exposure, and less is known about effective environmental interventions to reduce exposure. Our long-term goal is to create healthy indoor school environments for children. The overall objective of this application is to identify environmental predictors of and potential interventions influencing respiratory virus exposure in elementary schools. We will extend the robust infrastructure of the School Inner-City Asthma Intervention Study (SICAS-2, ClinicalTrials.gov NCT02291302), a five-year randomized controlled trial conducted by our group of a placebo-controlled classroom high efficiency particulate air (HEPA) cleaner intervention to continue cohort recruitment in the post-COVID-19 pandemic period. We will test our central hypothesis that modifiable built environment factors influence airborne respiratory virus exposure and infection in elementary schools through the following specific aims: (1) To determine the efficacy of a randomized placebo controlled HEPA cleaner intervention in reducing classroom airborne respiratory virus exposure; (2) To determine the efficacy of a randomized placebo controlled HEPA cleaner intervention in reducing symptomatic and asymptomatic respiratory viral infections in asthmatic children. The approach is innovative, because we are simultaneously interrogating all major human respiratory viruses in the context of a school-based randomized trial focused on an environmental intervention. The proposed research is significant, because if the HEPA intervention can reduce respiratory virus exposure and infections in schools, it is an immediately actionable and practical intervention to create safer indoor environments for elementary school children. Results from this proposal may be generalizable to other public indoor settings.