Leveraging our institution’s diverse and experienced investigator base, our success in leading collaborative and single-site randomized clinical trials (RCTs) and mechanistic and observational studies, and our access to a large population of urban, disadvantaged, and largely minority youth with asthma, we propose the District of Columbia’s Childhood Asthma in Urban Settings Clinical Research Center (DC CAUSE-CRC). It will implement network-wide research projects with a multi-disciplinary team of senior and junior investigators bringing diverse backgrounds in pediatric asthma, allergy and immunology, airway multi-omics, and computational biology. The proposed clinical leadership has repeatedly succeeded as top enrollers in multi-site asthma research collaboratives, and our institution houses the required infrastructure to facilitate CAUSE’s collaborative studies. For our site-specific project, we will build on the prior work of the Inner City Asthma Consortium (ICAC) and explore the mechanistic and clinical aspects of the paradigm-shifting use of a single dose of omalizumab in the fall season to prevent exacerbations. Specifically, while providing pilot clinical data for a possible future RCT, we will examine the interaction of the nasal microbiome and the nasal inflammatory responses during viral upper respiratory infections (URIs) with and without a single dose of anti-IgE. Working synergistically in exacerbation-prone urban youth, allergic sensitization, allergen exposure, and rhinovirus (and other viral) URIs trigger a strong Th2 response and asthma exacerbations that occur most frequently after school begins (the “September epidemic”). The ICAC has demonstrated that when administered across the entire fall season, omalizumab reduces the odds of exacerbations by >50%. Given the cost and complexity of this approach, however, and noting that serum levels of omalizumab rise following subcutaneous injection within a time frame sufficient to prevent a virally induced exacerbation (7-8 days), we propose an entirely new strategy: Omalizumab Before Onset of Exacerbations (OBOE). It is a pilot, non-therapeutic, mechanistic RCT of omalizumab or placebo administered within 72 hours of onset of an URI. Over three fall seasons, OBOE will randomize at least 100 youth aged 6-17 years with persistent asthma, high atopy, and a recent exacerbation. We will “capture” their URIs for 90 days after school starts, sampling their nasal airways twice (within 72 hours of URI onset and again in a window between 7-10 days after URI onset). Our specific aims are: (1) to be leaders in the collaborative studies of the CAUSE network while fostering the next generation of local institutional leadership for DC CAUSE-CRC; (2) to determine the relationship among the nasal airway microbiome, host transcriptome, and Th2 responses in children treated with single dose omalizumab or placebo at the onset of viral URIs; (3) to determine the relationship between host nasal airway antivi...