OBOE is a prospective, pilot, parallel group RCT with the overall aim of examining the effect of a single dose of anti-IgE (omalizumab) vs. placebo administered at the onset of URIs in the fall season among highly exacerbation-prone, urban, and atopic youth aged 6-17 years with persistent asthma. OBOE will recruit and randomize participants over 3 years (3 annual cohorts of participants). Recruitment for each of the yearly cohorts of OBOE will begin in February. Each cohort will be followed for a 2-6-month run-in period with the objective to gain control of each participant's asthma and to stabilize the required controller medication step level. Participants will receive routine asthma care every 1-2 months (a total of 2-4 times) during run-in using a previously described algorithm developed by the Inner-city Asthma Consortium and successfully employed in the PROSE study. The primary outcome is the change in the amount of nasal IFN-α recovered by nasal fluid absorption between two time points, within 72 hours of onset of a URI as defined by onset of (or substantial worsening of) rhinorrhea, nasal congestion or sneezing (single or multiple symptoms) and 3-6 days after study drug injection.

Inclusion Criteria at Study Entry:

Participants must meet the following:

1. Parent or guardian must be able to understand and provide informed consent in English and participants ≥7 must be able to provide assent

2. 6-17 years, inclusive at time of screening

3. Physician-diagnosed persistent asthma

4. ≥1 exacerbation of asthma requiring systemic corticosteroids in the 6-month period before the planned start of the participant's upcoming school year or ≥2 exacerbations of asthma requiring systemic corticosteroids in the 12-month period before the planned start of the participant's upcoming school year

5. Sensitization to ≥1 perennial aeroallergen

6. Total serum IgE and weight appropriate for omalizumab dosing

7. Insurance that covers standard of care medications

8. Primary family residence (home where child sleeps a majority of nights) in a Metropolitan Statistical Area where ≥10% of families have income below poverty line and/or publicly funded health insurance

9. At least one of the following criteria:

   1. peripheral eosinophilia >300µL
   2. total serum IgE >300kU/L
   3. sensitization to ≥3 perennial aeroallergens

10. Females of childbearing potential must have a negative pregnancy test upon study entry

11. Females with reproductive potential must agree to use FDA approved methods of birth control for the duration of the study

Additional Inclusion Criteria (these must be met prior to randomization at the fall season sick visit A (SVa) during the 90-day outcome period):

In order to be eligible for randomization at the SVa visit, participants must also meet all of the following criteria:

1. Reporting onset of URI symptoms within 72 hours prior to SVa, confirmed by the study physician
2. Report no use of nasal corticosteroids or nasal vaccinations within 14 days prior to SVa
3. Have a negative rapid nasal swab antigen test for SARS-CoV-2
4. Be more than 14 days from the onset of any previous asthma exacerbation requiring systemic steroids
5. Have no current lower respiratory symptoms that, in the opinion of the study physician, require systemic corticosteroid treatment
6. Complete collection of nasal absorption sample within 72 hours of onset URI [defined by onset of (or substantial worsening of) rhinorrhea, nasal congestion or sneezing (single or multiple symptoms)] as determined by the study physician's assessment at the SVa visit

Exclusion Criteria:

1. Inability or unwillingness of a participant's parent or guardian to give written informed consent or comply with study protocol or inability or unwillingness of a participant ≥7 to provide assent
2. Contraindication to receipt of omalizumab
3. Presence of a second chronic medical condition (including but not limited to serious cardiorespiratory disorders, cancer, sickle cell disease, uncontrolled seizure disorder, auto-immune disorders, or type 1 diabetes)
4. Pregnancy or active lactation
5. History of latex allergy
6. Treatment with omalizumab or other monoclonal antibody, or aeroallergen immunotherapy in the prior six months
7. Plan for home schooling during the 90-day outcome period
8. History of life-threatening asthma defined by requirement for intubation or cardiorespiratory arrest
9. Inability of primary caregiver and child to speak English
10. In the opinion of the investigator, participant will not be able to wean from nasal steroids or to avoid nasal vaccinations during the 90-day fall outcome period
11. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study

The study site's research pharmacy will dispense the study drug as per the randomization schedule provided by REDCap. Prior to injection, an unblinded site pharmacist will confirm the expiration date, the dose, and randomization assignment. The injections will be administered in the Clinical Research Center at the study site by unblinded and trained nursing staff. The product will remain blinded to the investigators, other site staff, the participant, and legal guardians.