Project Summary The incidence and prevalence of food allergies is rising in children and adults, with peanut and tree nut being the most common food allergens. Current oral immunotherapy (OIT) protocols to desensitize patients to culprit allergens are associated with side effects that affect compliance and efficacy of OIT. More than 30% of patients with food allergies are allergic to more than one food. Safer OIT protocols that minimize side effects while improving challenge thresholds to multiple allergens are needed to be able to address this food allergy epidemic. To address these challenges, we propose a multi-site phase 2 clinical study in children and adults with peanut and tree nut allergies, using Omalizumab. Omalizumab is an anti-IgE monoclonal antibody which decreases free IgE in the blood and on mast cells and basophils, to minimize allergic inflammation. We hypothesize that omalizumab pre-treatment followed by low dose maintenance therapy of multi-food OIT will minimize side effects while increasing the challenge thresholds for multi-food allergic patients. Our approach is to design a randomized, controlled Phase 2 study with two arms: Omalizumab plus low dose multi-food OIT versus Omalizumab plus high dose multi-food OIT to contribute to the overall CoFAR objectives of improving safety and efficacy of OIT protocols. In implementing this study, we will create a comprehensive dataset of clinical outcomes from multiple sites within CoFAR and patient samples to understand mechanisms of treatment success. Our specific aims are 1) Test whether treatment of children and adults with Omalizumab and food OIT to peanut and walnut increases the ability to pass a food challenge to 2g of at least 2 allergens: peanut and walnut; 2) Determine whether treatment of children and adults in low vs high maintenance arms of multi food OIT with omalizumab is safer; and 3) Evaluate to what degree laboratory and clinical testing methods (i.e. endotypes and phenotypes of food allergic patients) are associated with safety and efficacy outcomes (in Specific Aims 1 and 2) in low dose versus high dose maintenance groups. If the aims of our proposal are met, we will determine the optimal maintenance dose protocol for desensitization to multiple foods with omalizumab that causes minimal side effects with optimal success rates.