Determinants of Convalescent and Vaccine-induced Mucosal Specific Immunity to SARS-CoV-2 and Variants of Concern in Children with Asthma

PROJECT SUMMARY/ABSTRACT In the wake of a global pandemic caused by the ancestral strain of SARS-CoV-2, infections with emerging variant strains are an ongoing cause of morbidity and mortality. Robust respiratory mucosal immune responses to SARS-CoV-2 infection and/or vaccination are vital to prevent re-infection and complications of emerging variant strains. Children with poorly controlled, Th2-mediated asthma treated with high-dose corticosteroids are an important at-risk population for hospitalization with variant strains of SARS-CoV-2, often in association with seasonal respiratory viral co-infections. Although children mount durable systemic adaptive immune responses to SARS-CoV-2 infection and/or vaccination, very little is known as to whether Th2 inflammation present in the lungs of many children with asthma dysregulates the lower respiratory mucosal adaptive immune response to the ancestral virus and its variant strains. Therefore, the broad goal of this proposal is to examine blood and lower respiratory adaptive mucosal immune signatures, including spike (S) and receptor-binding domain (RBD) antibodies, neutralizing antibodies, and T and B cell responses to previous infection with SARS-CoV-2 and variant strains (Specific Aim One) and/or mRNA vaccination (Specific Aim Two) in children with asthma and healthy controls. We will furthermore interrogate significant determinants of humoral and T cell adaptive immune response variables with generalized linear models to identify those determinants which most inform adaptive responses. To further examine mechanisms of allergen-induced inflammation on adaptive immunity to SARS- CoV-2 and variants in the blood and lungs, we will (Specific Aim Three) infect juvenile K18-hACE2 mice sensitized to house dust mite in the presence and absence of corticosteroid treatment and mRNA vaccination. New knowledge from these studies should increase the understanding of adaptive immunity to SARS-CoV-2 infection and/or vaccination in children in a way to advance anti-viral treatment, isolation measures, and development of novel booster vaccines targeting mucosal immunity. We are prepared to accomplish these aims through an established team of investigators with experience in childhood asthma and bronchoscopy, in partnership with immunologists with expertise in the investigation of respiratory mucosal immunity to SARS-CoV- 2 infection and mRNA vaccination.