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

项目总结/摘要 在由SARS-CoV-2的祖先菌株引起的全球大流行之后， 菌株是发病和死亡的持续原因。强的呼吸道粘膜免疫应答， SARS-CoV-2感染和/或疫苗接种对于预防新出现的变异株的再感染和并发症至关重要 菌株用大剂量皮质类固醇治疗控制不佳的Th 2介导的哮喘儿童， SARS-CoV-2变异株住院治疗的重要高危人群，通常与 季节性呼吸道病毒合并感染。尽管儿童会产生持久的全身适应性免疫反应， 对于SARS-CoV-2感染和/或疫苗接种，很少有人知道Th 2炎症是否存在于 许多哮喘儿童的肺部下呼吸道黏膜适应性免疫反应失调， 祖先病毒及其变异株。因此，这项建议的主要目标是检查血液， 下呼吸道适应性粘膜免疫特征，包括刺突（S）和受体结合结构域（RBD） 抗体、中和抗体以及T和B细胞对先前感染SARS-CoV-2的反应， 变异株（特异性目标1）和/或mRNA疫苗（特异性目标2）在哮喘儿童中的应用， 健康对照我们将进一步询问体液和T细胞适应性免疫的重要决定因素， 响应变量与广义线性模型，以确定这些决定因素，最告知适应性 应答为了进一步研究过敏原诱导的炎症对SARS适应性免疫的机制， CoV-2和变体在血液和肺中，我们将（具体目标三）感染幼年K18-hACE 2小鼠 在存在和不存在皮质类固醇治疗和mRNA疫苗接种的情况下对屋尘螨致敏。 这些研究的新知识应该增加对SARS-CoV-2的适应性免疫的理解 预防儿童感染和/或接种疫苗，以促进抗病毒治疗、隔离措施， 开发针对粘膜免疫的新型加强疫苗。我们准备实现这些目标 通过一个具有儿童哮喘和支气管镜检查经验的既定研究团队， 与具有SARS冠状病毒呼吸道粘膜免疫研究专业知识的免疫学家合作， 2感染和mRNA疫苗接种。

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.