SARS-CoV-2 Vaccine Responses in children with genetic or acquired B cell deficiencies

项目总结 高度传染性的SARS-CoV-2 B.1.617.2(Delta)变异株的出现并返回面对面学习 正在迅速增加新冠肺炎病在儿童中的发病率和传播率。因此，它是至关重要的 以保护年幼的孩子。为了实现这一目标，正在进行的新冠肺炎疫苗临床试验旨在覆盖 年仅6个月大。因为儿科试验涉及的参与者较少，儿童的死亡率较低 有症状的感染，儿科疫苗的效力最初将基于体外免疫学参数- SARS-CoV-2受体结合区(RBD)或S1片段的病毒中和抗体 斯派克蛋白。然而，这些相同的指标是否反映了正在开发的疫苗的有效反应 免疫系统(5岁)仍有待确定。对疫苗的免疫反应受以下因素影响 年龄相关的生理变化，特别是在生命的头5年，当B和T发生变化时 细胞分化和效应器功能、B细胞反应的亲和力成熟和髓系亚群 以及它们的细胞因子的产生。此外，在非常年幼的儿童中，粘膜免疫球蛋白A迅速达到成人水平，而 血清IgA只有在青春期才能达到成年人的水平。这种差异可能解释了不同的新冠肺炎 儿童疾病的发病率、传播和严重程度。儿科黏膜和粘膜的演变变化 系统免疫个体发育对SARS-CoV-2感染和mRNA疫苗诱导的免疫应答的影响 是不完全理解的。这里的总体目标是定义粘膜和系统性SARS-CoV-2 感染疫苗和信使核糖核酸疫苗在健康成熟儿童中诱导的分子和免疫细胞反应 免疫系统和病理性B细胞状态(先天或后天)。 在接受辉瑞疫苗的成人队列中，与健康成年人相比，我们发现B细胞耗尽的成年人 多发性硬化症患者表现出显著增加的RBD特异性CD8 T细胞反应，尽管 可忽略抗RBD免疫球蛋白的产生。有趣的是，在儿童中，体内平衡和诱导的IgA水平是 受B细胞耗尽疗法的影响最小。我们的中心假设是，在体内接种mRNA疫苗 儿童人群中最年轻的儿童黏膜(干扰素和IgA)和CD8T细胞免疫参数增加 儿童(&lt；5yo)相对于较大的儿童(&gt；5yo)。我们预测，这种免疫模式将与 疫苗和感染引起的反应，支持其有限的感染病理(目标1)；和二)成为 在B细胞缺陷儿童中进行增强(目标2)。为了检验这一假设及其预测，我们将i) 建立SARS-CoV-2感染/接种健康人群和B细胞缺陷人群的前瞻性纵向队列 跨年龄组的儿童；以及ii)应用转录、免疫表型和抗原特异性体液和 比较SARS-CoV-2疫苗和感染引起的分子和细胞特征的细胞研究 健康儿童和有先天和后天B细胞缺陷的儿童。由此产生的见解将定义 量度 的 感染/疫苗免疫，构成了朝着建立预防相关的第一步 免疫活性/B 欠缺 孩子们。

PROJECT SUMMARY Emergence of the highly transmissible SARS-CoV-2 B.1.617.2 (Delta) variant and return to in-person learning is rapidly increasing the COVID-19 disease incidence and transmission rate in children. Therefore, it is critical to protect younger children. Toward this goal, ongoing COVID-19 vaccine clinical trials aim to reach those as young as 6 months old. Because pediatric trials involve fewer participants and children have a lower rate of symptomatic infection, pediatric vaccine efficacy will be initially based on in vitro immunological parameters— virus neutralization and antibodies to the receptor-binding domain (RBD) or S1 fragment of the SARS-CoV-2 spike protein. However, whether these same metrics reflect an effective vaccine response in a developing immune system (<5 years old) remains to be determined. Immune responses to vaccines are influenced by age-associated physiological changes, particularly in the first 5 years of life when changes occur in B and T cell differentiation and effector functions, affinity maturation of B cell responses, and myeloid subpopulations and their cytokine production. Additionally, in very young children mucosal IgA rapidly reach adult levels, while serum IgA only reaches adult levels in adolescence. This difference may account for the disparate COVID-19 disease incidence, transmission, and severity in children. How evolving changes in pediatric mucosal and systemic immune ontogeny affect SARS-CoV-2 infection- and mRNA vaccination-elicited immune responses are incompletely understood. The overall objective here is to define mucosal and systemic SARS-CoV-2 infection- and mRNA vaccine- elicited molecular and immune cellular responses in healthy pediatric maturing immune systems and in pathological B cell states (inborn or acquired). In a Pfizer-vaccinated adult cohort, compared to healthy adults, we have found that B cell depleted adult multiple sclerosis patients exhibited a significantly increased RBD-specific CD8 T cell response, despite negligible production of anti-RBD IgG. Interestingly, in children homeostatic and induced IgA levels are minimally affected by B cell depleting therapies. Our central hypothesis is that mRNA vaccination within the pediatric population augments mucosal (IFN and IgA) and CD8 T cellular immune parameters in the youngest children (<5yo) relative to older children (>5yo). We predict that such immune profile will i) correlate with vaccine- and infection-elicited responses, supporting their limited infection pathology (Aim 1); and ii) become enhanced in those children with B cell deficiencies (Aim 2). To test this hypothesis and its predictions, we will i) establish a prospective longitudinal cohort of SARS-CoV-2 infected/vaccinated healthy and B cell deficient children across age groups; and ii) apply transcriptomic, immune phenotypic, and antigen-specific humoral and cellular studies to compare SARS-CoV-2 vaccine- and infection-elicited molecular and cellular signatures in healthy children and those with inborn and acquired B cell defects. Resulting insights will define metrics of infection/vaccine immunity, constituting an initial step toward establishing correlates of protection in immunocompetent/B deficient children.