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

项目概要 高传染性 SARS-CoV-2 B.1.617.2 (Delta) 变种的出现并回归面对面学习 正在迅速增加儿童中的 COVID-19 疾病发病率和传播率。因此，至关重要的是 以保护年幼的儿童。为了实现这一目标，正在进行的 COVID-19 疫苗临床试验旨在实现以下目标： 年仅6个月大。因为儿科试验的参与者较少，而且儿童的患病率较低 对于有症状的感染，儿科疫苗的功效最初将基于体外免疫学参数—— 病毒中和以及针对 SARS-CoV-2 受体结合域 (RBD) 或 S1 片段的抗体 刺突蛋白。然而，这些相同的指标是否反映了发展中国家的有效疫苗反应 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 与年龄相关的生理变化，特别是在生命的前 5 年，此时 B 和 T 发生变化 细胞分化和效应功能、B 细胞反应的亲和力成熟以及骨髓亚群 及其细胞因子的产生。此外，在非常年幼的儿童中，粘膜 IgA 迅速达到成人水平，而 血清IgA只有在青春期才达到成人水平。这种差异可能是造成不同的 COVID-19 的原因 儿童疾病的发病率、传播途径和严重程度。儿科粘膜如何不断变化 全身免疫个体发育影响 SARS-CoV-2 感染和 mRNA 疫苗接种引起的免疫反应 都没有完全理解。这里的总体目标是定义粘膜和系统性 SARS-CoV-2 感染和 mRNA 疫苗在健康儿科成熟过程中引发分子和免疫细胞反应 免疫系统和病理 B 细胞状态（先天或后天）。 在辉瑞疫苗接种的成人队列中，与健康成人相比，我们发现 B 细胞耗尽的成人 多发性硬化症患者表现出显着增加的 RBD 特异性 CD8 T 细胞反应，尽管 抗 RBD IgG 的产生可以忽略不计。有趣的是，儿童体内稳态和诱导的 IgA 水平是 受 B 细胞耗竭疗法的影响最小。我们的中心假设是 mRNA 疫苗接种 儿科人群增强了最年轻儿童的粘膜（IFN 和 IgA）和 CD8 T 细胞免疫参数 儿童（<5岁）相对于年龄较大的儿童（>5岁）。我们预测这种免疫特征将 i) 与 疫苗和感染引起的反应，支持其有限的感染病理学（目标 1）； ii) 成为 在患有 B 细胞缺陷的儿童中得到增强（目标 2）。为了检验这个假设及其预测，我们将 i) 建立 SARS-CoV-2 感染/接种疫苗的健康人和 B 细胞缺陷者的前瞻性纵向队列 各个年龄段的儿童； ii) 应用转录组学、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 健康儿童以及患有先天性和后天性 B 细胞缺陷的儿童。由此产生的见解将定义 指标 的 感染/疫苗免疫，这是建立保护相关性的第一步 免疫活性/B 缺乏的 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.