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

患有遗传性或后天性 B 细胞缺陷的儿童对 SARS-CoV-2 疫苗的反应

• 批准号: 10502936
• 负责人: WEN-YUAN E HSIEH
• 金额: $ 62.19万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-02 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10502936
• 关键词: 2019-nCoV; 5 year old; Adolescence; Adult; Affect; Affinity; Age; Antigens; B-Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; COVID-19; COVID-19 disparity; COVID-19 vaccination; COVID-19 vaccine; Child; Childhood; Cytokeratin-8 Staining Method; Defect; Disease; Exhibits; Future; Genetic; Goals; Growth; Immune; Immune response; Immune system; Immunity; Immunocompetent; Immunoglobulin A; Immunoglobulin G; Immunologics; In Vitro; Incidence; Infection; Interferons; Knowledge; Learning; Life; Longitudinal cohort; Mission; Molecular; Morbidity - disease rate; Mucous Membrane; Myelogenous; Participant; Pathologic; Pathology; Persons; Phenotype; Physiological; Population; Production; Public Health; RNA vaccination; RNA vaccine; Research; SARS-CoV-2 B.1.617.2; SARS-CoV-2 infection; SARS-CoV-2 spike protein; Serum; Severities; T cell differentiation; T cell response; Testing; United States National Institutes of Health; Vaccinated; Vaccination; Vaccine Clinical Trial; Vaccines; Virus; Work; adaptive immune response; age group; base; cohort; cytokine; humoral immunity deficiency; insight; mortality; multiple sclerosis patient; neutralizing antibody; prospective; receptor binding; response; stem; transcriptomics; transmission process; vaccination strategy; vaccine efficacy; vaccine response

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.

项目摘要 高度传播的SARS-COV-2 B.1.617.2（Delta）变体的出现并返回面对面学习 正在迅速增加儿童的疾病发生率和传播率。因此，这很关键 为了实现这一目标，正在进行的Covid-19疫苗临床试验旨在达到这些试验 年轻6个月大。因为儿科试验涉及的参与者较少，儿童的率较低 有症状的感染，小儿疫苗效率最初将基于体外免疫学参数 - SARS-COV-2的病毒神经化和对受体结合结构域（RBD）或S1片段的抗体 尖峰蛋白。但是，这些相同的指标是否反映了发展中的有效疫苗反应 免疫系统（<5岁）仍有待确定。对疫苗的免疫反应受到 与年龄相关的身体变化，特别是在B和T中发生变化的前5年 细胞分化和效应子功能，B细胞反应的亲和力成熟以及髓样亚群 以及它们的细胞因子产生。此外，在很小的孩子中，粘膜Iga迅速达到成人水平，而 血清IgA仅在青少年时才达到成人水平。这种差异可能解释了不同的Covid-19 儿童的疾病事件，传播和严重程度。小儿粘膜和 系统性免疫本体发育会影响SARS-COV-2感染和mRNA疫苗接种的免疫调查 不完全理解。这里的总体目的是定义粘膜和全身SARS-COV-2 健康小儿成熟中的感染和mRNA疫苗 - 引起分子和免疫细胞反应 免疫系统和病理B细胞状态（先天或获得）。 与健康成年人相比，在辉瑞疫苗接种的成人队列中，我们发现B细胞耗尽的成年 多发性硬化症患者暴露了RBD特异性CD8 T细胞反应，多叠岩的显着增加 抗RBD IgG的产生可忽略不计。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 小儿种群增强粘膜（IFN和IGA）和CD8 T细胞免疫参数最年轻 儿童（<5yo）相对于大孩子（> 5yo）。我们预测这样的免疫轮廓将i）与 疫苗和感染引起的反应，支持其有限的感染病理（AIM 1）； ii）成为 那些患有B细胞缺乏症的儿童的增强（AIM 2）。为了检验这一假设及其预测，我们将 建立一个前瞻性的纵向纵向队列的SARS-COV-2感染/疫苗接种健康和B细胞不足 跨年龄段的儿童； ii）应用转录组，免疫表型和抗原特异性的体液和 比较SARS-COV-2疫苗和感染引诱的分子和细胞特征的细胞研究 健康的孩子以及患有天生和获得B细胞缺陷的人。最终的见解将定义 指标 的 感染/疫苗免疫，构成建立保护相关性的第一步 免疫能力/b 不足 孩子们。