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 高传染性SARS-CoV-2 B.1.617.2（Delta）变异体的出现并恢复亲自学习 正在迅速增加COVID-19疾病在儿童中的发病率和传播率。因此， 保护年幼的孩子为了实现这一目标，正在进行的COVID-19疫苗临床试验旨在达到以下目标： 只有6个月大。由于儿科试验涉及的参与者较少，儿童的发病率较低， 症状感染，儿科疫苗效力最初将基于体外免疫学参数- SARS-CoV-2的受体结合域（RBD）或S1片段的病毒中和和抗体 刺突蛋白然而，这些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的影响： 年龄相关的生理变化，特别是在出生后的前5年，此时B和T发生变化 细胞分化和效应子功能、B细胞应答的亲和力成熟和髓样亚群 以及它们的细胞因子产生。此外，在非常年幼的儿童中，粘膜伊加迅速达到成人水平， 血清伊加仅在青春期达到成人水平。这种差异可能是COVID-19 儿童疾病的发病率、传播和严重程度。儿童粘膜和 系统性免疫个体发生影响SARS-CoV-2感染和mRNA疫苗诱导免疫应答 并不完全理解。这里的总体目标是定义粘膜和全身SARS-CoV-2 感染和mRNA疫苗在健康儿童中引起分子和免疫细胞应答 免疫系统和病理性B细胞状态（先天性或获得性）。 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细胞缺失的成人 多发性硬化症患者表现出显著增加的RBD特异性CD 8 T细胞应答， 抗RBD IgG的产生可忽略不计。有趣的是，在儿童中，稳态和诱导伊加水平是 受B细胞耗竭疗法的影响最小。我们的中心假设是， 儿童人群增加粘膜（IFN和伊加）和CD 8 T细胞免疫参数在最年轻的 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）;和ii）成为 在B细胞缺乏的儿童中增强（Aim 2）。为了验证这个假设及其预测，我们将i） 建立SARS-CoV-2感染/接种健康和B细胞缺陷前瞻性纵向队列 跨年龄组的儿童;和ii）应用转录组学、免疫表型和抗原特异性体液免疫， 细胞研究比较SARS-CoV-2疫苗和感染引起的分子和细胞特征， 健康儿童和先天性和后天性B细胞缺陷儿童。由此产生的见解将定义 度量 的 感染/疫苗免疫，构成建立保护相关性的第一步， 免疫活性/B 缺陷 孩子