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: 10633304
• 负责人: WEN-YUAN E HSIEH
• 金额: $ 61.32万
• 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/10633304
• 关键词: 11 year old; 16 year old; 2019-nCoV; 4 year old; 5 year old; Acute; Address; Adolescence; Adult; Affect; Affinity; Agammaglobulinemia; Age; Antibodies; Antigens; B cell differentiation; B cell therapy; B-Lymphocytes; Basic Science; Blood; Blood specimen; CD8-Positive T-Lymphocytes; CD8B1 gene; COVID-19; COVID-19 disparity; COVID-19 vaccination; COVID-19 vaccine; Child; Childhood; Clinic; Clinical Data; Clinical Sciences; Colorado; Cytometry; Data; Defect; Disease; Exhibits; Future; Genetic; Goals; Growth; Hospitalization; Immune; Immune response; Immune system; Immunity; Immunocompetent; Immunocompromised Host; Immunoglobulin A; Immunoglobulin G; Immunologic Memory; Immunologics; Immunologist; In Vitro; Incidence; Infection; Infrastructure; Interferons; Intramuscular; Knowledge; Lead; Learning; Life; Longitudinal cohort; Maintenance; Mission; Molecular; Morbidity - disease rate; Mucosal Immunity; Mucous Membrane; Multiple Sclerosis; Myelogenous; Participant; Pathologic; Pathology; Pediatric Hospitals; Pediatric cohort; Persons; Pfizer-BioNTech COVID-19 vaccine; Phenotype; Physicians; Physiological; Population; Production; Public Health; RNA vaccination; RNA vaccine; Research; Resources; Role; SARS-CoV-2 B.1.617.2; SARS-CoV-2 infection; SARS-CoV-2 spike protein; Saliva; Sampling; Scientist; Serum; Severities; Structure; Surface; T cell differentiation; T cell response; Testing; Translating; United States National Institutes of Health; Vaccinated; Vaccination; Vaccine Clinical Trial; Vaccines; Variant; Virus; Work; adaptive immune response; age group; biobank; cohort; cytokine; early childhood; follow-up; hospitalization rates; humoral immunity deficiency; insight; mortality; multiple omics; multiple sclerosis patient; nasopharyngeal swab; prospective; receptor binding; response; stem; transcriptome sequencing; transcriptomics; transmission process; vaccination strategy; vaccine efficacy; vaccine platform; vaccine response; vaccine trial

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.

项目总结

项目成果

Evidence for Aerosol Transfer of SARS-CoV-2-Specific Humoral Immunity.

• DOI: 10.4049/immunohorizons.2300027
• 发表时间: 2023-05-01
• 期刊: ImmunoHorizons
• 作者: Kedl RM;Hsieh EWY;Morrison TE;Samayoa-Reyes G;Flaherty S;Jackson CL;Rochford R
• 通讯作者: Rochford R

Innate and Adaptive Cell-Mediated Immune Responses to a COVID-19 mRNA Vaccine in Young Children.

• DOI: 10.1093/ofid/ofad608
• 发表时间: 2023-12
• 期刊: Open forum infectious diseases
• 影响因子: 4.2