Mucosal immunity to sapovirus in early childhood

幼儿期对沙波病毒的粘膜免疫

• 批准号: 10677051
• 负责人: Sylvia Irene Becker-Dreps
• 金额: $ 24.63万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-14 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677051
• 关键词: Acute; Address; Age; Age Months; Antibodies; Antibody Repertoire; Antigens; B cell repertoire; B-Lymphocytes; Binding; Biological; Birth; Body Fluids; Calicivirus; Cell Separation; Cells; Child; Childhood; Clone Cells; Cohort Studies; Collaborations; Collecting Cell; Data; Development; Diarrhea; Disease; Enteral; Epidemiology; Family; Feces; Funding; Future; Gastroenteritis; Genotype; Goals; Homing; Human; Humoral Immunities; Immune; Immune response; Immunity; Immunoglobulin A; Immunoglobulin G; Immunoglobulins; Immunologic Memory; Immunologics; Immunology; Incidence; Infection; Intestines; Kinetics; Laboratories; Learning; Life; Link; Longevity; Maps; Measurement; Measures; Memory B-Lymphocyte; Methods; Modeling; Monoclonal Antibodies; Mucosal Immunity; Mucous Membrane; Natural Immunity; Nicaragua; Nicaraguan; Norovirus; Pattern; Peripheral Blood Mononuclear Cell; Phenotype; Play; Population; Prevalence; Production; Publishing; Reporting; Resources; Role; Rotavirus; Saliva; Sampling; Sapovirus; Secretory Immunoglobulin A; Serum; Site; Small intestine mucous membrane; Stable Populations; Techniques; Testing; Time; United States National Institutes of Health; Vaccine Design; Vaccines; Viral Load result; Virus; Virus-like particle; analytical tool; burden of illness; cognitive development; cohort; early childhood; enteric pathogen; epidemiology study; experience; improved; innovation; interdisciplinary collaboration; multidisciplinary; neutralizing antibody; novel strategies; phase III trial; preventive intervention; receptor; response; saliva sample; stool sample; vaccine development; vaccine formulation

ABSTRACT Sapovirus (SaV), a genus in the Caliciviridae family alongside norovirus, is increasingly recognized as an important cause of acute gastroenteritis (AGE) in childhood. SaV ranked second among all enteric pathogens in its contribution to AGE incidence in children under 24 months of age in a large multi-site birth cohort study and was associated with lower cognitive development scores. While vaccines against rotavirus have lowered the burden of childhood AGE and a pediatric norovirus vaccine will be entering Phase III trials, currently, there are no vaccines against SaV. A major challenge to SaV vaccine development is that there is little known about natural immunity to serve as a guide for vaccine-elicited immunity. For other enteric viruses, such as rotavirus and norovirus, virus-specific IgA Abs in serum, saliva, and feces have been associated with protection against disease or decreased viral load after challenge. While mucosal Abs likely also play an important role in protection against this enteric pathogen, we are unaware of any published studies reporting on humoral immunity to SaV in saliva or stool or IgA responses to SaV in any compartment, likely due to the challenge in obtaining sapovirus antigens. Our ongoing epidemiological studies of SaV show that reinfection with the same genotype is uncommon, suggesting the development of genotype-specific immunity. Heterotypic infections do occur, although they lessen with age. Our interdisciplinary team is uniquely poised to substantially advance the understanding of natural humoral immunity to sapovirus with our platform for field epidemiology research in Nicaragua and state-of-the-art laboratory techniques to elucidate memory B cell repertoires. Building on an NIH- funded birth cohort of 444 children in León, Nicaragua, this project aims to characterize the kinetics of humoral immunity to sapovirus in longitudinal serum, saliva, and stool samples collected from 67 children experiencing a SaV gastroenteritis episode during the first two years of life. In addition, we will correlate these responses in different compartments and compare responses elicited by symptomatic vs. asymptomatic infections and in first vs. subsequent infections. In addition, we will use peripheral blood mononuclear cells collected 28 days after first SaV infections to reveal important immune phenotypes and produce stable populations of memory B cells to clone monoclonal antibodies (mAbs). Using our unique resource of a panel of sapovirus antigens representing the common circulating genotypes, we will investigate the breadth of SaV-specific antibodies produced from natural infections. Together, this unique collaboration allows us to exchange analytic tools to better understand the immunology of sapovirus in children. Specifically, this project will generate new data that are fundamental for the advancement of control and prevention interventions, including pediatric sapovirus vaccines.

摘要 Sapovirus（SaV）是杯状病毒科（Caliciviridae）家族中与诺如病毒（norovirus）一起的一个属， 是小儿急性胃肠炎（AGE）的重要病因。SaV在所有肠道病原体中排名第二， 在一项大型多中心出生队列研究中，其对24个月以下儿童AGE发病率的贡献， 与较低的认知发展分数有关。虽然针对轮状病毒的疫苗降低了 儿童年龄的负担和儿童诺如病毒疫苗将进入III期试验，目前，有 没有针对SaV的疫苗。SaV疫苗开发的一个主要挑战是， 天然免疫力作为疫苗诱导免疫力的指南。对于其他肠道病毒，如轮状病毒 和诺如病毒，血清，唾液和粪便中的病毒特异性伊加抗体与预防 疾病或病毒载量降低。虽然粘膜抗体也可能在保护中发挥重要作用， 针对这种肠道病原体，我们不知道任何已发表的关于SaV体液免疫的研究报告 唾液或粪便中或任何隔室中对SaV的伊加应答，可能是由于获得沙波病毒的挑战 抗原我们正在进行的SaV流行病学研究表明，同一基因型的再感染是 不常见，表明基因型特异性免疫的发展。异型感染确实会发生， 虽然随着年龄的增长而减少。我们的跨学科团队是独一无二的，以大幅推进 通过我们的现场流行病学研究平台，了解对sapovirus的天然体液免疫， 尼加拉瓜和最先进的实验室技术，以阐明记忆B细胞库。基于NIH- 在尼加拉瓜莱昂的444名儿童的资助出生队列中，该项目旨在描述体液免疫的动力学特征， 从67名儿童中收集的纵向血清、唾液和粪便样本中对沙波病毒的免疫力， SaV胃肠炎发作在生命的前两年。此外，我们还将这些反应与 不同的区室，并比较有症状与无症状感染引起的反应， vs.后续感染。此外，我们将使用28天后收集的外周血单个核细胞， 首次SaV感染揭示重要的免疫表型并产生稳定的记忆B细胞群 克隆单克隆抗体（mAb）。利用我们独特的一组痘病毒抗原资源， 常见的循环基因型，我们将研究SaV特异性抗体产生的广度， 自然感染。这种独特的合作使我们能够交换分析工具，以更好地了解 小儿痘病毒的免疫学。具体来说，这个项目将产生新的数据， 用于推进控制和预防干预措施，包括小儿痘病毒疫苗。