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.

抽象的 sapovirus（sav）是乳糜片菌科家族中的属属，越来越被认为是 儿童时期急性胃肠炎（年龄）的重要原因。 SAV在所有促进病原体中排名第二 在一项大型多站点出生队列研究中，它对24个月以下儿童的年龄事件贡献 与较低的认知发展分数有关。而针对轮状病毒的疫苗降低了 儿童年龄的负担和儿科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，关于 自然免疫，以作为疫苗吸收免疫的指南。用于其他肠道病毒，例如轮状病毒 诺如病毒，血清，唾液和粪便中的病毒特异性IgA ABS与保护有关 挑战后疾病或病毒负荷减少。虽然粘膜腹肌可能在保护中也起着重要作用 针对这种肠道病原体，我们不知道任何已发表的有关SAV的体液免疫的研究 在任何隔间中，在唾液或粪便或IGA对SAV的响应中，可能是由于获得Sapovirus的挑战 抗原。我们正在进行的SAV流行病学研究表明，与相同基因型的再感染是 罕见，表明基因型特异性免疫的发展。确实发生了异型感染， 尽管他们随着年龄的增长而减少。我们的跨学科团队被唯一的中毒，可以大大推动 通过我们的现场流行病学研究平台，了解天然的体液免疫力 尼加拉瓜和最先进的实验室技术，以阐明记忆B细胞库。建立在NIH- 该项目旨在表征尼加拉瓜莱昂（León）的444名儿童的生日队列 从67名儿童中收集的纵向血清，唾液和粪便样本中的肉食病毒的免疫力 在生命的头两年中，SAV胃肠炎发作。此外，我们将在 不同的隔室，并比较症状与无症状感染引起的反应，首先 与随后的感染。此外，我们将使用收集后28天收集的外周血单核细胞 首先SAV感染以揭示重要的免疫表型并产生稳定的记忆B细胞种群 克隆单克隆抗体（mAb）。使用我们代表的Sapovirus抗原面板的独特资源 常见的循环基因型，我们将研究由 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 儿童的肉食病毒的免疫学。具体而言，该项目将生成基本的新数据 为了改进控制和预防干预措施，包括小儿肉毒杆菌疫苗。