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 沙波病毒 (SaV) 是杯状病毒科的一个属，与诺如病毒一样，越来越多地被认为是一种 SaV是导致儿童急性胃肠炎（AGE）的重要原因，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，它对 24 个月以下儿童 AGE 发病率的贡献以及 与较低的认知发展分数有关，而针对轮状病毒的疫苗则降低了认知发展分数。 儿童AGE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 开发 SaV 疫苗的一个主要挑战是人们对它知之甚少。 自然免疫可作为疫苗引发免疫的指导，适用于其他肠道病毒，例如轮状病毒。 和诺如病毒、血清、唾液和粪便中的病毒特异性 IgA 抗体与预防感染相关 疾病或攻击后病毒载量减少，而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，我们不知道有任何已发表的研究报告对 SaV 的体液免疫 唾液或粪便中或任何区室中对 SaV 的 IgA 反应，可能是由于获得沙波病毒的挑战 我们正在进行的 SaV 流行病学研究表明，相同基因型的再次感染是可能的。 不常见，表明基因型特异性免疫的发展确实发生， 尽管它们会随着年龄的增长而减弱，但我们的跨学科团队有能力大幅推进这一目标。 通过我们的现场流行病学研究平台了解对沙波病毒的自然体液免疫 尼加拉瓜采用最先进的实验室技术来阐明 B 细胞记忆库。 该项目资助了尼加拉瓜莱昂 444 名儿童的出生队列，旨在描述体液动力学的特征 从 67 名患有沙波病毒的儿童身上收集的纵向血清、唾液和粪便样本中对沙波病毒的免疫力 此外，我们将在生命的头两年内将这些反应关联起来。 不同的区室并比较有症状感染与无症状感染引起的反应 与随后的感染相比，我们将使用28天后收集的外周血单核细胞。 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 使用我们代表沙波病毒抗原的独特资源来克隆单克隆抗体 (mAb)。 常见的循环基因型，我们将研究由 SaV 产生的特异性抗体的广度 这种独特的合作使我们能够交换分析工具以更好地理解自然感染。 具体来说，该项目将产生重要的新数据。 促进控制和预防干预措施，包括儿科沙波病毒疫苗。