Mucosal immunity to sapovirus in early childhood

摘要 萨普病毒(SAV)与诺如病毒同属杯状病毒科，日益被认为是一种 儿童急性胃肠炎(AGE)的重要原因。SAV在所有肠道病原体中排名第二 在一项大型多点出生队列研究中，它对24个月以下儿童年龄发病率的贡献 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 儿童负担和一种儿科诺如病毒疫苗将进入第三阶段试验，目前，有 没有针对SAV的疫苗。SAV疫苗开发的一个主要挑战是，人们对 自然免疫作为疫苗诱导免疫的指南。对于其他肠道病毒，如轮状病毒 而血清、唾液和粪便中的诺如病毒和病毒特异性IgA抗体与预防 疾病或挑战后病毒载量下降。而粘膜抗体也可能在保护中发挥重要作用 对于这种肠道病原体，我们不知道有任何已发表的研究报道对sav的体液免疫。 在唾液或粪便中或在任何隔间对SaV的IgA反应，可能是由于获取SAV病毒的挑战 抗原。我们正在进行的SAV流行病学研究表明，相同基因的再次感染是 不常见，提示发生了基因特异性免疫。异型感染确实会发生， 尽管它们随着年龄的增长而减少。我们的跨学科团队独一无二地准备大幅推进 利用我们的现场流行病学研究平台了解萨普病毒的自然体液免疫 尼加拉瓜和最先进的实验室技术来阐明记忆B细胞谱系。在美国国立卫生研究院的基础上- 在尼加拉瓜莱昂资助了444名儿童的出生队列，该项目旨在描述体液的动力学 从67名儿童采集的纵向血清、唾液和粪便样本中检测到对沙眼病毒的免疫反应 SAV在出生后头两年出现胃肠炎。此外，我们还将在 不同的隔室，比较有症状和无症状感染和第一次感染引起的反应 与随后的感染相比。此外，我们将使用28天后收集的外周血单个核细胞 首例SAV感染揭示重要免疫表型并产生稳定的记忆B细胞群 目的克隆单抗(MAbs)。利用我们独特的资源--一组萨巴病毒抗原代表 常见的流行基因型别，我们将调查SAV特异性抗体产生的广度 自然感染。总之，这一独特的合作使我们能够交换分析工具，以更好地理解 儿童沙眼病毒的免疫学研究。具体地说，该项目将生成基本的新数据 用于推进控制和预防干预措施，包括儿科沙普病毒疫苗。

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.