Natural infection of norovirus and sapovirus in a birth cohort in a Peruvian periurban community

秘鲁城郊社区出生队列中诺如病毒和沙波病毒的自然感染

• 批准号: 8961698
• 负责人: ROBERT H GILMAN
• 金额: $ 73.16万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-16 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8961698
• 关键词: 3 year old; Acute; Address; Age; Antibodies; Area; Binding; Binding Sites; Birth; Blood Group Antigens; Calicivirus; Capsid Proteins; Cessation of life; Child; Childhood; Cohort Studies; Collaborations; Communities; Data; Data Collection; Development; Diarrhea; Disease; Disease Outbreaks; Epidemic; Epidemiology; Feces; Gastroenteritis; Genetic; Genetic Heterogeneity; Genetic Variation; Genotype; Grant; Growth; Herd Immunity; Hospitalization; Human; Immune; Immune response; Immunity; Immunoglobulin A; Incidence; Infant; Infection; Influenza; Kinetics; Knowledge; Laboratories; Length; Life; Mediating; Morbidity - disease rate; Mutation; Newborn Infant; Norovirus; Nutritional status; Outpatients; Patients; Pattern; Peru; Predisposition; Reagent; Rehydrations; Reporting; Research; Risk; Role; Rotavirus; Saliva; Sampling; Sapovirus; Series; Serum; Sewage; Specificity; Specimen; Symptoms; Testing; Time; United States National Institutes of Health; Universities; Vaccination; Vaccine Design; Variant; Viral; Viral Load result; Virus; Work; acquired immunity; cohort; cross reactivity; enteric pathogen; pathogen; protective effect; public health relevance; receptor; response; time interval; vaccine evaluation

 DESCRIPTION (provided by applicant): Norovirus (NV) is the leading cause of diarrhea in patients of all ages worldwide. After rotavirus, NV is the 2nd most frequent cause of pediatric gastroenteritis and hospitalizations for diarrhea, and is estimated to cause 200,000 annual deaths. When rotavirus vaccination is broadly implemented, NV is likely to become the leading cause of pediatric diarrheal hospitalization and deaths. However, the true burden of NV in young children and the extent of acquired immunity remain incompletely understood. Human NV infections are divided into two predominant genogroups (GI and GII), and at least 36 genotypes. Susceptibility to NV infection is thought to be mediated by viral binding to histo-blood group antigens, whose specificity as receptors varies by NV genotype. GII type 4 (GII.4) predominates in outbreaks and sporadic infections for which data are available. An evolving series of GII.4 variants has been detected over the past decade, due to mutations in the major NV capsid protein that change the configuration of the binding site and enable evasion of herd immunity in an epidemiological pattern reminiscent of influenza. Major questions raised by the genetics of NV include the extent and duration of cross-reacting, genotype- and GII.4 variant-specific immunity, and the implications for vaccine design and testing. We propose to conduct a newborn cohort study in a peri-urban community of Lima, Peru, where we have worked since the 1980s, to address these questions in a setting of frequent natural NV infection. Our collaboration with Emory University provides access to a leading NV laboratory with the expertise and state-of-the-art reagents to evaluate naturally-acquired immunity. We begin with newborns because first infections occur very early in life. Our preliminary data demonstrate much higher genetic heterogeneity than is assumed to be the norm: 18 different genotypes were identified of which 40% were GII.4, including 5 different variants. Repeat infections with the same genotype or GII.4 variant were rare, suggesting acquired genotype-specific immunity. We proposed to extend our knowledge of NV epidemiology in endemic diarrhea in young children with this proposal to address issues key to effective vaccine design and deployment. We will quantify the role of NV genotypes in mild and moderate gastroenteritis and evaluate acquisition of protective immunity by correlating serum, saliva and stool antibodies to NVs with NV disease, infection, length of shedding and linear growth. In addition, we will evaluate the role of sapoviru as an enteric pathogen, and will explore the use of community sewage surveillance to track circulating viral strains.

 描述（由申请人提供）：诺如病毒（NV）是全球所有年龄段患者腹泻的主要原因。在轮状病毒之后，NV是儿科胃肠炎和腹泻住院的第二大最常见原因，估计每年造成20万人死亡。当轮状病毒疫苗接种被广泛实施时，NV可能成为小儿腹泻住院和死亡的主要原因。然而，NV在幼儿中的真正负担和获得性免疫的程度仍然不完全清楚。人类NV感染分为两个主要的基因组（GI和GII）和至少36种基因型。对NV感染的易感性被认为是由病毒与组织血型抗原的结合介导的，其作为受体的特异性因NV基因型而异。GII 4型（GII.4）在有数据的暴发和散发感染中占主导地位。在过去的十年中，由于主要NV衣壳蛋白的突变改变了结合位点的构型，并使群体免疫逃避的流行病学模式令人想起流感，已检测到一系列不断演变的GII.4变体。NV遗传学提出的主要问题包括交叉反应的程度和持续时间，基因型和GII.4变异特异性免疫，以及对疫苗设计和测试的影响。我们建议在秘鲁利马的城郊社区进行一项新生儿队列研究，我们自20世纪80年代以来一直在那里工作，以解决这些问题，在一个频繁的自然NV感染的设置。我们与埃默里大学的合作提供了一个领先的NV实验室的专业知识和最先进的试剂来评估自然获得性免疫。我们从新生儿开始开始，因为第一次感染发生在生命的早期。我们的初步数据表明，遗传异质性比假设的标准高得多：确定了18种不同的基因型，其中40%是GII.4，包括5种不同的变异体。重复感染相同的基因型或GII.4变异体是罕见的，这表明获得性基因型特异性免疫。我们建议扩大我们的知识，NV流行病学在地方性腹泻的幼儿与这个建议，以解决问题的关键，有效的疫苗设计和部署。我们将量化NV基因型在轻度和中度胃肠炎中的作用，并通过将血清、唾液和粪便抗体与NV疾病、感染、脱落长度和线性生长相关联来评估获得保护性免疫。此外，我们将评估沙波病毒作为肠道病原体的作用，并将探索使用社区污水监测来跟踪循环病毒株。