Comprehensive functional assesment of the human antibody response to Enterovirus 71

人类抗体对肠道病毒 71 反应的综合功能评估

• 批准号: 9112307
• 负责人: SCOTT Kendall DESSAIN
• 金额: $ 25.82万
• 依托单位: LANKENAU INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-13 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9112307
• 关键词: Acute; Acute respiratory infection; Address; Adult; Affect; Affinity; Age; Animal Model; Antibodies; Antibody Repertoire; Antibody Response; Antigenic Diversity; Area; Aseptic Meningitis; Asia; Atrophic; Binding; Brain Stem; Cardiopulmonary; Cessation of life; Child; Childhood; Cloning; Colorado; Complication; Country; Data; Data Set; Deglutition Disorders; Developmental Delay Disorders; Disease; Disease Outbreaks; District of Columbia; Encephalitis; Enterovirus; Enterovirus 68; Enterovirus 71; Epidemic; Escape Mutant; Exanthema; Failure; Family Picornaviridae; Generations; Hand, Foot and Mouth Disease; Heart failure; Hour; Human; Human poliovirus; Hybridomas; Hypercapnic respiratory failure; Immune response; Immunity; Immunoglobulin G; Immunoglobulin M; Impaired cognition; Individual; Infection; Intravenous Immunoglobulins; Knowledge; Leg; Limb structure; Liquid substance; Mass Spectrum Analysis; Mechanical ventilation; Memory B-Lymphocyte; Methods; Monoclonal Antibodies; Mus; Neurologic; Oral; Paralysed; Patients; Pattern; Pharmaceutical Preparations; Population; Preparation; Proteins; Proteomics; Protocols documentation; Pulmonary Edema; Quadriplegia; RNA Viruses; Research; Research Proposals; Resistance; Role; Serum; Source; Specificity; Study models; Supportive care; Syndrome; Taiwan; Techniques; Therapeutic; Therapeutic Uses; Therapeutic antibodies; United States; Vaccines; Viral; Virus; Virus Shedding; Work; cohort; design; human monoclonal antibodies; innovation; mouse model; neurotropic; next generation sequencing; novel; pathogen; prevent; prototype; public health relevance; research study; resistant strain; respiratory; response; screening; transmission process

 DESCRIPTION (provided by applicant): Enterovirus 71 (EV71) is an emerging picornavirus that has become endemic in Asia-Pacific regions. EV71 infection commonly manifests in childhood as an exanthem known as hand, foot, and mouth disease (HFMD), but in children under the age of 5, severe complications may occur, such as brainstem and/or cerebellar encephalitis, aseptic meningitis, and acute flaccid paralysis. The most devastating complication of EV71 neurologic disease is neurogenic cardiac failure with pulmonary edema. This syndrome can be fatal within hours of onset. There are no specific anti-viral drugs or vaccines approved for EV71 disease. But, in endemic areas, intravenous immunoglobulins (IVIG) are a standard component of supportive care, as IVIG in those regions have significant EV71 IgG titers. Should EV71 spread to non-endemic areas, such as the United States, IVIG will not be useful due to low EV71 IgG titers. Essentially nothing is known about the human antibody response to EV71 at the level of individual antibodies. The objective of the research is to characterize the human neutralizing IgG response to EV71 in subjects who have survived endemic EV71 infection in Taiwan. Two innovative techniques will be used for studying the human antibody response to EV71. A proteomics approach will identify the specific EV71-reactive IgG clonotypes found in sera of naturally infected EV71 patients. This method is an innovative combination of protein mass spectrometry and a NextGen sequencing method that preserves natural HC:LC pairing. Concurrently, a novel hybridoma method of human antibody cloning will functionally screen human mAbs from the same patients in order to identify those with EV71 neutralizing activity. Correlation of these combined datasets will allow an assignment of functions to the exact antibodies present in the serum repertoire. This unprecedented level of detail about the human anti- EV71 antibody repertoire will enable studies to understand the function of antibodies in protection from EV71, including structural studies and animal modeling. The research will seek to identify pairs of non-cross-resistant mAbs with broad-spectrum neutralization activity that will establish proof-of-concept for an EV71 therapeutic intended for use in the USA.

 描述（由申请方提供）：肠道病毒71（EV 71）是一种新出现的小核糖核酸病毒，已成为亚太地区的地方病。EV 71感染通常在儿童时期表现为称为手足口病（HFMD）的皮疹，但在5岁以下的儿童中，可能发生严重的并发症，如脑干和/或小脑脑炎，无菌性脑膜炎和急性弛缓性麻痹。EV 71神经系统疾病最具破坏性的并发症是神经源性心力衰竭伴肺水肿。这种综合症在发病后数小时内可能致命。目前还没有针对EV 71的特定抗病毒药物或疫苗获批。但是，在流行地区，静脉注射免疫球蛋白（IVIG）是支持性护理的标准组成部分，因为IVIG在这些地区具有显著的EV 71 IgG滴度。如果EV 71传播到非流行地区，如美国，由于EV 71 IgG滴度低，IVIG将不起作用。基本上，在个体抗体水平上对EV 71的人抗体应答一无所知。本研究旨在探讨台湾地区肠病毒71型流行性感染存活者对肠病毒71型的中和IgG反应。两项创新技术将用于研究人类对EV 71的抗体反应。蛋白质组学方法将鉴定在自然感染的EV 71患者的血清中发现的特异性EV 71反应性IgG克隆型。该方法是蛋白质质谱和NextGen测序方法的创新组合，保留了天然HC：LC配对。与此同时，一种新的克隆人抗体的杂交瘤方法将从相同的患者中功能性筛选人单克隆抗体，以鉴定具有EV 71中和活性的人单克隆抗体。这些组合数据集的相关性将允许将功能分配给血清库中存在的确切抗体。这种前所未有的关于人抗EV 71抗体库的详细程度将使研究能够理解抗体在保护免受EV 71中的功能，包括结构研究和动物建模。该研究将寻求确定具有广谱中和活性的非交叉耐药mAb对， 为拟在美国使用的EV 71治疗药物建立概念验证。