Naturally occurring human antibodies to alphavirus infection

天然存在的人类抗甲病毒感染抗体

基本信息

批准号：
8652431
负责人：
Patricia Veronica Aguilar
金额：
$ 19.92万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-15 至 2015-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8652431
关键词：
Accounting Affinity Alphavirus Alphavirus Infections American Antibodies Antibody Formation Antibody Repertoire Antigens Antiviral Therapy Area Arthralgia Arthropods B-Lymphocytes Blood Blood Circulation Blood specimen Categories Chikungunya virus Country Data Dengue Diagnosis Encephalitis Epitopes Exanthema Exhibits Exploratory/Developmental Grant Generations Glycoproteins Goals Hemagglutinin Human Hybridomas Immune response In Vitro Individual Infection Influenza Influenza A virus Knowledge Libraries Maps Mayaro virus Measures Mediating Medical Membrane Fusion Methods Monoclonal Antibodies Morbidity - disease rate Mus National Institute of Allergy and Infectious Disease Peripheral Blood Mononuclear Cell Peru Play Population Recruitment Activity Recurrence Role Sindbis Virus Site Specificity Technology Therapeutic Therapeutic Agents United States Vaccines Venezuelan Equine Encephalitis Virus Venezuelan Equine Encephalomyelitis Viral Virus Virus Diseases combinatorial cross reactivity design human monoclonal antibodies human subject improved in vivo influenzavirus innovation insight neutralizing antibody pandemic disease pandemic influenza pathogen peripheral blood public health relevance transmission process vaccine development

项目摘要

DESCRIPTION (provided by applicant): Alphaviruses are arthropod-transmitted viruses that cause medically-important human infections worldwide. Specific therapeutics for these viruses are lacking, and only experimental vaccines are available for these infections. In this Developmental/Exploratory Grant, we will generate and characterize in detail human anti- alphavirus antibodies, filling an unaddressed gap in our knowledge regarding the human antibody repertoire to alphavirus infection. Although past studies have characterized antibody responses to prototypical alphaviruses, such as Sindbis virus, in mice; little is known regarding the specific epitopes or the repertoire of human antibodies to natural alphavirus infection. We propose to use human hybridoma technology that has proven capable of generating potent neutralizing antibodies to each of the three 20th century pandemic viruses, despite the fact that each of these viruses circulated many years ago, to generate human antibodies to two medically important alphaviruses, Venezuelan equine encephalitis (VEE) and Mayaro (MAY) virus. We will obtain blood from a unique population of individuals from endemic areas of alphavirus transmission in Peru who have been definitively diagnosed with recent VEE or MAY virus infection. From the B cells of these individuals, we will generate human monoclonal antibodies that neutralize VEE and MAY viruses, and we will characterize in vitro and in vivo the human monoclonal antibodies. VEE and MAY viruses cause significant morbidity in Latin American countries and also pose threats to the United States. VEE virus alone accounts for as much as 7% of the supposed dengue fever cases in certain tropical regions and is considered a NIAID Category B priority pathogen whereas MAY virus causes recurrent incapacitating arthralgias that can last several months, similar to Chikungunya virus. Completion of this study will generate the first naturally- occurring human antibodies to VEE and MAY virus, providing insight into the antibody repertoire toward these important human pathogens. It will also seek to identify VEE and MAY virus-specific and more broadly cross- reactive (to other alphaviruses) antibodies and their epitopes. Such antibodies are potential therapeutics, and information regarding their epitopes, particularly cross-reactive epitopes, may suggest optimized vaccine approaches that may successfully target multiple alphaviruses.

描述（由申请人提供）：α病毒是节肢动物传播的病毒，引起全世界医学重要的人类感染。缺乏针对这些病毒的特定治疗剂，并且仅可用于这些感染的实验疫苗。在这种发展/探索赠款中，我们将生成和特征人类抗α病毒抗体，从而填补了关于α病毒感染的人类抗体曲目的知识，填补了尚未解决的差距。尽管过去的研究表征了小鼠对原型α病毒（例如信德氏病）的抗体反应。关于特定表位或人类对天然α病毒感染的人类抗体的曲目知之甚少。我们建议使用人类杂交瘤技术，该技术已证明能够对20世纪三种20世纪大流行病毒中的每一种产生有效的中和抗体，尽管事实上，这些病毒中的每种病毒都在许多年前流传，可以对两种具有医学重要的alphaviruess，委内瑞拉省降级抗体（Veee）和Mayaro（Mayaro）和Mayaro（Mayarus）生成人类抗体。我们将从秘鲁的alphavirus传播流行区域的独特个体中获得血液，这些地区已被确定地诊断出患有最近的VEE或可能的病毒感染。从这些个体的B细胞中，我们将产生人类的单克隆抗体，以中和Vee和May病毒，我们将在体外和体内表征人类单克隆抗体。 VEE和可能的病毒在拉丁美洲国家引起了巨大的发病率，并对美国构成威胁。在某些热带地区，仅VEE病毒就占登革热病例的7％，被认为是B类优先级病原体病原体，而病毒可能会导致复发性无行为能力，可持续几个月，类似于Chikungunya病毒。这项研究的完成将产生第一种天然发生的人类对VEE和病毒的抗体，从而对这些重要的人类病原体的抗体曲目提供见解。它还将寻求识别VEE，并可能特异性病毒特异性，更广泛地反应性（与其他α病毒）抗体及其表位。这种抗体是潜在的治疗剂，有关其表位的信息，尤其是交叉反应性表位，可能会提出优化的疫苗方法，可以成功靶向多个α病毒。