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）：甲病毒是节肢动物传播的病毒，在全世界引起医学上重要的人类感染。目前缺乏针对这些病毒的特异性治疗方法，并且只有实验性疫苗可用于这些感染。在这项发展/探索性资助中，我们将产生并详细描述人类抗甲病毒抗体，填补我们关于甲病毒感染的人类抗体库的知识中尚未解决的空白。尽管过去的研究已经描述了小鼠对典型甲病毒（例如辛德比斯病毒）的抗体反应；关于天然甲病毒感染的人类抗体的特定表位或全部知识知之甚少。我们建议使用人类杂交瘤技术，该技术已被证明能够对 3 种 20 世纪大流行病毒中的每一种产生有效的中和抗体，尽管这些病毒中的每一种病毒在许多年前就已传播，但我们建议使用人类杂交瘤技术来产生针对两种医学上重要的甲病毒（委内瑞拉甲病毒）的人类抗体。马脑炎 (VEE) 和马亚罗 (MAY) 病毒。我们将从秘鲁甲病毒传播流行区的一个独特人群中获取血液，这些人最近被明确诊断为 VEE 或 MAY 病毒感染。从这些个体的 B 细胞中，我们将产生中和 VEE 和 MAY 病毒的人单克隆抗体，并且我们将在体外和体内表征人单克隆抗体。 VEE 和 MAY 病毒在拉丁美洲国家造成严重发病，也对美国构成威胁。在某些热带地区，仅 VEE 病毒就占了假定登革热病例的 7%，被认为是 NIAID B 类优先病原体，而 MAY 病毒会引起复发性关节痛，可持续数月，与基孔肯雅病毒类似。这项研究的完成将产生第一个针对 VEE 和 MAY 病毒的天然人类抗体，从而深入了解针对这些重要人类病原体的抗体库。它还将寻求识别 VEE 和 MAY 病毒特异性和更广泛的交叉反应性（与其他甲病毒）抗体及其表位。此类抗体是潜在的治疗方法，并且有关其表位，特别是交叉反应表位的信息可能会建议可以成功靶向多种甲病毒的优化疫苗方法。