Naturally occurring human antibodies to alphavirus infection

天然存在的人类抗甲病毒感染抗体

• 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
• 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

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（由申请方提供）：甲病毒是节肢动物传播的病毒，在全球范围内引起医学上重要的人类感染。目前缺乏针对这些病毒的特定疗法，只有实验性疫苗可用于这些感染。在这项开发/探索性资助中，我们将生成并详细表征人抗甲病毒抗体，填补我们关于甲病毒感染的人抗体库知识中未解决的空白。尽管过去的研究已经表征了小鼠中对原型甲病毒（如辛德毕斯病毒）的抗体应答;但关于天然甲病毒感染的人抗体的特异性表位或库知之甚少。我们建议使用人杂交瘤技术，该技术已被证明能够产生针对三种20世纪世纪大流行病毒中的每一种的有效中和抗体，尽管这些病毒中的每一种都在多年前传播，以产生针对两种医学上重要的甲病毒（委内瑞拉马脑炎（VEE）和马亚罗（MAY）病毒）的人抗体。我们将从秘鲁甲病毒传播流行区的独特人群中采集血液，这些人群已明确诊断为近期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的发病率，也对美国构成威胁。在某些热带地区，仅VEE病毒就占假定登革热病例的7%，并被认为是NIAID B类优先病原体，而MAY病毒引起可持续数月的复发性失能性关节痛，类似于基孔肯雅病毒。这项研究的完成将产生第一个天然存在的VEE和MAY病毒的人类抗体，提供对这些重要的人类病原体的抗体库的了解。它还将寻求鉴定VEE和MAY病毒特异性和更广泛的交叉反应性（对其他甲病毒）抗体及其表位。此类抗体是潜在的治疗剂，并且关于其表位（特别是交叉反应性表位）的信息可以建议可以成功靶向多种甲病毒的优化的疫苗方法。