IDENTIFICATION OF PROTECTIVE / PATHOGENIC HUMAN B CELL EPITOPES IN DENGUE VIRUS

登革热病毒中保护性/致病性人类 B 细胞表位的鉴定

• 批准号: 8360452
• 负责人: John Scribner Schieffelin
• 金额: $ 20.42万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360452
• 关键词: Antibodies; Antibody Formation; Antibody-Dependent Enhancement; Attenuated; B-Lymphocyte Epitopes; B-Lymphocytes; Caribbean region; Cell Line; Contracts; Culicidae; Dengue; Dengue Hemorrhagic Fever; Dengue Virus; Development; Disease; Epidemic; Epitopes; Foundations; Funding; Genomics; Goals; Grant; Human; Human Herpesvirus 4; Immunity; Immunology; Infection; Lead; Libraries; Life; Louisiana; Mentors; Monoclonal Antibodies; Mus; National Center for Research Resources; Patients; Principal Investigator; Proteins; Publishing; Reagent; Research; Research Infrastructure; Research Personnel; Resources; Risk; Role; Solid; Source; United States; United States National Institutes of Health; Vaccination; Vaccines; Virus; Virus Diseases; cost; human monoclonal antibodies; neutralizing antibody; peripheral blood; statistics; vaccine development; virology

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Dengue viruses are the most common cause of mosquito-borne viral disease in tropical and subtropical regions around the world. Although it is no longer endemic to the United States, sporadic cases do occur and epidemics are increasingly common in the Caribbean and along the southern border of the U.S. Antibody produced during dengue virus infection provides homotypic immunity. However, pre-existing, circulating antibodies can produce a non-protective antibody response that can intensify the course of disease in a subsequent heterotypic infection. Theoretically, an attenuated live virus or whole protein vaccine could lead to severe disease during a post-vaccination primary infection. An understanding of this antibody dependent enhancement phenomenon, as it occurs in humans, is critical to the development of vaccines that will provide long-term protection without increasing the risk of dengue hemorrhagic fever (DHF). To date, most published anti-dengue monoclonal antibodies (MAbs) are of mouse origin. However, mice are neither normal hosts for dengue virus nor do they develop severe infection, such as DHF, after inoculation. Therefore, these reagents may not reflect the repertoire and roles of antibody produced by humans during natural infection. Epstein-Barr Virus (EBV) transformation of B cells isolated from the peripheral blood of previously infected patients can be performed to develop cell lines which produce naturally occurring human monoclonal antibodies. Preliminary research by the candidate has successfully produced multiple such lines. The primary goals of the proposed research are to: 1. Increase our understanding of the human antibody response to dengue virus infection by creating a library of anti-dengue human monoclonal antibodies; 2. Identify which antibodies are neutralizing or enhancing; 3. Identify the epitopes that these antibodies target. This research is not only critical to the development of an effective and safe vaccine, but it will also provide a solid foundation for the candidate in the fields of virology and vaccine immunology. It is expected that the candidate will be ready to compete for independent federal funding within two to three years. Several available cores will be utilized to achieve these goals including the genomics, immunology sequencing, statistics and grants and contracts cores.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 登革热病毒是世界各地热带和亚热带地区蚊媒病毒性疾病的最常见原因。虽然它不再是美国的地方病，但仍有零星病例发生，并且在加勒比海和美国南部边境沿着流行病越来越普遍。登革热病毒感染期间产生的抗体提供同型免疫。然而，预先存在的循环抗体可产生非保护性抗体应答，其可在随后的异型感染中强化疾病进程。从理论上讲，减毒活病毒或全蛋白疫苗在接种后初次感染期间可能导致严重疾病。了解这种抗体依赖性增强现象，因为它发生在人类中，是至关重要的疫苗，将提供长期的保护，而不会增加登革出血热（DHF）的风险的发展。迄今为止，大多数已发表的抗登革热单克隆抗体（MAb）均来源于小鼠。然而，小鼠既不是登革病毒的正常宿主，也不会在接种后发生严重感染，如DHF。因此，这些试剂可能无法反映人类在自然感染期间产生的抗体的库和作用。可以对从先前感染的患者的外周血中分离的B细胞进行EB病毒（EBV）转化，以开发产生天然存在的人单克隆抗体的细胞系。候选人的初步研究已经成功地产生了多个这样的线。 本研究的主要目的是：1.通过建立抗登革病毒人源单克隆抗体库，增加我们对登革病毒感染的人源抗体应答的理解; 2.确定哪些抗体是中和或增强; 3.确定这些抗体的目标表位。这项研究不仅对开发有效和安全的疫苗至关重要，而且还将为病毒学和疫苗免疫学领域的候选人提供坚实的基础。预计这位候选人将在两到三年内准备好竞争独立的联邦拨款。几个可用的核心将被用来实现这些目标，包括基因组学，免疫测序，统计和赠款和合同的核心。