Human T-cell Epitopes in SARS

SARS 中的人类 T 细胞表位

• 批准号: 6968951
• 负责人: Michael Joseph Buchmeier
• 金额: $ 51.95万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6968951
• 关键词: SARS virus; clinical research; cytotoxic T lymphocyte; epitope mapping; genetically modified animals; helper T lymphocyte; histocompatibility antigens; human subject; human tissue; laboratory mouse; severe acute respiratory syndrome; vaccine development; vaccinia virus; vector vaccine

DESCRIPTION (provided by applicant): The discovery and validation of HLA-restricted cytotoxic and helper T cell epitopes derived from the Severe Acute Respiratory Syndrome coronavirus (SARS CoV) represents a significant challenge because of the large genome size and because of the extreme polymorphism of HLA alleles. Herein, we propose to combine bioinformatic approaches and high throughput MHC- peptide binding assays to identify epitopes restricted by HLA class I and class II molecules representative of >95% of the general population, irrespective of ethnicity. These epitopes will be further validated with in vivo and in vitro immunogenicity studies utilizing HLA transgenic mice and human PBMC from healthy unexposed donors. Animal models are likely to play a vital role in the development of SARS specific vaccines and diagnostics. Accordingly, we also plan to identify epitopes presented by mouse and human MHC molecules expressed in human MHC transgenic mice. In the final part of this application, we propose to explore development of a multi-epitope SARS vaccine construct. This construct could be utilized by itself, or in conjunction with other vaccine constructs aimed at inducing anti-SARS antibody responses. Because the proposed approach is based on a systematic definition of the immunogenic potential of SARS-derived peptide sequences, only minimal use of live SARS virus or biological samples from infected or convalescent individuals is required. The studies proposed herein will lead to the definition of a broad range of epitopes, facilitate the development of diagnostic reagents necessary to rigorously evaluate T cell responses associated with infection in humans, and enable the evaluation, at the level of T cell immunity, of the performance of different vaccine candidates.

描述（由申请人提供）：HLA限制的细胞毒性和助手T细胞表位的发现和验证源自严重的急性呼吸综合症冠状病毒（SARS COV），这是一个重大挑战，因为HLA其他HLA其他其他等位基因的极端多态性。本文中，我们建议将生物信息学方法和高吞吐量MHC-肽结合测定法相结合，以识别由HLA I类和II类分子限制的表位，代表> 95％的一般人群，不论种族如何。这些表位将通过体内和体外免疫原性研究进一步验证，利用健康未暴露供体的HLA转基因小鼠和人PBMC进行了体外免疫原性研究。动物模型可能在特定于SAR的疫苗和诊断的开发中起着至关重要的作用。因此，我们还计划鉴定小鼠和人类MHC分子在人类MHC转基因小鼠中表达的表位。在本应用程序的最后一部分中，我们建议探索多型SARS疫苗构建体的开发。该构建体可以自身使用，也可以与旨在诱导抗SARS抗体反应的其他疫苗结构一起使用。由于所提出的方法是基于对SARS衍生肽序列的免疫原性潜力的系统定义，因此只需要最少使用来自感染或恢复个体的生物样品或生物样品。本文提出的研究将导致广泛的表位定义，从而有助于制定严格评估与人类感染相关的T细胞反应所必需的诊断试剂，并在T细胞免疫的水平上评估不同疫苗候选者的性能。