EPITOPE DISCOVERY--NEW ROUTE TO VACCINES

表位的发现——疫苗的新途径

• 批准号: 6519316
• 负责人: GEORGE PEARSON SMITH
• 金额: $ 29万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-07-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6519316
• 关键词: B cell receptor; B lymphocyte; active immunization; antibody formation; antigen antibody reaction; babesiosis; bacteriophage T4; circular dichroism; cow; disease /disorder model; laboratory mouse; nuclear magnetic resonance spectroscopy; nucleic acid sequence; peptide library; protozoal antigen; protozoal vaccine; technology /technique development; vaccine development; vector vaccine

"Epitope discovery" is a new way to identify antigenic fragments of pathogen proteins. Starting with a library of tens or hundreds of millions of random fragments of pathogen proteins, anti-pathogen antibodies are used to select fragments that bind particularly tightly to subspecificities within the antibody population. Selection is accomplished with simple microbiological methods by means of phage display technology. The selected peptides, having won a rigorous competition among all the structures in the initial library, have strong credentials as candidate components of synthetic or recombinant peptide vaccines. But are these peptides good "immunogenic mimics"? That is, are they able on their own to induce antibodies that cross-react with the pathogen itself--as they must if they are to protect against disease? This key question will be addressed using bacteriophage T4 as a model "pathogen" (T4 is readily and safely produced in large amounts, allowing cross-reactions to be quantified directly by simple immunochemical techniques). From the results we will learn which intrinsic properties of peptides can be used to predict outstanding immunogenic mimicry a priori, without having to assess it directly in living subjects--a difficult task in the context of actual diseases. Immunogenic mimicry is necessary but not sufficient for vaccine performance, however, since not all pathogen-reactive antibodies actually protect against disease. Using a second model system--the cattle disease caused by the tick-borne, malaria-like parasite Babesia bovis--we will show how antigenic peptides can be screened in vitro for the likelihood of protective value. Taken together, the constellation of innovations to be explored--isolating particularly promising peptides via epitope discovery, assessing them for properties that correlate with superior immunogenic mimicry, and screening them in vitro for the capacity to engender protective effects--promise to deliver vaccine candidates with excellent prospects for efficacy, before a single trial in a living subject must be undertaken.

“表位发现”是鉴定病原体蛋白抗原片段的一种新方法。 从数千万或数亿个病原体蛋白随机片段的文库开始，抗病原体抗体用于选择与抗体群体内的亚特异性特别紧密结合的片段。 通过噬菌体展示技术用简单的微生物方法完成选择。所选择的肽在初始文库中的所有结构中赢得了严格的竞争，具有作为合成或重组肽疫苗的候选组分的强有力的证书。但是这些肽是良好的“免疫原性模拟物”吗？ 也就是说，它们是否能够自己诱导出与病原体本身发生交叉反应的抗体--如果它们要抵御疾病，就必须这样做？ 这个关键问题将使用噬菌体T4作为模型“病原体”来解决（T4容易且安全地大量产生，允许通过简单的免疫化学技术直接定量交叉反应）。 从结果中，我们将了解肽的哪些内在特性可用于先验预测突出的免疫原性模拟，而不必直接在活体中进行评估-这在实际疾病的背景下是一项艰巨的任务。然而，免疫原性模拟对于疫苗性能是必要的，但不是充分的，因为并非所有的病原体反应性抗体实际上都能抵抗疾病。 使用第二个模型系统-由蜱传的，疟疾样寄生虫牛巴氏杆菌引起的牛疾病-我们将展示如何在体外筛选抗原肽的保护价值的可能性。总之，一系列有待探索的创新--通过表位发现分离出特别有前途的肽，评估它们与上级免疫原性模拟相关的特性，并在体外筛选它们产生保护作用的能力--有望在必须进行活体试验之前，提供具有良好疗效前景的候选疫苗。