EPITOPE DISCOVERY--NEW ROUTE TO VACCINES

“表位发现”是鉴定病原蛋白抗原片段的一种新方法。从病原体蛋白质的数千万或数亿随机片段的文库开始，抗病原体抗体被用来选择与抗体群体中的亚特异性结合特别紧密的片段。通过噬菌体展示技术，用简单的微生物方法完成筛选。所选的多肽在初始文库的所有结构中赢得了激烈的竞争，具有很强的合成或重组多肽疫苗候选成分的资质。但是这些多肽是好的“免疫原性模拟物”吗？也就是说，它们是否能够单独诱导与病原体本身发生交叉反应的抗体--如果它们要预防疾病，就必须这样做？这一关键问题将使用噬菌体T4作为模式“病原体”来解决(T4容易且安全地大量生产，允许通过简单的免疫化学技术直接量化交叉反应)。从结果中，我们将了解到多肽的哪些内在属性可以用来预先预测出色的免疫原性模仿，而不必直接在活着的受试者中进行评估--这在实际疾病的背景下是一项困难的任务。然而，免疫原性模仿对于疫苗的性能是必要的，但并不是充分的，因为并不是所有的病原体反应性抗体都能真正预防疾病。使用第二个模型系统--由扁虱传播的类似疟疾的牛巴贝斯虫引起的牛疾病--我们将展示如何在体外筛选抗原肽以确定其保护价值的可能性。综上所述，有待探索的一系列创新--通过表位发现分离特别有希望的多肽，评估它们与高级免疫原性模仿相关的特性，并在体外筛选它们产生保护作用的能力--承诺在必须进行一项活的受试者单一试验之前，提供具有良好疗效前景的候选疫苗。

"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.