SYNTHETIC VACCINE AGAINST SHIGELLOSIS

由志贺氏菌1型引起的志贺氏菌病仍然是主要的 世界范围内的肠道疾病 因为多重抗生素耐药性 在志贺氏菌的许多菌株中，志贺氏菌病的治疗是困难的。 虽然需要疫苗来控制这种疾病， 根据世界卫生组织的记录，目前还没有针对志贺氏菌病的许可疫苗。 在罗宾斯和同事发现血清抗体 对S.假单胞菌1型 赋予人类保护性免疫力，我们假设 OSP的片段也可能适合于诱导保护性的 当偶联至免疫原性蛋白质时， 这样的构象合奏的方法， 天然多糖的构象决定簇。 使用 具有确定结构的合成多糖， 复杂的体系结构可能提供的优势包括增强 结合物的均匀性和分析困难的消除 与已建立的多糖蛋白疫苗有关。 基于 基于这一假设，我们正在开发合成的寡聚体， 具有明确特征的基于多糖的免疫原。 我们 设计了一种制备S.痢疾 1型。 OSP由四糖重复单元组成，即 由D-半乳糖、N-乙酰基-D-葡糖胺和L-鼠李糖组成。 从单糖构建模块开始， 保护和活化基团，四糖供体/受体 分子组装。 这个构建块的迭代组合 得到对应于以下的重复单元的二聚体、三聚体和四聚体 八碳、十二碳和十六碳。 核磁共振 光谱表明，十二碳和十六碳 显示出与天然O-SP高度的构象相似性 我们认为这是产生保护性抗体的先决条件。 体外实验表明，合成的β-内酰胺酶抑制 OSP与同源单克隆抗体的结合。

Shigellosis caused by Shigella dysenteriae type 1 continues to be a major enteric disease worldwide. Because of the multiple-antibiotic resistance of many strains of Shigellae, the treatment of shigellosis is difficult. Although the need for vaccines to control this disease has been documented by the WHO, there is no licenced vaccine against shigellosis. Following the discovery by Robbins and coworkers that serum antibodies against the O-specific polysaccharide (OSP) of S. dysenteriae type 1 confer protective immunity in humans we hypothesized that extended fragments of the OSP may also be suitable for the induction of protective antibodies when coupled to immunogenic proteins, provided that the conformational ensemble of such saccharides approaches that of the conformational determinant of the native polysaccharide. The use of synthetic saccharides of defined structure instead of polysaccharides of complex architecture is likely to offer advantages including enhanced uniformity of conjugates and elimination of the analytical difficulties associated with the established, polysaccharide-protein vaccines. Based on this hypothesis we are developing synthetic oligo- and poly-saccharide-based immunogens of well-defined characteristics. We designed a strategy to prepare fragments of the OSP of S. dysenteriae type 1. The OSP consists of a tetrasaccharide repeating unit that is composed of D-galactose, N-acetyl-D-glucosamine, and L-rhamnose. Starting from monosaccharide building blocks that carry orthogonal protecting and activating groups, a tetrasaccharide donor/acceptor molecule was assembled. Iterative combination of this building block afforded di-, tri- and tetramers of the repeating unit corresponding to octa-, dodeca- and hexadeca-saccharides. Nuclear magnetic resonance spectroscopy indicated that the dodeca- and the hexadeca-saccharides exhibit a high degree of conformational similarity to the native O-SP which we believe is a prerequisite for protective antibody induction. In vitro experiments showed that the synthetic saccharides inhibit the binding of the OSP to homologous monoclonal antibodies.