Delivery of anti-bacterial glycan vaccines to cells and subcellular compartments

项目3：多功能聚糖疫苗的配制和递送 项目摘要 病毒样颗粒（VLP）是小分子结构的高效载体，所述小分子结构刺激细胞增殖， 免疫系统对这些表位的反应。VLP具有重复的结构和包装TLR激活 RNA，可以进行化学和遗传修饰，并且足够大以显示不同的功能， 分子的方式，使他们能够有效地他们的细胞目标。我们的实验室开发了 Qb和PP 7衣壳蛋白，学习有效聚糖展示的规则，以引发 产生亲和力成熟的抗体。我们现在寻求超越以前设计的局限性， 参与抗原呈递细胞摄取、加工和呈递的各种机制， 在延长的时间段内递送基于VLP的疫苗，以利用 通过持续抗原暴露使生发中心成熟。探索性研究将使用代表性的 葡萄球菌金黄色葡萄球菌三糖缀合至稳健的II类肽作为展示单元，排列该基序 对VLP进行工程改造，以同时呈递DC-SIGN、Fcg受体或补体受体的配体 已知增强B细胞对肽免疫原应答。我们还将探索免疫细胞的招募 细胞通过展示天然抗原鼠李糖以及释放糖肽或刺激性糖肽， VLP内部携带的分子。同时，我们将开发和测试一种新的 可降解的水凝胶材料，其可以被编程以在不同的时间段内释放疫苗。 这一雄心勃勃的计划的成果应该是一个高度优化和模块化的疫苗输送平台 这将立即应用于产生针对耐药细菌的高亲和力抗体 对人类健康构成直接和长期威胁的病原体。

Project 3: Formulation and Delivery of Multifunctional Glycan Vaccines Project Summary Virus-like particles (VLPs) are highly effective carriers of small-molecule structures that stimulate the immune system’s response to such epitopes. VLPs have repetitive structures and package TLR-activating RNA, are amenable to chemical and genetic modification, and are large enough to display different functional molecules in a manner that allows them to effectively their cellular targets. Our laboratories have developed Qb and PP7 capsid proteins for this purpose, learning the rules for effective glycan display to elicit the production of affinity-matured antibodies. We now seek to go beyond the limitations of previous designs by engaging various mechanisms of antigen presenting cell uptake, processing, and presentation, and by delivering VLP-based vaccines over extended periods of time to take advantage of feedback amplification of germinal center maturation by continuous antigen exposure. Exploratory studies will use a representative Staph. aureus trisaccharide conjugated to a robust class II peptide as the displayed unit, arraying this motif on VLPs engineered to simultaneously present ligands for DC-SIGN, Fcg receptors, or complement receptors known to enhance B cell response to peptide immunogens. We will also explore the recruitment of immune cells by the display of the natural antigen rhamnose as well as the release of glycopeptide or stimulatory molecules carried in the interior of the VLP. Simultaneously, we will develop and test a new class of degradable hydrogel materials that can be programmed to release vaccines over different periods of time. The outcome of this ambitious program should be a highly optimized and modular vaccine delivery platform that will be immediately applied to the generation of high-affinity antibodies against drug-resistant bacterial pathogens that pose immediate and long term threats to human health.