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

将抗菌聚糖疫苗递送至细胞和亚细胞区室

• 批准号: 10549647
• 负责人: M.G. Finn
• 金额: $ 30.45万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-09 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549647
• 关键词: Adjuvant; Affinity; Anti-Bacterial Agents; Antibodies; Antibody Affinity; Antigen Presentation; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Bacterial Infections; Bacterial RNA; CD209 gene; Capsid Proteins; Carbohydrates; Cells; Chemicals; Chemistry; Complement Receptor; Conjugate Vaccines; Dangerousness; Development; Dimensions; Disease; Drug Delivery Systems; Drug resistance; Engineering; Epitopes; Feedback; Formulation; Freeze Drying; Friends; Generations; Genetic; Glycopeptides; Goals; Health; Human; Hydrogels; Immune; Immune response; Immune system; Immunologic Sensitization; Immunologic Stimulation; Immunologics; Implant; Laboratories; Learning; Ligands; Modification; Molecular; Molecular Profiling; Molecular Target; Nature; Nucleoproteins; Oligosaccharides; Outcome; Pattern recognition receptor; Peptides; Peptidoglycan; Polysaccharides; Positioning Attribute; Preparation; Preventive vaccine; Process; Production; Proteins; RNA; Refrigeration; Reporting; Rhamnose; Serotyping; Signal Induction; Signal Transduction; Streptococcus pneumoniae; Structure; Structure of germinal center of lymph node; System; T-Lymphocyte; Testing; Time; Trisaccharides; Vaccines; Virus-like particle; Work; adaptive immune response; carbohydrate structure; cellular targeting; chemical stability; combat; density; design; fighting; improved; insight; lymph nodes; nanoparticle; nanoparticle delivery; pathogen; pathogenic bacteria; programs; receptor; reconstitution; recruit; response; scaffold; small molecule; success; sugar; therapeutic vaccine; tool; uptake; vaccine delivery; vaccine development

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.

项目3：多功能葡聚糖疫苗的研制和交付 项目摘要 病毒样颗粒(VLP)是一种高效的小分子结构载体，可刺激 免疫系统对这些表位的反应。VLP具有重复结构和包装TLR激活 RNA，可以进行化学和遗传修饰，并且足够大，可以显示不同的功能 分子以一种允许它们有效地实现其细胞靶标的方式。我们的实验室已经发展出 QB和PP7衣壳蛋白为此，学习有效的糖蛋白展示规则，以诱导 产生亲和力成熟的抗体。我们现在寻求通过以下方式超越以前设计的限制 参与抗原提呈细胞摄取、处理和提呈的各种机制，并通过 在更长的时间内提供VLP疫苗，以利用反馈放大 生发中心通过持续抗原暴露而成熟。探索性研究将使用具有代表性的 葡萄球菌。金黄色三糖结合到一个强健的II类肽上作为展示单位，排列这个基序 关于同时呈现DC-SIGN、FCG受体或补体受体配体的VLP 已知可增强B细胞对肽免疫原的反应。我们还将探索招募免疫 细胞通过展示天然抗原鼠李糖以及释放糖肽或刺激性 VLP内部携带的分子。同时，我们将开发和测试一个新的类别 可降解的水凝胶材料，可以通过编程在不同的时间段释放疫苗。 这一雄心勃勃的计划的结果应该是一个高度优化和模块化的疫苗交付平台 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。