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：多功能聚糖疫苗的形成和输送 项目摘要 病毒样颗粒（VLP）是刺激刺激的小分子结构的高效载体 免疫系统对这种表位的反应。 VLP具有重复的结构和包装TLR激活 RNA，适合化学和遗传修饰，足够大以显示不同的功能 分子以使它们有效的细胞靶标的分子。我们的实验室已经发展 为此目的 亲和成熟抗体的产生。现在，我们试图超越以前设计的局限 参与抗原呈现细胞摄取，加工和表现的各种机制，并通过 在很长一段时间内提供基于VLP的疫苗，以利用反馈放大 通过连续抗原暴露通过生发中心成熟。探索性研究将使用代表 葡萄球菌。金黄色金黄色三糖在显示的单元时结合到了强大的II类胡椒粉中 在设计的VLP上，简单地呈现DC-SIGN，FCG受体或补体受体的配体 已知可以增强B细胞对肽免疫原子的反应。我们还将探索免疫原子的募集。 通过展示天然抗原鼠李糖以及糖肽或刺激性的细胞 在VLP内部携带的分子。同时，我们将开发和测试一类 可以编程以在不同时间内释放疫苗的可降解水凝胶材料。 这个雄心勃勃的计划的结果应该是一个高度优化的模块化疫苗输送平台 这将立即应用于针对耐药细菌的高亲和力抗体的产生 对人类健康构成直接和长期威胁的病原体。