Project 1: Neutralizing and decolonizing Clostridioides difficile using mRNA vaccines

项目 1：使用 mRNA 疫苗对艰难梭菌进行中和和去定植

• 批准号: 10625577
• 负责人: DREW WEISSMAN
• 金额: $ 30.12万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625577
• 关键词: Adhesions; Adjuvant; Alginates; Animal Model; Antibiotics; Antibodies; Antigens; Artificial nanoparticles; Bacterial Proteins; Cell Wall; Cells; Cessation of life; Charge; Chemistry; Chitosan; Clinical; Clostridium difficile; Cohort Studies; Collaborations; Data; Disease; Economic Burden; Elderly; Encapsulated; Engineering; Epithelial Cells; Exposure to; Ferritin; Filament; Formulation; Gastrointestinal Diseases; Genes; Genomics; Gut Mucosa; Homing; Human; Hydrogels; IL17 gene; Immune; Immune Evasion; Immune Targeting; Immune response; Immunoglobulin A; Immunology; Immunomodulators; Individual; Infection; Interleukin-6; Intestinal Mucosa; Intestines; Intramuscular; Laboratories; Libraries; Life Cycle Stages; Ligands; Lipids; Maleimides; Mediating; Membrane Proteins; Messenger RNA; Microspheres; Morbidity - disease rate; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Mus; Nucleosides; Oral; Organ; Pediatric Hospitals; Penetration; Philadelphia; Primary Infection; Production; Property; Proteins; RNA vaccine; Recurrence; Reproduction spores; Resources; Science; Severity of illness; Stomach; Sulfhydryl Compounds; Surface; Testing; Therapeutic; Time; Toxin; Transforming Growth Factor beta; Tropism; Vaccines; Work; clinically relevant; cytokine; design; experience; immunogenicity; immunoregulation; improved; improved outcome; inhibitor; innovation; insight; integrin alpha4beta7; interleukin-22; interleukin-23; knowledge base; lipid nanoparticle; mRNA delivery; microbiota; mortality; mucosal addressin cell adhesion molecule-1; mucosal vaccination; multidisciplinary; multiple omics; nanoparticle; novel; novel therapeutics; novel vaccines; pathogen; prevent; primary outcome; prophylactic; rational design; recurrent infection; response; secondary infection; success; vaccine development; vaccine efficacy; vaccine platform; vaccine response; vaccine trial

SUMMARY- PROJECT 1 (VACCINE DEVELOPMENT) Clostridioides difficile is a gram negative spore forming pathogen that causes mild to severe gastrointestinal disorders and death in the elderly, immune compromised individuals and those exposed to systemic antibiotics. Increased recurrence and difficulties treating the disease following antibiotic administration highlight the need to develop novel therapeutic and prophylactic strategies. To date, vaccines against C. difficile demonstrated promising results but failed to meet primary outcome criteria to mitigate/reduce primary infections. Therefore, novel and innovative strategies/approaches are required. Our objective is to develop a clinically relevant highly effective multivalent mRNA-LNP vaccine to prevent colonization and treat C. difficile infection. Our strategy relies on our extensive experience with the nucleoside-modified mRNA and mRNA-LNP platforms, large libraries of ionizable lipids, and a multipronged approach to vaccine development and novel target discovery, as well as the unique multidisciplinary expertise and resources available to us. We hypothesize that multivalent targeting of disease causing toxins and bacterial proteins (e.g., surface proteins) will 1) mitigate primary infection in healthy individuals, and 2) prevent disease and promote decolonization in infected individuals. Improving mucosal immunity following intramuscular administration of mRNA-LNP through ligand and charge mediated tropism, oral delivery of mRNA-LNP vaccines capsulated in hydrogels and/or the addition of immune modulators will improve the efficacy of the multivalent vaccine to decolonize C. difficile in the gut lumen. Insight from the proposed multi-omic approach for target discovery (Project 2 and Core B), and a better understanding of human immune responses to C difficile (Project 3 and Core C) will support a translational workflow that leverages fundamental science and knowledge based approach for the discovery and rational design of novel vaccine targets to treat and prevent C. difficile.

摘要 - 项目 1（疫苗开发） 艰难梭菌是一种革兰氏阴性孢子形成病原体，可导致轻度至重度胃肠道感染 老年人、免疫受损者和接触全身抗生素的人的疾病和死亡。 抗生素治疗后复发率增加和治疗困难突出表明需要 制定新的治疗和预防策略。迄今为止，针对艰难梭菌的疫苗已证明 有希望的结果，但未能满足减轻/减少原发感染的主要结果标准。所以， 需要新颖和创新的战略/方法。我们的目标是开发一种临床相关的 高效多价 mRNA-LNP 疫苗可预防定植并治疗艰难梭菌感染。 我们的策略依赖于我们在核苷修饰 mRNA 和 mRNA-LNP 平台方面的丰富经验， 大型可电离脂质库，以及疫苗开发和新靶标的多管齐下的方法 发现，以及我们可用的独特的多学科专业知识和资源。我们假设 致病毒素和细菌蛋白（例如表面蛋白）的多价靶向将 1) 减轻健康个体的原发感染，2) 预防疾病并促进非定植 感染者。肌肉注射 mRNA-LNP 后改善粘膜免疫 通过配体和电荷介导的趋向性，口服递送封装在水凝胶中的 mRNA-LNP 疫苗 和/或添加免疫调节剂将提高多价疫苗去定植艰难梭菌的功效。 肠腔内的艰难梭菌。从拟议的多组学方法中发现靶标（项目 2 和核心 B)，更好地了解人类对艰难梭菌的免疫反应（项目 3 和核心 C）将支持 转化工作流程利用基础科学和基于知识的方法来发现和 合理设计新的疫苗靶点来治疗和预防艰难梭菌。