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

基本信息

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
项目类别：
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

项目摘要

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、免疫功能低下的人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。