mVACS--mRNA Vaccines for C. difficile Suppression

mVACS--用于抑制艰难梭菌的 mRNA 疫苗

• 批准号: 10625573
• 负责人: Frederic D Bushman
• 金额: $ 153万
• 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/10625573
• 关键词: 2019-nCoV; Antibiotics; Antigens; Bioinformatics; Biological Response Modifier Therapy; Biology; Cessation of life; Clinical; Clostridium difficile; Colitis; Collaborations; Complement; Data; Dedications; Development; Diarrhea; Disease; Dose; Ecology; Engineering; Environment; Formulation; Gastrointestinal Diseases; Genomics; Goals; Human; Immune; Immune response; Immunize; Immunology; Individual; Infection; Intervention; Intestines; Lead; Lipids; Literature; Membrane Proteins; Messenger RNA; Metadata; Methods; Microbiology; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Mus; Nucleic acid sequencing; Nutrient; Pathogenesis; Phase I Clinical Trials; Primary Infection; Primary Prevention; Production; Public Health; RNA vaccine; Recurrence; Reporting; Research; Risk; Sampling; Series; Severities; Shapes; System; Technology; Testing; Toxin; United States; Vaccinated; Vaccination; Vaccine Design; Vaccines; Work; adaptive immune response; antitoxin; archive data; data archive; design; global health; gut colonization; improved; industry partner; insight; member; microbial; microbiota; mouse model; nanoparticle; novel; novel therapeutic intervention; novel vaccines; pathogen; patient population; prevent; programs; rational design; recurrent infection; response; sample archive; skills; transmission process; vaccine candidate; vaccine delivery; vaccine development; vaccine efficacy; vaccine formulation; vaccine platform

SUMMARY – mVACS PROGRAM Clostridioides difficile is the most reported nosocomial pathogen in the United States and a major public health threat worldwide. Challenges in treating infections with conventional antibiotics and increasing rates of recurrent infection underscore the need for new interventions. To date, no vaccine has proven to be effective at clearing C. difficile from infected individuals. The mVACS program—"mRNA Vaccines for C. difficile Suppression”—is tightly focused on the goal of designing and implementing improved vaccines to mitigate or eliminate C. difficile infection (CDI). For this we will employ modified mRNA vaccine technology, which has been pioneered so successfully by team member Dr. Drew Weissman and his collaborators at BioNTech to immunize against SARS- CoV-2. Already Drs. Weissman, Alameh, and Zackular have established a collaboration with BioNTech to develop an mRNA targeting C. difficile toxins and other antigens and shown their lead formulation to be highly protective in mice challenged with a lethal dose of C. difficile. However, C. difficile is not fully cleared from the mice, and there is mild transient pathogenesis, so there is more to be done. The team is moving forward with this anti-toxin vaccine, but improvements in design are necessary for optimal efficacy. The mVACS team is a highly skilled and synergistic group dedicated to developing modified mRNAs to oppose C. difficile infection and pathogenesis. The program consists of three projects and three cores. Project 1 (Vaccine Development) (Project Leads: Alameh and Weissman) will test new mRNAs against multiple C. difficile targets, as well as mixtures of mRNAs and novel nanoparticle/lipid formulations. Project 2 (Antigen Discovery) (Project Lead: Zackular) will take advantage of advanced analysis of C. difficile microbiology and ecology of infection to produce a series of novel vaccine targets. Project 3 (Immunology) (Project Lead: Abt) will quantify mucosal adaptive immune responses against C. difficile in humans and mouse systems, identifying gaps and correlates of efficacy. Projects 2 (Antigen Discovery) and Project 3 (Immunology) will flow new data to Project 1 (Vaccine Development) to optimize vaccine design. The Projects will be complemented by three Cores: Core A (Administrative Core) (Core Leads: Bushman and Weissman), Core B (Genomics Core) (Core Leads: Bittinger, Bushman, and Moustafa) and Core C (Clinical Core) (Core Leads: Kelly and Conrad). Together with our industry partner BioNTech, we are highly optimistic that we can advance effective new vaccine designs to suppress C. difficile.

摘要-mVACS计划 艰难梭状芽胞杆菌是美国报告最多的医院病原体，也是一种主要的公共卫生 全球范围的威胁。用常规抗生素治疗感染面临的挑战和复发率的增加 感染凸显了新干预措施的必要性。到目前为止，还没有一种疫苗被证明能有效清除 来自感染者的艰难梭菌。MVACS计划--“艰难梭菌抑制基因疫苗”--是 紧紧围绕设计和实施改进的疫苗以减轻或消除艰难梭菌的目标 感染(CDI)。为此，我们将采用改良的mRNA疫苗技术，这是我们的先驱 团队成员德鲁·魏斯曼博士和他在BioNTech的合作者成功地为SARS接种了疫苗- CoV-2。Weissman博士、Alameh博士和Zackular博士已经与BioNTech建立了合作关系 开发一种针对艰难梭菌毒素和其他抗原的信使核糖核酸，并显示它们的铅配方高度 对用致死剂量的艰难梭菌攻击的小鼠具有保护作用。然而，艰难梭菌并未完全从 小鼠，而且有轻微的一过性发病机制，所以还有更多的工作要做。这个团队正在向前推进， 这是一种抗毒素疫苗，但必须改进设计才能获得最佳疗效。MVACS团队是一名 高技能和协作性小组致力于开发修饰的mRNA以对抗艰难梭菌感染和 发病机制。该计划由三个项目和三个核心组成。项目1(疫苗开发) (项目负责人：Alameh和Weissman)将测试针对多个艰难梭菌靶标的新mRNA，以及 MRNAs和新型纳米颗粒/脂类制剂的混合物。项目2(抗原发现)(项目负责人： Zackular)将利用艰难梭菌微生物学和感染生态学的高级分析来生产 一系列新的疫苗靶点。项目3(免疫学)(项目负责人：ABT)将量化粘膜适应性 在人类和小鼠系统中对艰难梭菌的免疫反应，确定疗效的差距和相关性。 项目2(抗原发现)和项目3(免疫学)将向项目1(疫苗)输送新数据 开发)，以优化疫苗设计。这些项目将得到三个核心的补充：核心A (管理核心)(核心领导：Bushman和Weissman)、核心B(基因组核心)(核心领导： Bittinger、Bushman和Moustafa)和Core C(临床核心)(核心线索：Kelly和Conrad)。与.一起 我们的行业合作伙伴BioNTech，我们非常乐观地认为，我们可以推进有效的新疫苗设计，以 抑制艰难梭菌。