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 梭状芽胞杆菌艰难梭菌是美国报告最多的医院病原体，是主要的公共卫生 全球威胁。传统抗生素治疗感染和复发率提高的挑战 感染强调了对新干预措施的需求。迄今为止，尚无疫苗可在清除方面有效 C.受感染个体的艰难梭菌。 MVACS计划 - “用于艰难梭菌抑制的mRNA疫苗” - 紧密专注于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，该技术已经开创了 团队成员Drew Weissman博士和他在Biontech的合作者成功地对SARS进行免疫接种 COV-2。已经博士了。 Weissman，Alameh和Zackular已与Biontech建立了合作 开发靶向艰难梭菌毒素和其他抗原的mRNA，并显示其铅配方高度 艰难梭菌致死剂量的小鼠保护性。但是，艰难梭菌并未完全清除 小鼠，并且有轻度的瞬时发病机理，因此还有更多要做的事情。团队正在前进 这种抗毒素疫苗，但设计的改进是最佳效率所必需的。 MVACS团队是 高技能和协同群体致力于开发改良的mRNA，以反对艰难梭菌感染和 发病。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 and Weissman）将测试针对多个艰难梭菌目标的新mRNA，以及 mRNA和新型纳米颗粒/脂质配方的混合物。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先进分析，以产生 一系列新型疫苗靶标。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，确定效率的差距和相关性。 项目2（抗原发现）和项目3（免疫学）将把新数据流向项目1（疫苗 开发）以优化疫苗设计。这些项目将由三个核心完成：核心A （行政核心）（核心线索：布什曼和魏斯曼），核心B（基因组核心）（核心线索： Bittinger，Bushman和Moustafa）和C核C（临床核心）（核心线索：Kelly和Conrad）。一起 我们的行业合作伙伴Biontech，我们非常乐观，我们可以将有效的新疫苗设计推向 抑制艰难梭菌。