Enhancing C. difficile vaccination in the context of TcdB-mediated immunosuppression.

在 TcdB 介导的免疫抑制背景下加强艰难梭菌疫苗接种。

• 批准号: 10625175
• 负责人: Jimmy D. Ballard
• 金额: $ 35.61万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-25 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625175
• 关键词: Adopted; Amino Acid Sequence; Animals; Antibody Response; Antigens; Cells; Cessation of life; Clinical Trials; Clostridium difficile; Combined Vaccines; Data; Disease; Drug Metabolic Detoxication; Effectiveness; Ensure; Epitopes; Event; FDA approved; Futility; Generations; Genetic Engineering; Goals; Hamsters; Human; Immune; Immune response; Immunologic Memory; Immunosuppression; Infection; Investigation; Mediating; Memory; Modeling; Mus; Phase III Clinical Trials; Polysaccharides; Production; Proteins; Publishing; Relapse; Reporting; Rodent; Structure; Testing; Toxic effect; Toxin; Toxoids; Vaccinated; Vaccination; Vaccines; Virulence; Virulence Factors; Work; design; experimental study; gastrointestinal; human monoclonal antibodies; immune activation; in vivo; memory recall; mouse model; mutant; neutralizing antibody; next generation; novel; novel vaccines; pathogen; prevent; response; vaccine candidate; vaccine effectiveness

PROJECT SUMMARY (Project 1) The most recent reports indicate Clostridioides difficile is the cause of over 400,000 cases of gastrointestinal illness and nearly 30,000 deaths annually. The goals of this project are to develop an effective next generation vaccine to prevent C. difficile disease and investigate the virulence-related activities of C. difficile that might reduce vaccine effectiveness. A leading candidate developed for vaccination in the Ballard lab is a mutant of TcdB lacking a key cell entry sequence. This mutant is unable to interact with cells but appears to retain aspects critical to promoting a neutralizing antibody response. This vaccine candidate will be further optimized and modified to ensure stability and a total absence of toxicity. Comparisons will be made between this mutant and a toxoid of TcdB. Next, the TcdB derivative will be used in combination with a polysaccharide antigen derived from C. difficile to generate a novel combination vaccine. All vaccine candidates will be tested for protection against C. difficile disease in a mouse model and the most promising of those will be further tested in a hamster model of infection. Using strains of C. difficile genetically engineered to express inactive TcdB, we will also determine if C. difficile inactivates key immune cells needed to provide effective memory responses in vaccinated animals. Together, these studies will both identify new C. difficile vaccines and determine the extent to which this pathogen can subvert their effectiveness.

项目摘要（项目1） 最近的报告表明，梭菌梭菌的艰难梭菌是胃肠道超过40万例的原因 疾病和近30,000例死亡。该项目的目标是发展有效的下一代 预防艰难梭菌疾病并研究艰难梭菌的毒力相关活性的疫苗 降低疫苗有效性。在巴拉德实验室中开发用于疫苗接种的领先候选人是一个突变体 TCDB缺乏关键单元格的序列。该突变体无法与细胞相互作用，但似乎保留了各个方面 对于促进中和抗体反应至关重要。该疫苗候选者将得到进一步优化，并且 修改以确保稳定性和完全没有毒性。将在此突变体和 TCDB的毒素。接下来，将使用TCDB衍生物与衍生的多糖抗原结合使用 从艰难梭菌产生一种新型组合疫苗。所有候选疫苗的候选者都将进行保护 在小鼠模型中针对艰难梭菌疾病，最有前途的仓鼠将进一步测试 感染模型。使用艰难梭菌的菌株进行基因设计以表达非活动性TCDB，我们还将 确定艰难梭菌是否会使关键免疫细胞失活以在接种疫苗中提供有效的记忆反应 动物。这些研究共同确定了新的艰难梭菌疫苗，并确定 这种病原体可以颠覆其有效性。