Novel C. Difficile Vaccine Using Nano-vesicle Delivery System

使用纳米囊泡递送系统的新型艰难梭菌疫苗

• 批准号: 10010542
• 负责人: Christopher Locher
• 金额: $ 29.99万
• 依托单位: VERSATOPE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-11 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10010542
• 关键词: 3-Dimensional; Adjuvant; Adverse effects; American; Animal Model; Antibiotic Therapy; Antibodies; Antigen Presentation; Antigens; Bacteria; Bacterial Infections; Bacteriology; Cell Wall; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chimeric Proteins; Clinical; Clinical Research; Clostridium difficile; Complex; Development; Diarrhea; Drug resistance; Endotoxins; Escherichia coli; Evaluation; Fermentation; Formalin; Foundations; Francisella tularensis; Genes; Genetic; Hamsters; Health Sciences; Hospital Costs; Hospitals; Immune response; Immunity; Individual; Infection; Infection prevention; Length of Stay; Lipopolysaccharides; Membrane; Membrane Proteins; Meningococcal Infections; Meningococcal vaccine; Mesocricetus auratus; Methods; Modeling; Modification; Monoclonal Antibodies; Neisseria meningitidis; Outcome; Pathogenesis; Patients; Phase; Pilum; Polysaccharides; Prevention; Probiotics; Proteins; Published Comment; Readiness; Recombinants; Recurrence; Reporting; Reproduction spores; Research; Risk; Site; Staphylococcus aureus; Surface; Surface Antigens; System; Targeted Toxins; Texas; Therapeutic; Toxic effect; Toxin; Toxoids; Universities; Vaccines; Vesicle; Virus Diseases; Work; alpha Toxin; aluminum sulfate; antitoxin; bactericide; base; c new; clinical efficacy; cost; efficacy evaluation; flexibility; improved; innovation; lipoteichoic acid; manufacturing process; microbial; nanoparticle; nanovesicle; novel; novel strategies; novel vaccines; pandemic influenza; polypeptide; pre-clinical; prevent; primary endpoint; programs; protective efficacy; recurrent infection; resistant strain; response; scale up; skills; thermostability; translational medicine; vaccine candidate; vaccine delivery; vaccine development; vaccine safety

Abstract Clostridium difficile is a Gram-positive, spore-forming bacteria that causes severe diarrhea and C. difficile infection (CDI) ranks fourth among the highest number of infections in hospitals. Annually, CDI causes as many as 500,000 infections and 15,000 deaths in the USA and costs up to $4.8 billion. Development of effective vaccines is important for prevention and treatment of CDI. There are C. difficile vaccine candidates that are comprised of inactivated toxins A and B (called toxoids) and none have demonstrated significant clinical efficacy in CDI prevention. We propose to use our novel vaccine delivery platform that presents antigens on the surface of nanoparticles derived from recombinant outer membrane vesicles (rOMVs) of probiotic E. coli strains. rOMVs represent a promising, low-cost vaccine delivery method with improved features over conventional vaccines including better antigen presentation, technical readiness, simplicity, thermostability and flexibility of the manufacturing process. The OMV-based vaccine platform has been validated clinically by an approved vaccine (Bexsero, GSK) that is efficacious in prevention of group B meningococcal infections. Versatope’s scientific founders have demonstrated that our rOMV-based vaccines containing polypeptide antigens and poly-N-acetylglucosamine (PNAG, a conserved bacterial surface polysaccharide) are effective in prevention of bacterial and viral infections in animal models. In this study, we hypothesize that C. difficile toxoids A and B, and PNAG presented on the surface of E. coli rOMV will be displayed in a three- dimensional antigenic complex to generate strong and long-lasting immunity responses that may result in a better protection against CDI than the conventional vaccines composing purified toxoids formulated with the Alum adjuvant. The primary objective of this proposal is to select a novel C difficile vaccine candidate(s) for further evaluation and development.

抽象的 艰难梭状芽胞杆菌是一种革兰氏阳性的形成孢子的细菌，会导致严重的腹泻和C。 艰难梭菌感染（CDI）在医院的最高感染中排名第四。每年，CDI 在美国导致多达500,000次感染和15,000人死亡，费用高达48亿美元。 有效疫苗的开发对于预防和治疗CDI很重要。有艰难梭菌 包括灭活的毒素A和B（称为毒素）的疫苗候选者，没有 在CDI预防方面表现出明显的临床效率。我们建议使用我们的新型疫苗 递送平台，该平台在重组外部的纳米颗粒表面上呈现抗原 益生菌大肠杆菌菌株的膜蔬菜（ROMV）。 ROMV代表一种有希望的低成本疫苗 交付方法具有超过传统疫苗（包括更好抗原）的特征 制造的演示，技术准备，简单性，热稳定性和灵活性 过程。基于OMV的疫苗平台已通过批准的疫苗在临床上进行了验证 （Bexsero，GSK）有效预防B组脑膜炎球菌感染。 Versatope的 科学创始人表明，我们的基于ROMV的疫苗含有多肽抗原 和聚-N-乙酰葡萄糖胺（PNAG，保守细菌表面多糖）在有效 预防动物模型中细菌和病毒感染。在这项研究中，我们假设艰难梭菌 在大肠杆菌ROMV表面呈现的毒素A和B和PNAG将显示在三个 尺寸抗原复合物可产生强大而持久的免疫反应，可能导致 比构成纯化的毒素的常规疫苗更好地保护CDI 使用明矾调整。该提议的主要目的是选择一种新型的艰难梭菌疫苗 候选人进行进一步的评估和发展。