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.

摘要 艰难梭菌是一种革兰氏阳性，孢子形成细菌，导致严重的腹泻和C。 艰难梭菌感染（CDI）在医院感染人数最多的病例中排名第四。每年，CDI 在美国造成多达50万例感染和1.5万例死亡，花费高达48亿美元。 有效疫苗的开发对于CDI的预防和治疗至关重要。有C。艰难 由灭活毒素A和B（称为类毒素）组成的候选疫苗， 在CDI预防中显示出显著的临床功效。我们建议使用我们的新型疫苗 递送平台，其将抗原呈递在来源于重组外膜的纳米颗粒的表面上， 益生菌E.大肠杆菌菌株。rOMV是一种有前途的低成本疫苗 具有优于常规疫苗的改进特征的递送方法，包括更好的抗原 展示、技术准备、简单性、热稳定性和制造的灵活性 过程基于OMV的疫苗平台已通过获批疫苗的临床验证 （Bexsero，葛兰素史克），可有效预防B群脑膜炎球菌感染。Versatope's 科学创始人已经证明，我们的含有多肽抗原的rOMV疫苗 和聚-N-乙酰葡糖胺（PNAG，一种保守的细菌表面多糖）有效地 在动物模型中预防细菌和病毒感染。在这项研究中，我们假设C。艰难 类毒素A、B和PNAG存在于E.大肠杆菌rOMV将显示在一个三- 三维抗原复合物，以产生强烈和持久的免疫反应， 在对CDI的更好保护方面， 加入明矾佐剂该提案的主要目的是选择一种新型艰难梭菌疫苗 候选人进一步评估和发展。