Novel C. Difficile Vaccine Using Nano-vesicle Delivery System

摘要 艰难梭菌是一种革兰氏阳性芽胞形成细菌，可引起严重腹泻和C. 艰难梭菌感染(CDI)在医院感染人数最多的医院中排名第四。每年，CDI 在美国造成多达50万人感染和1.5万人死亡，造成高达48亿美元的损失。 开发有效的疫苗对预防和治疗CDI具有重要意义。有艰难梭菌 由灭活的毒素A和B(称为类毒素)组成的候选疫苗，并且没有 在预防CDI方面显示出显著的临床疗效。我们建议使用我们的新型疫苗 将抗原呈现在由重组外膜衍生的纳米颗粒表面的递送平台 益生菌大肠杆菌菌株的膜泡(ROMV)。ROMV是一种前景看好的低成本疫苗 具有比传统疫苗(包括更好的抗原)更好的特性的递送方法 表现性、技术准备、简单性、热稳定性和制造灵活性 进程。基于OMV的疫苗平台已通过批准的疫苗进行临床验证 (Bexsero，GSK)，对预防B组脑膜炎双球菌感染有效。韦尔萨托普的 科学创始人已经证明，我们的基于rOMV的疫苗含有多肽抗原 和多-N-乙酰氨基葡萄糖(PNAG，一种保守的细菌表面多糖)对 在动物模型中预防细菌和病毒感染。在这项研究中，我们假设艰难梭菌 毒素A和B，以及呈现在大肠杆菌rOMV表面的PNAG将以三种形式展示。 立体抗原复合体产生强大而持久的免疫反应，可能导致 比由纯化类毒素组成的传统疫苗对CDI有更好的保护作用 加了明矾佐剂。这项建议的主要目标是选择一种新的艰难梭菌疫苗 候选人(S)，需要进一步评估和发展。

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.