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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的艰难梭菌是一种革兰氏阳性芽孢细菌，可引起严重腹泻和艰难梭菌。艰难梭菌感染（CDI）在医院感染人数中排名第四。在美国造成多达 500,000 例感染和 15,000 人死亡，损失高达 48 亿美元。开发有效的疫苗对于 CDI 的预防和治疗具有重要意义。候选疫苗由灭活毒素 A 和 B（称为类毒素）组成，并且没有我们建议使用我们的新型疫苗在预防 CDI 方面具有显着的临床效果。递送平台，将抗原呈现在源自重组外源的纳米粒子表面上益生菌大肠杆菌菌株的膜囊泡 (rOMV) 是一种有前景的低成本疫苗。与传统疫苗相比具有改进功能的递送方法，包括更好的抗原制造的介绍、技术准备、简单性、热稳定性和灵活性基于 OMV 的疫苗平台已通过批准的疫苗进行了临床验证。（Bexsero，GSK）可有效预防 B 组脑膜炎球菌感染。科学创始人已经证明，我们基于 rOMV 的疫苗含有多肽抗原和聚-N-乙酰氨基葡萄糖（PNAG，一种保守的细菌表面多糖）可有效在动物模型中预防细菌和病毒感染。在这项研究中，我们研究了艰难梭菌。类毒素 A 和 B，以及呈现在大肠杆菌 rOMV 表面的 PNAG 将显示在三层中立体抗原复合物产生强烈而持久的免疫反应，可能导致与由纯化类毒素组成的常规疫苗相比，能够更好地预防 CDI 该提案的主要目的是选择一种新型艰难梭菌疫苗。供进一步评估和发展的候选人。