Multivalent Bacillus mucosal vaccines against Clostridium difficile infection

针对艰难梭菌感染的多价芽孢杆菌粘膜疫苗

• 批准号: 8968632
• 负责人: Xingmin Sun
• 金额: $ 7.63万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-10 至 2016-02-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8968632
• 关键词: Acids; Antibiotics; Antibodies; Antibody Response; Antigens; Antitoxins; Bacillus (bacterium); Bacillus subtilis; Caspase; Cessation of life; Clostridium difficile; Colitis; Diarrhea; Disease; Disease Progression; Dose; Encapsulated; Environment; Excretory function; Family suidae; Feces; Flagellin; Gastrointestinal tract structure; Genetic Engineering; Glucosyltransferase; Growth; Growth Factor; Hamsters; High temperature of physical object; Immunization; Immunodominant Epitopes; Infection; Licensing; Mediating; Membrane Proteins; Metronidazole; Mus; Onset of illness; Oral; Oral mucous membrane structure; Outcome; Parents; Play; Production; Proteins; Proteolysis; Recombinant Fusion Proteins; Recombinants; Recurrence; Reporting; Reproduction spores; Research; Resistance; Risk; Role; Salmonella typhimurium; Site; Structure; Surface; Symptoms; System; Toll-Like Receptor 5; Toxin; Vaccines; Vancomycin; Virulence Factors; Virulent; Work; cost; disease transmission; disorder risk; economic cost; effective therapy; enteric pathogen; factor C; fliC gene product; gut microbiota; immunogenic; immunogenicity; microbiome; mucosal vaccine; neutralizing antibody; novel; novel vaccines; oral vaccine; prevent; prototype; public health relevance; receptor binding; research study; response; standard care; transmission process; vaccine candidate

 DESCRIPTION (provided by applicant): Clostridium difficile causes over 500,000 cases of infections per year, with an estimated 15,000 deaths and a conservatively estimated economic cost at $1-3 billion in the US annually. Currently, standard treatment for C. difficile infection (CDI) is the administration of one of several antibiotics which include metronidazole, vancomycin or the newly developed fidaxomicin. While effective, these treatments have a disease recurrence rate of 15-35%, due to their disruptive impact on the gut microbiome. More effective strategies to treat primary and recurrent CDI are urgently needed. No vaccine is currently licensed against CDI. The objective of this project is to develop novel vaccines that target both C. difficile colonization/growth factors and C. difficile toxins. The symptoms of CDI are attributed to liberation of two C. difficile toxins, TcdA and TcdB. We recently constructed a recombinant fusion protein, mTcd138, which contains the immunodominant regions of TcdA and TcdB. Since spores are the major cause of disease transmission and recurrence, we propose to enhance our prototype vaccine by including additional virulence factor antigens to reduce or eliminate the excretion of spores. Decreasing spore excretion will reduce or eliminate the risk of disease recurrence and transmission. In Aim 1 we will first construct fusion immunogens containing mTcd138 and major C. difficile colonization factors, and then determine the immunogenicity and protection against CDI and C. difficile spore colonization in mice immunized intramuscularly or sublingually with the fusion immunogens. Mucosal is often more effective against enteric pathogens such as C. difficile. In Aim 2 we will develop a mucosal/oral vaccine by expressing the chosen vaccine candidate from Aim1 in the Bacillus subtilis mucosal delivery system.

 描述（由申请人提供）：艰难梭菌每年在美国引起超过 500,000 例感染，估计有 15,000 人死亡，保守估计每年造成的经济损失为 1-30 亿美元。目前，艰难梭菌感染（CDI）的标准治疗是使用几种抗生素中的一种，包括甲硝唑、万古霉素或新开发的非达霉素。这些疗法虽然有效，但由于它们对肠道微生物群的破坏性影响，其疾病复发率为 15-35%。迫切需要更有效的策略来治疗原发性和复发性 CDI。目前还没有针对 CDI 的疫苗获得许可。该项目的目标是开发针对艰难梭菌定植/生长因子和艰难梭菌毒素的新型疫苗。 CDI 的症状归因于两种艰难梭菌毒素 TcdA 和 TcdB 的释放。我们最近构建了一个重组融合蛋白mTcd138，它包含TcdA和TcdB的免疫显性区域。由于孢子是疾病传播和复发的主要原因，我们建议通过添加额外的毒力因子抗原来增强我们的原型疫苗，以减少或消除孢子的排泄。减少孢子排泄将减少或消除疾病复发和传播的风险。在目标1中，我们将首先构建含有mTcd138和主要艰难梭菌定植因子的融合免疫原，然后确定用该融合免疫原肌内或舌下免疫的小鼠的免疫原性和对CDI和艰难梭菌孢子定植的保护作用。粘膜通常对艰难梭菌等肠道病原体更有效。在目标 2 中，我们将通过在枯草芽孢杆菌粘膜递送系统中表达 Aim1 中选定的候选疫苗来开发粘膜/口服疫苗。