Multivalent Bacillus mucosal vaccines against Clostridium difficile infection

 描述（由申请人提供）：艰难梭菌每年导致超过500，000例感染，估计有15，000例死亡，保守估计美国每年的经济成本为10 - 30亿美元。目前，C.艰难梭菌感染（CDI）是施用几种抗生素之一，所述抗生素包括甲硝唑、万古霉素或新开发的非达霉素。虽然有效，但由于其对肠道微生物组的破坏性影响，这些治疗的疾病复发率为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。本项目的目标是开发针对C.艰难梭菌定植/生长因子和C.艰难梭菌毒素CDI的症状归因于两个C的释放。艰难梭菌毒素TcdA和TcdB。我们最近构建了一个重组融合蛋白，mTcd 138，它包含TcdA和TcdB的免疫优势区域。由于孢子是疾病传播和复发的主要原因，我们建议通过包括额外的毒力因子抗原来减少或消除孢子的排泄来增强我们的原型疫苗。减少孢子排泄将减少或消除疾病复发和传播的风险。目的一：首先构建含mTcd 138和C.艰难梭菌定植因子，然后测定免疫原性和对CDI和C.用融合免疫原肌内或舌下免疫的小鼠中艰难孢子定殖。粘多糖通常对肠道病原体如C.很难在目标2中，我们将通过在枯草芽孢杆菌粘膜递送系统中表达来自Aim 1的所选疫苗候选物来开发粘膜/口服疫苗。

 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.