A vaccine specifically targeting T3SS-negative Pseudomonas aeruginosa

总结 铜绿假单胞菌是一种重要的人类机会致病菌，可导致严重的感染， 患有囊性纤维化（CF）、烧伤、严重创伤、肺炎的患者，以及需要 插管或导管插入术。清除Pa已经成为问题，因为它，特别是，已经变得越来越多， 抗生素抗性。这是加剧了这一事实，即最大的风险因素的负面结果相关 多药耐药Pa是高龄。虽然有Pa疫苗正在开发中，但没有一种获得许可。 我们已经开发了一种自佐剂融合抗原平台，以靶向使用免疫球蛋白的革兰氏阴性菌。 III型分泌系统（T3SS）用于介导感染的发作。T3SS装置（T3SA）针尖和 给定属（例如志贺氏菌）或种（例如Pa）内的转运蛋白是高度保守的。通过 通过基因融合T3SA针尖和第一转位蛋白，我们可以诱导广泛的非依赖于基因型的 保护Pa融合，称为PaF，是PcrV和PopB的遗传融合。以dmLT为佐剂， 鼻内（IN）给药时，小鼠肺负荷降低约90%。当我们基因融合LTA1时， 将dmLT的活性部分连接到PaF的N-末端（L-PaF）。L-PaF降低小鼠和大鼠的肺负荷 我们假设我们的制剂将提供针对所有菌株的广泛保护， 铜绿假单胞菌，包括MDR种属/菌株。

SUMMARY Pseudomonas aeruginosa is an important opportunistic human pathogen that causes severe infections in patients with cystic fibrosis (CF), burns, severe wounds, pneumonia, and critically ill patients who require intubation or catheterization. Clearing Pa has become problematic as it, in particular, has become increasingly antibiotic resistant. This is exacerbated by the fact that the biggest risk factor for negative outcomes associated with MDR Pa is advanced age. While there are Pa vaccines in development, none are licensed. We have developed a self-adjuvanting fusion antigen platform to target Gram-negative bacteria that use the type III secretion system (T3SS) for mediating onset of infection. The T3SS apparatus (T3SA) needle tip and translocator proteins within a given genus (e.g. Shigella) or species (e.g. Pa) are highly conserved. By genetically fusing the T3SA needle tip and first translocator proteins, we can elicit broad serotype-independent protection. The Pa fusion, called PaF, is a genetic fusion of PcrV and PopB. With dmLT as the adjuvant, PaF reduced mouse lung burden by ~90% when delivered intranasally (IN). When we genetically fused LTA1, the active moiety of dmLT, to the N-terminus of PaF (L-PaF). L-PaF reduces mouse and rat lung burdens significantly.We hypothesize that our formulation will provide broad protection against all strains of Pseudomonas aeruginosa including MDR species/strains.