A vaccine specifically targeting T3SS-negative Pseudomonas aeruginosa

摘要 铜绿假单胞菌是一种重要的人类致病菌，可引起严重感染。 囊性纤维化(CF)、烧伤、严重创伤、肺炎和危重病人需要 插管或插管。清理PA变得有问题，特别是它已经变得越来越 对抗生素有耐药性。负面结果的最大风险因素与 耐多药患者年龄偏高。虽然有PA疫苗正在开发中，但没有一种是获得许可的。 我们已经开发了一种自我调节的融合抗原平台来靶向使用 III型分泌系统(T3SS)，用于调节感染的发生。T3SS装置(T3SA)针尖和 特定属(如志贺氏菌)或物种(如PA)中的转位蛋白高度保守。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血清型无关 保护。PA融合，称为PAF，是PcrV和POPB的遗传融合。以dmLT为佐剂，PAF 经鼻腔给药(IN)可使小鼠的肺负荷降低约90%。当我们通过基因融合LTA1时， DmLT的活性部分位于PAF的N-末端(L-PAF)。L多糖对小鼠和大鼠肺负担的减轻作用 非常重要。我们假设我们的配方将提供广泛的保护，防止所有菌株 铜绿假单胞菌包括多药耐药种/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.