A prophylactic vaccine to prevent colonization by Pseudomonas aeruginosa

预防铜绿假单胞菌定植的预防性疫苗

• 批准号: 10582221
• 负责人: Wendy L Picking
• 金额: $ 80.07万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-27 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582221
• 关键词: Achievement; Acute Pneumonia; Adjuvant; Age; Agonist; Antibiotic Resistance; Antibiotics; Antibodies; Antigens; B-Lymphocytes; Burn injury; Catheterization; Cell membrane; Cells; Critical Illness; Cystic Fibrosis; Cytoplasm; Development; Distal; Dose; Elderly; Emulsions; Explosion; Formulation; Goals; Health; Human; IL17 gene; Immune response; Immunoglobulins; Infection; Infection prevention; Injury; Intubation; Knockout Mice; Licensing; Lipid A; Lung; Manuscripts; Measures; Mediating; Modeling; Molecular; Morbidity - disease rate; Mucous Membrane; Multi-Drug Resistance; Mus; Natural Immunity; Needles; Oils; Outcome; Pathogenesis; Patients; Pneumonia; Preparation; Preventive vaccine; Procedures; Proteins; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Public Health; Publishing; Rattus; Risk; Risk Factors; Rodent; Rodent Model; Serum; Syringes; TLR4 gene; Time; Toxin; Type III Secretion System Pathway; Vaccinated; Vaccination; Vaccines; Virulence Factors; Water; cystic fibrosis patients; efficacy evaluation; emerging antibiotic resistance; enterotoxigenic Escherichia coli; human pathogen; influenza virus vaccine; middle age; mortality; mouse model; multidrug-resistant Pseudomonas aeruginosa; novel; novel vaccines; pathogen; pathogenic bacteria; prevent; protective efficacy; resistant strain; vaccine efficacy; vaccine formulation; wound

PROJECT SUMMARY Vaccination is the greatest public health achievement of our time. With an explosion of antibiotic resistance, new vaccines against multi-drug resistant (MDR) bacterial pathogens are more important than ever. Pseudomonas aeruginosa (Pa) is an opportunistic human pathogen that causes severe infections in patients with cystic fibrosis (CF), burns, severe wounds, pneumonia, as well as critically ill patients who require intubation or catheterization. Clearing Pa has become problematic as it 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. After 60, there is a significant increase in morbidity and mortality resulting from MDR Pa. While there are Pa vaccines in development, none are licensed. Like many Gram-negative pathogens, Pa strains of the PAO1/PA14-clades possess a type III secretion system (T3SS), a virulence factor that allows avoidance of host innate immunity and is required for the onset of infection. Structurally resembling a molecular syringe with an external needle, the T3SS apparatus (T3SA) provides an energized conduit from the bacterial cytoplasm into the host cell for transporting effector proteins that mediate key aspects of infection. A needle tip protein and the first of two translocator proteins localize to the distal end of the T3SA needle to mediate host cell contact. These proteins, PcrV and PopB, respectively, are required for pathogenesis and are 95-98% conserved among Pa. We have fused PcrV and PopB to give PaF. After demonstrating the protective efficacy of PaF, we genetically fused LTA1, the active moiety of labile toxin from ETEC, to the N-terminus of PaF (L-PaF). L-PaF reduces mouse and rat lung burdens significantly. When compared to PBS-vaccinated mice, L-PaF-vaccinated mice possessed significantly higher OPK activity in the sera and elevated levels of IL-17 were secreted from lung cells. Recently, Pa outliers have been identified that are devoid of the T3SS entirely and use ExlA to disrupt host cell membranes. Thus, we have added ExlA to our L-PaF (L-PaFE) emulsion and have demonstrated protection in PAO1/14/7 clades when delivered intranasally. Furthermore, we have added BECC438, a novel monophosphoryl lipid A (MPL) biosimilar (a TLR4 agonist), to increase OPK activity (L-PaFEB438). The goal of the R01 is to continue to develop our broadly protective Pa vaccine formulation by assessing the protective immune response in rodent models. Knowing the vaccine efficacy and immune response in these models will allow us to finalize the vaccine formulation and the demonstrate the potential utility of that formulation in humans.

项目概要 疫苗接种是我们这个时代最伟大的公共卫生成就。随着抗生素耐药性的爆发， 针对多重耐药（MDR）细菌病原体的新疫苗比以往任何时候都更加重要。 铜绿假单胞菌 (Pa) 是一种机会性人类病原体，可导致患者严重感染 患有囊性纤维化（CF）、烧伤、严重伤口、肺炎以及需要插管的危重患者 或导管插入术。由于 Pa 的抗生素耐药性越来越强，清除 Pa 已成为问题。这 与 MDR Pa 相关的负面结果的最大风险因素已提前，这一事实加剧了这一情况 年龄。 60 岁以后，MDR Pa 导致的发病率和死亡率显着增加。 Pa 疫苗正在开发中，尚未获得许可。 与许多革兰氏阴性病原体一样，PAO1/PA14 分支的 Pa 菌株具有 III 型分泌 系统（T3SS），一种毒力因子，可以避免宿主先天免疫，并且是病毒发作所必需的 感染。 T3SS 装置 (T3SA) 结构类似于带有外部针头的分子注射器 提供从细菌细胞质到宿主细胞的通电管道，用于运输效应蛋白 介导感染的关键方面。针尖蛋白和两个易位蛋白中的第一个定位于 T3SA 针的远端介导宿主细胞接触。这些蛋白质 PcrV 和 PopB 分别是 发病机制所必需的，并且在 Pa 中保守性为 95-98%。我们将 PcrV 和 PopB 融合以产生 PaF。 在证明了 PaF 的保护功效后，我们通过基因融合了不稳定毒素的活性部分 LTA1 从 ETEC 到 PaF (L-PaF) 的 N 末端。 L-PaF 显着降低小鼠和大鼠的肺部负担。什么时候 与接种 PBS 的小鼠相比，接种 L-PaF 的小鼠在组织中具有显着更高的 OPK 活性。 血清和肺细胞分泌的 IL-17 水平升高。最近，Pa 异常值已被确定为 完全缺乏 T3SS，并使用 ExlA 破坏宿主细胞膜。因此，我们将 ExlA 添加到我们的 L-PaF (L-PaFE) 乳剂在鼻内给药时已证明对 PAO1/14/7 分支具有保护作用。 此外，我们还添加了 BECC438，一种新型单磷酰脂质 A (MPL) 生物仿制药（TLR4 激动剂），以 增加 OPK 活性 (L-PaFEB438)。 R01 的目标是继续开发我们广泛的保护措施 通过评估啮齿动物模型中的保护性免疫反应来配制 Pa 疫苗。知道 这些模型中的疫苗功效和免疫反应将使我们能够最终确定疫苗配方和 证明该配方在人类中的潜在效用。