A vaccine specifically targeting T3SS-negative Pseudomonas aeruginosa

专门针对 T3SS 阴性铜绿假单胞菌的疫苗

基本信息

批准号：
10313003
负责人：
Wendy L Picking
金额：
$ 22.73万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-12 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10313003
关键词：
Achievement Acute Acute Pneumonia Adjuvant Age Antibiotic Resistance Antibiotics Antibodies Antigen-Presenting Cells Antigens Burn injury Catheterization Cell membrane Cells Critical Illness Cytoplasm Development Distal Elderly Emulsions Exhibits Explosion Formulation Genetic Goals Gram-Negative Bacteria Health Immune response Immunize Infection Infection prevention Injury Interleukin-17 Intubation L Cells Laboratories Lung Mediating Microbial Biofilms Molecular Morbidity - disease rate Mucous Membrane Multi-Drug Resistance Mus Natural Immunity Needles Outcome Pathogenesis Patients Pneumonia Preventive vaccine Procedures Proteins Pseudomonas Pseudomonas aeruginosa Pseudomonas aeruginosa infection Public Health Rattus Risk Risk Factors Rodent Serotyping Shigella Structure Syringes Technology Time Toxin Type III Secretion System Pathway Vaccinated Vaccination Vaccines Virulence Factors clinically relevant cystic fibrosis patients cytokine enterotoxigenic Escherichia coli experimental study human pathogen mortality multidrug-resistant Pseudomonas aeruginosa mutant novel vaccines pathogen pathogenic bacteria prevent resistant strain uptake vaccine development wound

项目摘要

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.

概括铜绿假单胞菌是一种重要的机会性人类病原体，可引起严重的感染囊性纤维化（CF）患者、烧伤患者、重伤患者、肺炎患者以及需要进行治疗的危重患者插管或导管插入术。清除 Pa 已经成为一个问题，因为它变得越来越多抗生素耐药。负面结果的最大风险因素与相关因素相关，这一事实加剧了这种情况患有 MDR Pa 的人已经高龄了。虽然 Pa 疫苗正在开发中，但尚未获得许可。我们开发了一种自我辅助融合抗原平台来靶向革兰氏阴性细菌，该平台使用 III 型分泌系统（T3SS）用于介导感染的发生。 T3SS 装置 (T3SA) 针尖和特定属（例如志贺氏菌）或物种（例如 Pa）内的易位蛋白是高度保守的。经过通过基因融合 T3SA 针尖和第一个易位蛋白，我们可以引发广泛的血清型依赖性保护。 Pa融合体称为PaF，是PcrV和PopB的基因融合体。以 dmLT 为佐剂，PaF 鼻内 (IN) 给药时，小鼠肺负荷减少约 90%。当我们基因融合 LTA1 时， dmLT 的活性部分连接至 PaF (L-PaF) 的 N 末端。 L-PaF 减少小鼠和大鼠的肺部负担显着。我们假设我们的配方将为所有菌株提供广泛的保护铜绿假单胞菌，包括 MDR 物种/菌株。