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：
10636201
负责人：
Wendy L Picking
金额：
$ 19.56万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10636201
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 Pulmonary Challenge Rattus Risk Risk Factors Rodent Serotyping Shigella 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 formulation 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重要的机会性人类病原体，会引起严重的感染患有囊性纤维化（CF），烧伤，严重伤口，肺炎和重症患者的患者需要插管或导管插入。清除PA已经变得有问题，因为它已经变得越来越多抗生素抗性。与负面结果的最大风险因素相关的事实使这一事实加剧了与MDR PA是高龄的。虽然有PA疫苗正在开发中，但没有任何许可。我们已经开发了一个自动辅助融合抗原平台，以靶向使用革兰氏阴性细菌 III型分泌系统（T3SS）用于介导感染发作。 T3SS设备（T3SA）针头和给定属（例如志贺氏菌）或物种（例如PA）内的转运蛋白是高度保守的。经过从遗传上融合T3SA针尖和第一个转运蛋白，我们可以引起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。用DMLT作为佐剂，PAF 鼻内传递时，小鼠肺负担减少了约90％（IN）。当我们遗传融合LTA1时 DMLT的活性部分，到PAF（L-PAF）的N端。 L-PAF减轻了小鼠和老鼠肺负担我们假设我们的表述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。