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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.

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。