CYstic Fibrosis bacterioPHage Study at Yale (CYPHY): A Single-site, Randomized, Double-blind, Placebo-controlled Study of Bacteriophage Therapy YPT-01 for Pseudomonas Aeruginosa Infections in Adults With Cystic Fibrosis

This is a Phase 2 study with primary objective of looking whether YPT-01 phage therapy reduces sputum bacterial load in cystic fibrosis subjects with Pseudomonas aeruginosa.
In addition, study evaluates the safety profile of phage therapy in this patient population.

开始日期2021-03-29

申办/合作机构

Yale University

NCT02696902 / Completed临床2期

A Phase 2 Proof-of-concept Study to Evaluate the Efficacy and Safety of MEDI3902 in Mechanically Ventilated Patients for the Prevention of Nosocomial Pneumonia Caused by Pseudomonas Aeruginosa

Clinical trial looking to evaluate the efficacy and safety of MEDI3902 in mechanically ventilated participants for the prevention of nosocomial pneumonia caused by Pseudomonas aeruginosa.

开始日期2016-03-25

申办/合作机构

MedImmune LLC

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100 项与 PcrV 相关的临床结果

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100 项与 PcrV 相关的转化医学

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0 项与 PcrV 相关的专利（医药）

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项与 PcrV 相关的文献（医药）

2024-10-08·Antimicrobial Agents and Chemotherapy

Novel humanized anti-PcrV monoclonal antibody COT-143 protects mice from lethal Pseudomonas aeruginosa infection via inhibition of toxin translocation by the type III secretion system

Article

作者: Yamane, Shoji ; Maki, Hideki ; Hara, Takafumi ; Okuno, Yosuke ; Yamano, Yoshinori ; Numata, Shunsuke ; Sato, Takafumi ; Sato, Yasuhiko ; Izawa, Masaaki

ABSTRACT Treatment of Pseudomonas aeruginosa infection is challenging due to its intrinsic and acquired antibiotic resistance. As the number of current therapeutic options for P. aeruginosa infections is limited, developing novel treatments against the pathogen is an urgent clinical priority. The suppression of virulence of P. aeruginosa could be a new therapeutic option, and the type III secretion system (T3SS), which enables the bacteria to translocate various kinds of toxins into host cells and inhibits cellular functions, is considered as one possible target. In this report, we examined T3SS inhibition by COT-143/INFEX702, a humanized monoclonal antibody against PcrV, T3SS component, and present the crystal structure of the antibody-PcrV complex. COT-143 inhibited T3SS-dependent cytotoxicity and protected mice from the mortality caused by P. aeruginosa infection. The inhibition of cytotoxicity coincided with inhibition of translocon formation in a host cell membrane, which is necessary for T3SS intoxication. COT-143 protected murine neutrophils and facilitated phagocytosis of P. aeruginosa . These results suggest that COT-143 facilitates P. aeruginosa clearance by protecting neutrophil via inhibition of T3SS-dependent toxin translocation. This is the first report to show that an anti-PcrV antibody directly interferes with translocon formation to inhibit intoxication of host cells.

2024-09-02·Journal of Wound Care

Impact of continuous topical oxygen therapy on biofilm gene expression in a porcine tissue model

Article

作者: Ball, Christopher ; Schultz, Gregory ; Thomas, Hannah ; Jones, Hannah ; Cole, Windy ; Woodmansey, Emma

Objective: The effect of continuous topical oxygen therapy (cTOT) on Pseudomonas aeruginosa biofilm gene transcription profiles following inoculation onto porcine skin, using a customised molecular assay was determined. Method: Sterilised porcine skin explants were inoculated with Pseudomonas aeruginosa in triplicate: 0 hours as negative control; 24 hours cTOT device on; 24 hours cTOT device off. The oxygen delivery system of the cTOT device was applied to the inoculated tissue and covered with a semi-occlusive dressing. All samples were incubated at 37±2°C for 24 hours, with the 0 hours negative control inoculated porcine skin samples recovered immediately. Planktonic suspensions and porcine skin biopsy samples were taken at 0 hours and 24 hours. Samples were processed and quantifiably assessed using gene specific reverse transcription-quantitative polymerase chain reaction assays for a panel of eight Pseudomonas aeruginosa genes (16S, pelA, pslA, rsaL, pcrV, pscQ, acpP, cbrA) associated with biofilm formation, quorum sensing, protein secretion/translocation and metabolism. Results: Transcriptional upregulation of pelA, pcrV and acpP, responsible for intracellular adhesion, needletip protein production for type-3 secretion systems and fatty acid synthesis during proliferation, respectively, was observed when the cTOT device was switched on compared to when the device was switched off. Data suggest increased metabolic activity within bacterial cells following cTOT treatment. Conclusion: cTOT is an adjunctive therapy that supports faster healing and pain reduction in non-healing hypoxic wounds. Oxygen has previously been shown to increase susceptibility of biofilms to antibiotics through enhancing metabolism. Observed gene expression changes highlighted the impact of cTOT on biofilms, potentially influencing antimicrobial treatment success in wounds. Further in vitro and clinical investigations are warranted.

2024-08-12·Journal of Biomolecular Structure and Dynamics

Development of a multi-epitope vaccine candidate againstPseudomonas aeruginosacausing urinary tract infection and evaluation of its immunoreactivity in a rabbit model

Article

作者: Ferdousi, Atosa ; Asadi Karam, Mohammad Reza ; Habibi, Mehri ; Mohammadian, Taher ; Kalantari, Hamidreza

Pseudomonas aeruginosa is associated with different infections such as urinary tract infections (UTIs). The increased antibiotic resistance reaches the need to develop vaccine against the infections. In the present study, bioinformatics approaches were applied to design a novel multi-epitope of PcrV and OmpE from P. aeruginosa. The raised antibody against the multi-epitope was evaluated and challenge experiment was done to evaluate the efficacy of the multi-epitope. The results of epitope mapping of B-cells indicated 8 regions for PcrV and OmpE. The predicted 3D structure showed C-score = -1 and Z-score = -8.12. Molecular docking indicated high interaction between residues of Toll-like receptor 2 (TLR2) and TLR4 with the multi-epitope. The results of in silico simulation of the immune responses showed elevated levels of B-cell, T-cell, and memory cells. PcrV, OmpE, and the multi-epitope were expressed in pET28a-E. coli BL21 (DE3) and purified by Nickel columns. Our findings indicated that the sera collected from immunized rabbits with the multi-epitope reacted with the multi-epitope, PcrV, and OmpE in western blot. According to the ELISA results, the antibody developed against the multi-epitope showed cross-reactivity with individual proteins PcrV and OmpE. The level of antibody raised against the multi-epitope was significantly higher than the antibody reacted with PcrV or OmpE alone in ELISA. The challenge results confirmed that the load of bacteria was decreased in immunized rabbits as compared to the control. The results present the multi-epitope composed of PcrV and OmpE as a promising candidate against P. aeruginosa. Further evaluations are under investigation in animal model.Communicated by Ramaswamy H. Sarma.

项与 PcrV 相关的新闻（医药）

2023-07-03

·生物制品圈

日本科学家首次开发针对铜绿假单胞菌III型毒力分泌系统的mRNA细菌疫苗。

日益严峻的细菌耐药危机一直是缠绕在全球公共卫生安全头上挥之不去的阴云。虽说细菌耐药性的出现是一个必然的自发过程，但是，自打抗生素出现以后，人们肆意地滥用抗生素无意间反而筛选出对抗生素耐受能力更强的菌落，直接加速各种耐药菌的出现。大家害怕的是如今稀松平常的细菌感染在将来变成无药可治的超级细菌，所以，迫切需要寻找替代抗生素的新型治疗方法来抵御细菌感染，这其中就包括了预防性细菌疫苗的研发。随着 mRNA-LNP 技术在新冠疫苗研发中大获成功，人们也开始尝试将其应用于细菌疫苗的开发。与天然适应真核表达系统的病毒抗原不同，利用 mRNA 技术表达细菌抗原时会变得更加具有挑战性。我们前面介绍过 Ofer Cohen 等人利用 mRNA-LNP 技术平台，设计出编码 F1 抗原的鼠疫 mRNA 疫苗，能够完全保护小鼠免受鼠疫耶尔森氏菌感染引发的死亡。本期内容，我们来看看京都府立医科大学医学研究生院泽贞二团队关于铜绿假单胞菌 mRNA 疫苗的最新研究。2023 年 6 月 10 号，他们在 BioRxiv 上传文章：mRNA vaccine induces protective immunity against the type III secretory virulence of Pseudomonas aeruginosa。铜绿假单胞菌，又称为绿脓杆菌，属于革兰氏阴性菌，是引起免疫功能低下或者有基础疾病人群肺炎的主要病原体之一。铜绿假单胞菌的治疗非常困难，因为它对多种抗生素耐受，且极易形成生物膜，生命力顽强。尽管几十年来疫苗研发一直在蓬勃发展，但目前还没有获得临床许可的针对铜绿假单胞菌的疫苗。细菌比病毒拥有更多基因，选择适当的抗原对于细菌疫苗的研发至关重要。磷脂酶毒素 ExoU 是铜绿假单胞菌的 III 型分泌毒素，可诱导急性肺上皮损伤和肺泡巨噬细胞死亡，在肺损伤中起关键作用。铜绿假单胞菌通过 III 型分泌系统(TTSS) 将毒素直接注射到真核细胞中。早在 1999 年，泽贞二等人就发现位于 III 型分泌系统顶端的 PcrV 蛋白是针对铜绿假单胞菌主动和被动免疫的有效靶点。针对 PcrV 的特异性抗体通过抑制毒素易位到真核细胞中消除毒力。因此，阻断 PcrV 可减轻肺部损伤并提高小鼠在铜绿假单胞菌感染后的存活率。2012 年，法国科学家开展了一项关于 PcrV PEG 化单抗在在铜绿假单胞菌定植（未发生感染）的机械通气患者体内的安全性和药代动力学临床试验。这里需要说明一个概念，所谓定植菌指的的是细菌入侵人体后不会引发病理性改变，也没有临床症状。当人体免疫力下降，定植菌会大量繁殖并导致感染，此时这类细菌可称为致病菌。与安慰剂注射组（60%）相比，静脉注射 PcrV PEG 化单抗组发生铜绿假单胞菌肺炎的频率较低（31%-33%）。上述结果促使泽贞二尝试开发编码 pcrV 抗原的 mRNA-LNP 铜绿假单胞菌 mRNA 疫苗，设计出 3 种编码 pcrV 抗原的 mRNA 序列：第一种：pcrV-mRNA，仅仅由 pcrV 抗原 CDS 序列组成；第二种：ss-pcrV-mRNA，在 pcrV 抗原 CDS 序列前面加上人组织纤溶酶原激活剂分泌信号 (tPAss) ;第三种: ss-pcrV-f mRNA，在已添加 tPAss 信号序列的基础上，pcrV 抗原 CDS 序列后面加上折叠子（三聚化结构域）。用上述 3 种编码 pcrV 抗原的 mRNA-LNP 疫苗免疫小鼠。结果发现，pcrV-mRNA 疫苗无法诱导小鼠产生特异性的血清 IgG 抗体，将 tPAss 分泌信号序列添加到 pcrV mRNA 序列中 (ss-pcrV) 可显着增加血清中抗 PcrV IgG 抗体滴度，继续将折叠子添加到 pcrV mRNA 序列中（ss-pcrV-f ）并没有进一步增加抗 PcrV IgG 血清抗体滴度。在攻毒试验一天后，检测肺部匀浆中的 IgA 水平，ss-pcrV 和 ss-pcrV-f mRNA 疫苗免疫小鼠的肺部可检测到显著高于对照组（生理盐水）IgA 水平。这说明利用 mRNA 技术产生的铜绿假单胞菌 pcrV 抗原在小鼠体内是具有免疫原性的。首次免疫 42 天后，用1.0 × 10 6 CFU 的铜绿假单胞菌 PA103 感染 mRNA 疫苗接种小鼠。所有小鼠在感染铜绿假单胞菌 4 小时内均出现体温骤降，表明铜绿假单胞菌成功感染小鼠。发生感染后的 4 小时和 8 小时，ss-pcrV 和 ss-pcrV-f 免疫组小鼠的体温明显高于盐水处理组。感染 24 小时后，与盐水处理组相比，ss-pcrV 和 ss-pcrV-f 免疫组小鼠（存活和死亡）肺部的细菌载量降低 10-30 倍，肺部髓过氧化物酶活性和IL-6水平显著下降，肺部组织病理变化也更轻。这项研究首次在小鼠模型中证实接种 mRNA 疫苗对于预防铜绿假单胞菌感染是有效的。接种编码 pcrV 抗原的 mRNA 疫苗在小鼠体内可触发明显的血清 IgG 抗体和肺部 IgA 抗体，从而抑制铜绿假单胞菌将毒素注射到肺部细胞，减轻肺部损伤，同时，提升巨噬细胞存活率，减少肺部细菌载量。此外，mRNA 接种还可减轻肺部炎症反应，这时疫苗免疫小鼠肺部损伤减弱的另一个重要原因。总的来说，相比于盐水对照组，这些机制共同提升了mRNA免疫小鼠感染铜绿假单胞菌后的存活率。这些结果是非常振奋人心的，因为一般来说，采用 mRNA 技术在哺乳动物细胞中表达细菌抗原，会发生与细菌中截然不同的翻译后修饰，这可能会导致细菌抗原的免疫原性减弱。鼠疫 mRNA 疫苗和铜绿假单胞菌 mRNA 疫苗开发的有效数据将会给予我们开发更多细菌 mRNA 疫苗的坚定信心。

疫苗信使RNA临床3期微生物疗法