Development of an alpha-1 phosphate mannan vaccine against the emerging fungal pathogen Candida auris.

开发针对新兴真菌病原体耳念珠菌的 α-1 磷酸甘露聚糖疫苗。

• 批准号: 10573467
• 负责人: David L. Williams
• 金额: $ 22.5万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573467
• 关键词: Acids; Address; Adjuvant; Antifungal Agents; Antifungal Therapy; Awareness; B-Lymphocytes; Candida; Candida albicans; Candida auris; Candidiasis; Carbohydrates; Cell surface; Clinical; Dangerousness; Data; Decontamination; Development; Disease Outbreaks; Dose; Drug resistance; Emerging Communicable Diseases; Environment; Exhibits; Fluconazole resistance; Formulation; Foundations; Fungal Drug Resistance; Future; Genetic Transcription; Goals; Health Personnel; Healthcare; Hospitals; Immune; Immune response; Immunity; Immunologics; Infection; Innate Immune Response; Literature; Mannans; Morbidity - disease rate; Mus; Nursing Homes; Patients; Persons; Phagocytes; Phenotype; Prevention; Protocols documentation; Public Health; Reagent; Reporting; Research; Resistance; Side; Skin; Skin colonization; Structure; Surface; T-Lymphocyte; Time; Vaccination; Vaccines; adaptive immune response; draining lymph node; efficacy evaluation; immunological status; inorganic phosphate; mortality; mouse model; novel; organ injury; pathogen; pathogenic fungus; prevent; prototype; resistant strain; response; sugar; transmission process; vaccine development; vaccine efficacy; vaccine formulation; virtual

Candida auris is a fungal pathogen that has been identified as an emerging infectious disease and a public health threat. C. auris is notable for its resistance to antifungal therapy, its transmissibility, its high mortality rate as well as its ability to colonize patients, healthcare personnel and healthcare environments. C. auris strains are typically resistant to fluconazole and approximately half of C. auris strains are resistant to two or more anti-fungal drugs. C. auris causes nosocomial outbreaks of invasive candidiasis with mortality rates of ~60%. There are five distinct clades of C. auris, all of which appear to have evolved since 1996. In addition to its drug resistance, C. auris can colonize skin, spread from person-to-person and survive in healthcare environments for long periods of time. These features are unique to C. auris. C. auris is resistant to many standard decontamination reagents and protocols, which has resulted in the rapid spread of this pathogen throughout the world. This makes it a particularly dangerous emerging fungal pathogen. Thus, it is not surprising that C. auris is the first fungal pathogen that has been identified as a public health threat. What is needed is a C. auris specific vaccine that can prevent and/or ameliorate the morbidity, mortality and dissemination of this emerging fungal pathogen. The research outlined in this proposal directly addresses this pressing need. We have discovered that the mannan which coats the outermost surface of C. auris clinical strains is both structurally and biologically unique, i.e. it contains two unique acid labile Mα1-PO4 side chains that are not found in other fungal mannans or other fungal pathogens. Thus, C. auris mannan distinguishes it from virtually all other fungal pathogens. This suggests that C. auris mannan represents a target of opportunity for the development of a C. auris vaccine. We hypothesize that the dual Mα1-PO4 mannan structure can be used to develop a C. auris vaccine that will be effective against multiple C. auris strains. The goals of this R21 proposal are to: i) evaluate the efficacy of the vaccine in a murine model of C. auris infection and ii) evaluate the anti-fungal immune response to the vaccine. To address these objectives we propose two specific aims. Aim 1. Evaluate the efficacy of a C. auris mannan based vaccine formulation against systemic C. auris infection. Aim 2. Assess innate and adaptive immune responses elicited by the C. auris mannan vaccine.

耳念珠菌是一种真菌病原体，已被确定为一种新发传染病和公共公共卫生问题。 耳念珠菌以其对抗真菌治疗的耐药性、传播性和高死亡率而闻名。 以及其在患者、医护人员和医疗环境中定殖的能力。 通常对氟康唑耐药，大约一半的耳念珠菌菌株对两种或多种抗真菌药物具有耐药性 耳念珠菌药物会导致医院内爆发侵袭性念珠菌病，死亡率约为 60%。有 5 种。 C. auris 的不同分支，所有这些分支似乎都是自 1996 年以来进化的。除了耐药性之外，C. auris 耳念珠菌可以在皮肤上定殖，在人与人之间传播，并在医疗环境中存活很长时间 这些特征是耳念珠菌所独有的，它对许多标准去污试剂具有抵抗力。 协议，导致这种病原体在世界范围内迅速传播。 特别危险的新兴真菌病原体因此，耳念珠菌是第一种真菌也就不足为奇了。 已被确定为公共健康威胁的病原体需要一种能够预防耳念珠菌的特异性疫苗。 预防和/或改善这种新兴真菌病原体的发病率、死亡率和传播。 该提案中概述的研究直接解决了这一迫切需求，我们发现甘露聚糖。 覆盖耳念珠菌临床菌株最外层的表面在结构和生物学上都是独特的，即 含有两个独特的酸不稳定 Mα1-PO4 侧链，在其他真菌甘露聚糖或其他真菌中未发现 因此，耳念珠菌甘露聚糖将其与几乎所有其他真菌病原体区分开来。 耳念珠菌甘露聚糖代表了耳念珠菌疫苗开发的机会目标。 双 Mα1-PO4 甘露聚糖结构可用于开发耳念珠菌疫苗，可有效对抗 该 R21 提案的目标是： i) 评估疫苗在小鼠中的功效。 耳念珠菌感染模型，以及 ii) 评估疫苗的抗真菌免疫反应。 目标 我们提出两个具体目标 目标 1. 评估耳念珠菌甘露聚糖疫苗的功效。 目标 2. 评估由耳念珠菌引起的先天性和适应性免疫反应。 耳念珠菌甘露聚糖疫苗。