Development of immunotherapeutic strategies and vaccines against multidrug resistant C. auris disseminated infection

针对多重耐药耳念珠菌播散性感染的免疫治疗策略和疫苗的开发

• 批准号: 10433683
• 负责人: Hong Xin
• 金额: $ 22.05万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-24 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433683
• 关键词: Acute; Address; Affect; Antibiotic Therapy; Antibodies; Antifungal Agents; Antifungal Therapy; Blood; CD4 Positive T Lymphocytes; Candida; Candida auris; Cell surface; Chronic; Combined Vaccines; Development; Disease; Disseminated candidiasis; Drug resistance; Epitopes; Fungal Vaccines; Future; Goals; Healthcare; Hematogenous; Hospitals; Hour; Human; Immune response; Immunity; Immunocompetent; Immunocompromised Host; Immunoglobulin G; Immunotherapeutic agent; Individual; Infection; Interferon Type II; Life; Mediating; Medical; Modeling; Modernization; Monoclonal Antibodies; Morbidity - disease rate; Multi-Drug Resistance; Mus; Organ; Patients; Peptide Vaccines; Peptides; Pharmaceutical Preparations; Pharmacotherapy; Phase; Play; Population; Preventative vaccination; Preventive vaccine; Production; Public Health; Recurrence; Regimen; Resistant candida; Role; Sepsis; Stream; Therapeutic; Time; Toxic effect; Treatment Efficacy; Treatment Protocols; United States; Vaccine Therapy; Vaccines; Work; adaptive immunity; effective therapy; fungus; high risk; infancy; mortality; mouse model; novel therapeutic intervention; pathogenic fungus; peptide drug; prevent; protective efficacy; response; synthetic peptide; therapeutic vaccine; therapeutically effective; vaccine candidate; vaccine development; vaccine-induced immunity; work-study

Development of immunotherapeutic strategies and vaccines against multidrug resistant C. auris disseminated infection PROJECT SUMMARY Disseminated candidiasis is a life-threatening disease and remains the third most common bloodstream infection in hospitalized patients in the United States, with a mortality of 40-60%. Particularly, Candida auris is a multi- drug resistant, health care-associated fungal pathogen, and has recently emerged as the first fungal pathogen to cause a global public health threat. There are no effective vaccines for Candida infection or indeed for any fungi, and significant therapeutic challenges remain. Current anti-Candida treatments are plagued by significant toxicity and poor efficacy, especially in immunocompromised patients for treating drug resistant Candida species. Thus, there is a pressing and urgent need for new treatment options. A therapeutic vaccine could bolster both the protective TH1-mediated immune response and induce protective antibodies, thereby slowing or halting the progression of dissemination, as well as recurrent in future. Our prior work in mice has demonstrated therapeutic efficacy of a double peptide vaccine in the acute phase of Candida invasive infection evidenced by significantly reduction in organ fungal burdens, as well as prolonged survival. This work is a stride towards the development of a therapeutic C. auris vaccine that seeks to prevent or reduce the mortality in patients infected with C. auris. This is the first study that demonstrates therapeutic efficacy of a synthetic peptide vaccine in a mouse model of C. auris disseminated infection. Our ultimate goals are to develop the first therapeutic double-peptide vaccine composed of peptides that have high homology in all the medically significant Candida species including C. auris, and to elucidate protective mechanisms against disseminated candidiasis. In Aim 1, we will seek to investigate whether our double peptide vaccines could be effective in already established C. auris invasive infection. In Aim 2, we will evaluate the potential of peptide vaccine candidates serve as immunotherapeutic adjuncts to antibiotic treatment regimens for C. auris disseminated infection. We will further determine the protective efficacy of the therapeutic peptide vaccine in immunocompromised mouse models of C. auris invasive infection.

针对多重耐药耳念珠菌的免疫治疗策略和疫苗的开发 播散性感染 项目概要 播散性念珠菌病是一种危及生命的疾病，仍然是第三大常见的血液感染 在美国住院患者中，死亡率为 40-60%。特别是，耳念珠菌是一种多 耐药性、与医疗保健相关的真菌病原体，最近成为第一种真菌病原体 造成全球公共卫生威胁。没有针对念珠菌感染的有效疫苗，也没有针对任何念珠菌感染的有效疫苗。 真菌，并且仍然存在重大的治疗挑战。目前的抗念珠菌治疗受到显着的困扰 毒性和疗效差，特别是在免疫功能低下的患者中用于治疗耐药念珠菌属。 因此，迫切需要新的治疗方案。治疗性疫苗可以增强两者 保护性 TH1 介导的免疫反应并诱导保护性抗体，从而减缓或停止 传播的进展，以及未来的反复发生。我们之前在小鼠身上的工作已经证明了治疗作用 双肽疫苗在念珠菌侵袭性感染急性期的功效显着 减少器官真菌负担，并延长生存期。这项工作是向发展迈出的一大步 一种治疗性耳念珠菌疫苗，旨在预防或降低耳念珠菌感染患者的死亡率。 这是第一项证明合成肽疫苗在小鼠模型中的治疗效果的研究 耳念珠菌播散性感染。 我们的最终目标是开发第一种由具有以下特性的肽组成的治疗性双肽疫苗： 在包括耳念珠菌在内的所有具有医学意义的念珠菌属物种中具有高度同源性，并阐明保护性念珠菌 对抗播散性念珠菌病的机制。在目标 1 中，我们将寻求研究我们的双肽是否 疫苗可能对已经确定的耳念珠菌侵袭性感染有效。在目标 2 中，我们将评估 候选肽疫苗作为抗生素治疗方案的免疫治疗辅助剂的潜力 用于耳念珠菌播散性感染。我们将进一步确定治疗肽的保护功效 耳念珠菌侵袭性感染免疫受损小鼠模型中的疫苗。