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.

多药耐药金黄色葡萄球菌免疫治疗策略和疫苗的研究进展 播散性感染 项目总结 播散性念珠菌病是一种威胁生命的疾病，仍然是第三种最常见的血液感染。 在美国的住院患者中，死亡率为40%-60%。特别是，金黄色念珠菌是一种多菌种。 耐药，医疗保健相关的真菌病原体，最近已成为第一个真菌病原体 造成全球公共卫生威胁。目前还没有有效的疫苗来治疗念珠菌感染或任何 真菌，和重大的治疗挑战仍然存在。目前的抗念珠菌治疗受到明显的 毒性和疗效差，特别是在治疗耐药念珠菌的免疫功能低下的患者中。 因此，迫切需要新的治疗方案。一种治疗性疫苗可以增强这两种疾病 保护性TH1介导的免疫反应并诱导保护性抗体，从而减缓或阻止 传播的进展，以及未来的复发。我们之前在老鼠身上的研究已经证明了治疗作用 双肽疫苗对念珠菌侵袭性感染急性期的疗效显著 减少器官真菌负担，延长生存时间。这项工作是向发展迈出的一大步 一种治疗性金黄色葡萄球菌疫苗，旨在预防或降低感染金黄色葡萄球菌患者的死亡率。 这是第一项证明合成肽疫苗在小鼠模型中治疗效果的研究。 耳廓传播性感染。 我们的最终目标是开发第一个治疗性双肽疫苗，该疫苗由具有 包括金黄色念珠菌在内的所有具有医学意义的念珠菌物种的高度同源性，并阐明保护作用 抗播散性念珠菌病的机制。在目标1中，我们将试图研究我们的双肽 疫苗可能对已经确定的金黄色葡萄球菌侵袭性感染有效。在目标2中，我们将评估 候选多肽疫苗作为抗生素治疗方案的免疫治疗辅助药物的潜力 用于金黄色葡萄球菌传播性感染。我们将进一步确定治疗性多肽的保护效果 免疫功能低下的金黄色葡萄球菌侵袭性感染小鼠模型的疫苗。