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.

开发针对耐多药的C. Auris的免疫治疗策略和疫苗 传播感染 项目摘要 传播的念珠菌病是一种威胁生命的疾病，仍然是第三大常见的血液感染 在美国住院的患者中，死亡率为40-60％。特别是，念珠菌是一个多的 耐药性，与医疗保健相关的真菌病原体，最近成为第一个真菌病原体 造成全球公共卫生威胁。没有有效的念珠菌感染疫苗 真菌和重大的治疗挑战仍然存在。当前的抗candida治疗受到重大困扰 毒性和功效不佳，尤其是在免疫功能低下的患者中治疗耐药性念珠菌物种。 因此，迫切需要新的治疗选择。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，从而减慢或停止 传播的进展以及将来的复发。我们先前在小鼠的工作已经证明了治疗性 双肽疫苗在念珠菌侵袭性感染的急性阶段的功效 器官真菌负担的减轻以及长期生存。这项工作是迈向发展的大步 旨在预防或减少感染C. auris的患者的死亡率的治疗性甲状腺梭菌疫苗。 这是第一项证明合成肽疫苗在小鼠模型中的治疗功效的研究 C. Auris传播感染。 我们的最终目标是开发首个由具有的肽组成的治疗性双肽疫苗 所有具有医学意义的念珠菌物种在内 反对传播念珠菌病的机制。在AIM 1中，我们将寻求调查我们的双肽是否 疫苗可以在已经建立的Auris侵入性感染中有效。在AIM 2中，我们将评估 肽疫苗候选物的潜力是对抗生素治疗方案的免疫治疗辅助 用于C. Auris传播感染。我们将进一步确定治疗性肽的保护功效 Auris侵入性感染的免疫功能低下的小鼠模型中的疫苗。