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.

多药耐药念珠菌免疫策略及疫苗的研究进展Auris 播散性感染 项目摘要 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流感染 在美国的住院患者中，死亡率为40- 60%。特别是，耳念珠菌是一种多- 耐药，卫生保健相关的真菌病原体，最近出现的第一个真菌病原体 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， 真菌，并且仍然存在显著的治疗挑战。目前的抗念珠菌治疗受到显著的 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，迫切需要新的治疗选择。一种治疗性疫苗可以同时支持 保护性TH 1介导的免疫应答，并诱导保护性抗体，从而减缓或停止 传播的进展，以及在未来经常性。我们之前在小鼠身上的研究已经证明了 双肽疫苗在念珠菌侵袭性感染的急性期的有效性被显著地证实， 减少器官真菌负担，以及延长生存期。这项工作是向发展迈出的一大步 一个治疗C。auris疫苗旨在预防或降低感染C.耳。 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。 C.耳播散性感染。 我们的最终目标是开发第一个治疗性双肽疫苗， 在所有具有医学意义的念珠菌属物种中，包括C.耳，并阐明保护 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 疫苗在已经建立的C.耳侵袭性感染。在目标2中，我们将评估 肽疫苗候选物作为抗生素治疗方案的免疫抑制剂的潜力 梭耳播散性感染。我们将进一步确定治疗肽的保护功效 疫苗免疫功能低下的小鼠模型的C.耳侵袭性感染。