Vaccine Strategies for Disseminated Candidiasis

传播性念珠菌病的疫苗策略

• 批准号: 7561720
• 负责人: John E Edwards
• 金额: $ 33.44万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7561720
• 关键词: Accounting; Active Immunization; Adjuvant; Advanced Development; Animal Model; Animals; Antifungal Therapy; Antigens; Bacterial Adhesins; Benchmarking; Blood; Candida; Candida albicans; Candida albicans ALA1 protein; Candidiasis; Cells; Clinical; Clinical Research; Clinical Trials; Code; Disseminated candidiasis; Doctor of Medicine; Dose; Escherichia; Family; Foundations; Future; Genes; Helper-Inducer T-Lymphocyte; Human; Immunity; Immunization; Immunocompetent; Immunocompromised Host; Immunoglobulin G; Immunosuppression; Incidence; Individual; Infection; Intervention; Investigation; Klebsiella; Life; Long-Term Survivors; Mediating; Modeling; Mus; Nosocomial Infections; Organ; Organism; Patients; Peripheral Blood Lymphocyte; Preparation; Proteins; Recombinants; Research Design; Research Personnel; Resistance; Risk; Risk Factors; Schedule; Sepsis; Site; Steroids; Testing; United States; Vaccinated; Vaccination; Vaccines; attributable mortality; candidemia; catheter related infection; cost; cytokine; high risk; lymphocyte proliferation; member; mortality; oropharyngeal thrush; pathogen; prevent; programs; protective effect; research clinical testing; vaccine development; vaccine efficacy

Candida spp. are opportunistic fungal pathogens that have become among the most common nosocomial infections in the United States (U.S.) and worldwide. Candida spp. are now the third most common organism recovered from the blood of hospitalized patients, accounting for 10% of all nosocomial bloodstream infections. The cost associated with candidemia alone exceeds $1 billion per year in the U.S. Even with antifungal therapy, disseminated candidiasis has an unacceptable attributable mortality of 40-50%, and a >50% mortality in myeloablated patients. Furthermore, resistance to conventional antifungal therapies among Candida spp. is rising. For these reasons, a vaccine to prevent life threatening candidal infections is particularly attractive. We have investigated a gene encoding a potent adhesin for Candida albicans to human cells. In our preliminary studies, vaccination with Alslp has resulted in significant protection in both immunocompetent and immunocompromised (neutropenic or steroid-treated) mice with invasive Candida infections. We propose to define and optimize this protection in preparation for future clinical studies in humans through the following investigations: 1) Optimize the Als immunogen and adjuvant to maximize protection in the murine model of hematogenously disseminated candidiasis; 2) Define the mechanisms of protection of the vaccine by determining the impact of vaccination on organ-specific Type 1/Type 2 cytokine profiles at the site of infection and abrogating the identified cytokines; 3) Define the breadth of protection of the vaccine against multiple strains of C. albicans and multiple species of Candida in immunocompetent and immunocompromised mice; 4) Define immunological surrogate efficacy markers that correlate with vaccine- mediated protection. Accomplishing these aims will markedly advance the development of a vaccine for life-threatening candidal infections. The mechanisms of vaccine-mediated protection will be identified, the breadth of vaccine-mediated protection will be defined, and surrogate efficacy markers will be identified to allow optimization of the dosing schedule. In aggregate, these studies will establish the groundwork for future advanced animal and clinical testing of the vaccine.

念珠菌属。是机会性真菌病原体，已成为最常见的医院之一 美国（美国）和全球感染。念珠菌属。现在是第三大常见的 从住院患者的血液中回收的生物体，占所有医院的10％ 血液感染。仅与候选血症相关的费用在美国每年超过10亿美元 即使接受抗真菌疗法，散布念珠菌病的归因死亡率为40-50％， 骨髓的患者死亡率> 50％。此外，对常规抗真菌疗法的抗性 在念珠菌中。正在上升。由于这些原因，防止危及生命的候选感染的疫苗是 特别有吸引力。 我们已经研究了一个基因，该基因编码白色念珠菌对人类细胞的有效粘附素。在我们的 初步研究，ALSLP的疫苗接种已在两种免疫能力上都有明显的保护 以及具有侵入性念珠菌感染的免疫功能低下（中性粒细胞减少或类固醇治疗的）小鼠。我们 提议定义和优化这种保护，以准备通过 进行以下调查：1）优化ALS免疫原和辅助剂以最大化鼠的保护 血源性传播念珠菌病的模型； 2）定义保护疫苗的机制 通过确定疫苗接种对特定器官特异性1/类型2细胞因子特征的影响 感染并消除已鉴定的细胞因子； 3）定义疫苗保护的宽度 白色念珠菌的多种菌株和免疫能力的多种念珠菌， 免疫功能低下的小鼠； 4）定义与疫苗相关的免疫替代功效标记 介导的保护。 实现这些目标将明显推进开发疫苗以威胁生命 候选感染。将确定疫苗介导的保护的机制， 将定义疫苗介导的保护，并确定替代功效标记以允许 优化给药时间表。总体而言，这些研究将为未来树立基础 疫苗的晚期动物和临床测试。