Vaccine Strategies for Disseminated Candidiasis

传播性念珠菌病的疫苗策略

• 批准号: 7764734
• 负责人: John E Edwards
• 金额: $ 33.39万
• 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 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7764734
• 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.

念珠菌是机会性真菌病原体， 美国的感染情况（美国）和世界各地。念珠菌现在是第三常见的 从住院患者血液中回收的病原菌10株，占所有医院感染病原菌的10 血液感染在美国，仅与念珠菌血症相关的费用每年就超过10亿美元。 即使采用抗真菌治疗，播散性念珠菌病的归因死亡率也高达40- 50%， 并且骨髓清除患者的死亡率>50%。此外，对常规抗真菌治疗的耐药性 在念珠菌属中，正在上升由于这些原因，预防危及生命的念珠菌感染的疫苗是必要的。 特别有吸引力。 我们已经研究了一个基因编码一个有效的粘附素的白色念珠菌对人类细胞。在我们 初步研究表明，Alslp疫苗接种在免疫活性 和免疫功能低下的（激素或类固醇治疗的）侵袭性念珠菌感染小鼠。我们 建议定义和优化这种保护，为未来的人体临床研究做准备， 以下研究：1）优化Als免疫原和佐剂以最大化在鼠中的保护 血源性播散性念珠菌病模型; 2）确定疫苗的保护机制 通过确定疫苗接种对接种部位器官特异性1型/2型细胞因子谱的影响 感染和消除所鉴定的细胞因子; 3）定义疫苗针对感染的保护范围。 多株C.白念珠菌和多种念珠菌在免疫活性和 免疫受损小鼠; 4）定义与疫苗相关的免疫学替代功效标志物- 中介保护。 实现这些目标将显著推进威胁生命的疫苗的开发。 念珠菌感染将确定疫苗介导的保护机制， 将定义疫苗介导的保护，并确定替代疗效标志物， 优化给药方案。总的来说，这些研究将为未来的研究奠定基础。 疫苗的先进动物和临床试验。