Vaccine Strategies for Disseminated Candidiasis

传播性念珠菌病的疫苗策略

• 批准号: 7189876
• 负责人: John E Edwards
• 金额: $ 33.52万
• 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/7189876
• 关键词: Accounting; Active Immunization; Adjuvant; Advanced Development; Amyotrophic Lateral Sclerosis; 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; Invasive; 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; Therapeutic immunosuppression; United States; Vaccinated; Vaccination; Vaccines; attributable mortality; candidemia; catheter related infection; cost; cytokine; lymphocyte proliferation; member; mortality; oropharyngeal thrush; pathogen; prevent; programs; protective effect; research clinical testing; vaccine development; vaccine efficacy

DESCRIPTION (provided by applicant): 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 Als 1p 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.

性状（由申请方提供）：念珠菌属是机会性真菌病原体，已成为美国最常见的医院感染之一（美国）和世界各地。念珠菌现在是从住院患者血液中回收的第三大常见微生物，占所有医院血流感染的10%。在美国，仅与念珠菌血症相关的费用每年超过10亿美元。即使使用抗真菌治疗，播散性念珠菌病也具有不可接受的40- 50%的归因死亡率，并且在骨髓清除患者中具有>50%的死亡率。此外，念珠菌对传统抗真菌治疗的耐药性。正在上升出于这些原因，预防危及生命的念珠菌感染的疫苗特别有吸引力。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。在我们的初步研究中，接种Als 1 p疫苗对侵袭性念珠菌感染的免疫活性小鼠和免疫功能低下（激素或类固醇治疗）小鼠均产生了显著的保护作用。我们建议通过以下研究来确定和优化这种保护作用，为将来的人体临床研究做准备：1）优化Als免疫原和佐剂，以最大限度地保护血源性播散性念珠菌病小鼠模型; 2）通过确定疫苗接种对器官特异性1型/在感染部位的2型细胞因子谱和消除所鉴定的细胞因子; 3）确定疫苗针对多株C.白念珠菌和多种念珠菌; 4）定义与疫苗介导的保护相关的免疫替代功效标志物。实现这些目标将显著推进威胁生命的念珠菌感染疫苗的开发。将确定疫苗介导的保护机制，定义疫苗介导的保护范围，并确定替代疗效标志物，以优化给药方案。总的来说，这些研究将为疫苗未来的高级动物和临床试验奠定基础。