Vaccine Strategies for Disseminated Candidiasis

传播性念珠菌病的疫苗策略

基本信息

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
项目类别：
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

项目摘要

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.

描述（申请人提供）：念珠菌属。是机会主义的真菌病原体，已成为美国（美国）和全球最常见的医院感染之一。念珠菌属。现在是从住院患者血液中回收的第三大生物体，占所有医院血液感染的10％。在美国，仅与候选血症相关的成本也超过每年10亿美元，即使通过抗真菌疗法，散布的念珠菌病的归因死亡率为40-50％，而在骨髓状态的患者中的死亡率为> 50％。此外，念珠菌属中对常规抗真菌疗法的抗性。正在上升。由于这些原因，防止威胁生命的候选感染的疫苗特别有吸引力。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。在我们的初步研究中，ALS 1P的疫苗接种已在免疫功能和免疫功能低下（中性粒细胞减少或类固醇治疗）的小鼠中获得了明显的保护，并具有侵入性的念珠菌感染。我们建议通过以下研究为人类的未来临床研究定义和优化这种保护：1）优化ALS免疫原和辅助物，以最大程度地保护血源性传播念珠菌病模型； 2）通过确定疫苗接种对感染部位的器官特异性1/2型细胞因子谱的影响来定义疫苗保护的机制，并废除已鉴定的细胞因子； 3）在免疫能力和免疫功能低下的小鼠中，定义了疫苗对多种白色念珠菌和多种念珠菌的保护的广度； 4）定义与疫苗介导的保护相关的免疫替代功效标记。实现这些目标将明显推动开发疫苗，以危及生命的候选感染。将确定疫苗介导的保护的机制，将定义疫苗介导的保护的广度，并确定替代功效标记以允许优化给药时间表。总体而言，这些研究将为未来的晚期动物和疫苗的临床测试树立基础。