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（由申请人提供）：念珠菌属。是机会性真菌病原体，已成为美国和全世界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发现的第三大常见微生物，占所有医院血流感染的 10%。在美国，每年仅与念珠菌血症相关的费用就超过 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仍高达 40-50%，令人无法接受，而清髓患者的死亡率则超过 50%。此外，念珠菌属对传统抗真菌疗法的耐药性。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特别有吸引力。我们研究了编码白色念珠菌对人类细胞的有效粘附素的基因。在我们的初步研究中，接种 Als 1p 疫苗对患有侵袭性念珠菌感染的免疫功能正常和免疫功能低下（中性粒细胞减少或类固醇治疗）小鼠产生了显着的保护作用。我们建议通过以下研究来定义和优化这种保护，为未来的人类临床研究做准备：1) 优化 Als 免疫原和佐剂，以最大限度地提高血源性念珠菌病小鼠模型的保护作用； 2) 通过确定疫苗接种对感染部位器官特异性 1 型/2 型细胞因子谱的影响并废除已识别的细胞因子，定义疫苗的保护机制； 3) 确定疫苗在免疫功能正常和免疫功能低下的小鼠中针对多种白色念珠菌菌株和多种念珠菌的保护范围； 4) 定义与疫苗介导的保护相关的免疫替代功效标记。实现这些目标将显着推进针对危及生命的念珠菌感染的疫苗的开发。将确定疫苗介导的保护机制，定义疫苗介导的保护的广度，并确定替代功效标记物以优化给药方案。总的来说，这些研究将为未来疫苗的高级动物和临床测试奠定基础。