Vaccine Strategies for Disseminated Candidiasis

描述（由申请人提供）：念珠菌属是机会性真菌病原体，已成为美国和世界范围内最常见的医院感染之一。念珠菌现在是从住院病人血液中恢复的第三种最常见的微生物，占所有院内血液感染的10%。在美国，与念珠菌病相关的费用每年超过10亿美元。即使使用抗真菌治疗，播散性念珠菌病的死亡率仍高达40-50%，在骨髓清除患者中死亡率高达50 -50%。此外，念珠菌对常规抗真菌治疗的耐药性正在上升。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。我们已经研究了一种基因编码白色念珠菌对人类细胞的强效粘附素。在我们的初步研究中，接种al1p对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）小鼠都有显著的保护作用。我们建议通过以下研究来定义和优化这种保护，为将来的人类临床研究做准备：1)优化Als免疫原和佐剂，以最大限度地保护小鼠血源性播散性念珠菌病模型；2)通过确定疫苗接种对感染部位器官特异性1/ 2型细胞因子谱的影响，并废除已识别的细胞因子，确定疫苗的保护机制；3)确定疫苗在免疫功能正常和免疫功能低下小鼠中对多种白色念珠菌菌株和多种念珠菌的保护广度；4)定义与疫苗介导的保护相关的免疫替代功效标记。实现这些目标将显著促进针对危及生命的念珠菌感染的疫苗的开发。将确定疫苗介导保护的机制，确定疫苗介导保护的广度，并确定替代疗效标记，以便优化给药计划。总的来说，这些研究将为未来疫苗的高级动物和临床试验奠定基础。

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.