Vaccine Strategies for Disseminated Candidiasis

假丝酵母菌是机会性真菌病原体，已成为最常见的医院内 美国的感染情况(美国)以及世界范围内。假丝酵母菌现在是第三种最常见的 从住院患者血液中检出的微生物占医院总数的10% 血液感染。在美国，仅与念珠菌症相关的成本就超过每年10亿美元。 即使用抗真菌药物治疗，播散性念珠菌病也有40%-50%的不可接受的归因死亡率， 骨髓清除术者的死亡率为50%。此外，对传统抗真菌疗法的抗药性 在假丝酵母菌中。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是 特别吸引人。 我们已经研究了一种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 初步研究表明，接种ALSLP疫苗对两种免疫活性均有显著保护作用 和免疫受损(中性粒细胞减少或类固醇治疗)的侵袭性念珠菌感染的小鼠。我们 建议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，以最大限度地保护小鼠 血源性播散性念珠菌病模型；2)明确疫苗的保护机制 通过确定接种疫苗对器官特异性1型/2型细胞因子图谱的影响 感染和废除已确定的细胞因子；3)确定疫苗对 多株白色念珠菌和多种念珠菌的免疫活性和 免疫受损的小鼠；4)定义与疫苗相关的免疫替代效力标记- 中介保护。 实现这些目标将显著推进危及生命的疫苗的开发 念珠菌感染。疫苗介导的保护机制将被确定，广度 将定义疫苗介导的保护，并将确定替代效力标记，以允许 给药计划的优化。总的来说，这些研究将为今后的工作奠定基础。 该疫苗的高级动物和临床试验。

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.