Vaccine Strategies for Disseminated Candidiasis

传播性念珠菌病的疫苗策略

• 批准号: 7385990
• 负责人: John E Edwards
• 金额: $ 33.16万
• 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/7385990
• 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

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.

念珠菌是机会性真菌病原体，已成为最常见的医院致病菌之一