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. ? ? ?
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