Development of an alpha-1 phosphate mannan vaccine against the emerging fungal pathogen Candida auris.

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Candida auris is a fungal pathogen that has been identified as an emerging infectious disease and a public health threat. C. auris is notable for its resistance to antifungal therapy, its transmissibility, its high mortality rate as well as its ability to colonize patients, healthcare personnel and healthcare environments. C. auris strains are typically resistant to fluconazole and approximately half of C. auris strains are resistant to two or more anti-fungal drugs. C. auris causes nosocomial outbreaks of invasive candidiasis with mortality rates of ~60%. There are five distinct clades of C. auris, all of which appear to have evolved since 1996. In addition to its drug resistance, C. auris can colonize skin, spread from person-to-person and survive in healthcare environments for long periods of time. These features are unique to C. auris. C. auris is resistant to many standard decontamination reagents and protocols, which has resulted in the rapid spread of this pathogen throughout the world. This makes it a particularly dangerous emerging fungal pathogen. Thus, it is not surprising that C. auris is the first fungal pathogen that has been identified as a public health threat. What is needed is a C. auris specific vaccine that can prevent and/or ameliorate the morbidity, mortality and dissemination of this emerging fungal pathogen. The research outlined in this proposal directly addresses this pressing need. We have discovered that the mannan which coats the outermost surface of C. auris clinical strains is both structurally and biologically unique, i.e. it contains two unique acid labile Mα1-PO4 side chains that are not found in other fungal mannans or other fungal pathogens. Thus, C. auris mannan distinguishes it from virtually all other fungal pathogens. This suggests that C. auris mannan represents a target of opportunity for the development of a C. auris vaccine. We hypothesize that the dual Mα1-PO4 mannan structure can be used to develop a C. auris vaccine that will be effective against multiple C. auris strains. The goals of this R21 proposal are to: i) evaluate the efficacy of the vaccine in a murine model of C. auris infection and ii) evaluate the anti-fungal immune response to the vaccine. To address these objectives we propose two specific aims. Aim 1. Evaluate the efficacy of a C. auris mannan based vaccine formulation against systemic C. auris infection. Aim 2. Assess innate and adaptive immune responses elicited by the C. auris mannan vaccine.