Development of immunotherapeutic strategies and vaccines against multidrug resistant C. auris disseminated infection

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Development of immunotherapeutic strategies and vaccines against multidrug resistant C. auris disseminated infection PROJECT SUMMARY Disseminated candidiasis is a life-threatening disease and remains the third most common bloodstream infection in hospitalized patients in the United States, with a mortality of 40-60%. Particularly, Candida auris is a multi- drug resistant, health care-associated fungal pathogen, and has recently emerged as the first fungal pathogen to cause a global public health threat. There are no effective vaccines for Candida infection or indeed for any fungi, and significant therapeutic challenges remain. Current anti-Candida treatments are plagued by significant toxicity and poor efficacy, especially in immunocompromised patients for treating drug resistant Candida species. Thus, there is a pressing and urgent need for new treatment options. A therapeutic vaccine could bolster both the protective TH1-mediated immune response and induce protective antibodies, thereby slowing or halting the progression of dissemination, as well as recurrent in future. Our prior work in mice has demonstrated therapeutic efficacy of a double peptide vaccine in the acute phase of Candida invasive infection evidenced by significantly reduction in organ fungal burdens, as well as prolonged survival. This work is a stride towards the development of a therapeutic C. auris vaccine that seeks to prevent or reduce the mortality in patients infected with C. auris. This is the first study that demonstrates therapeutic efficacy of a synthetic peptide vaccine in a mouse model of C. auris disseminated infection. Our ultimate goals are to develop the first therapeutic double-peptide vaccine composed of peptides that have high homology in all the medically significant Candida species including C. auris, and to elucidate protective mechanisms against disseminated candidiasis. In Aim 1, we will seek to investigate whether our double peptide vaccines could be effective in already established C. auris invasive infection. In Aim 2, we will evaluate the potential of peptide vaccine candidates serve as immunotherapeutic adjuncts to antibiotic treatment regimens for C. auris disseminated infection. We will further determine the protective efficacy of the therapeutic peptide vaccine in immunocompromised mouse models of C. auris invasive infection.