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Vaccination with glucan particles (GP) containing the Cryptococcus neoformans chitin deacetylases Cda1 and Cda2 protect mice against experimental cryptococcosis. Here, immunological correlates of vaccine-mediated protection were explored. Studies comparing knockout and wild-type mice demonstrated CD4 + T cells are crucial, while B cells and CD8 + T cells are dispensable. Protection was abolished following CD4 + T cell depletion during either vaccination or infection but was retained if CD4 + T cells were only partially depleted. Vaccination elicited systemic and durable antigen-specific immune responses in peripheral blood mononuclear cells (PBMCs), spleens, and lungs. Following vaccination and fungal challenge, robust T-helper (Th) 1 and Th17 responses were observed in the lungs. Protection was abrogated in mice congenitally deficient in interferon (IFN) γ, IFNγ receptor, interleukin (IL)-1β, IL-6, or IL-23. Thus, CD4 + T cells and specific proinflammatory cytokines are required for GP-vaccine-mediated protection. Importantly, retention of protection in the setting of partial CD4 + T depletion suggests a pathway for vaccinating at-risk immunocompromised individuals., (© 2023. The Author(s).)

Despite the substantial global burden of human fungal infections, there are no approved fungal vaccines to protect at risk individuals. Here, we review the progress that has been made and the challenges that lie ahead in the quest towards efficacious fungal vaccines. In mouse studies, protection has been achieved with vaccines directed against fungal pathogens, including species of Candida, Cryptococcus, and Aspergillus, that most commonly cause life-threatening human disease. Encouraging results have been obtained with vaccines composed of live-attenuated and killed fungi, crude extracts, recombinant subunit formulations, and nucleic acid vaccines. Novel adjuvants that instruct the immune system to mount the types of protective responses needed to fight mycotic infections are under development. Candidate vaccines include those that target common antigens expressed on multiple genera of fungi thereby protecting against a broad range of mycoses. Encouragingly, three vaccines have reached human clinical trials. Still, formidable obstacles must be overcome before we will have fungal vaccines licensed for human use.