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No licensed vaccines are available. We explored the efficacy and immune responses of subunit cryptococcal vaccines adjuvanted with Cationic Adjuvant Formulation 01 (CAF01). CAF01 promotes humoral and T helper (Th) 1 and Th17 immune responses and has been safely used in human vaccine trials. Four subcutaneous vaccines, each containing single recombinant <jats:italic>Cryptococcus neoformans<\/jats:italic> protein antigens, partially protected mice from experimental cryptococcosis. Protection increased, up to 100%, in mice that received bivalent and quadrivalent vaccine formulations. Vaccinated mice that received a pulmonary challenge with <jats:italic>C<\/jats:italic>. <jats:italic>neoformans<\/jats:italic> had an influx of leukocytes into the lung including robust numbers of polyfunctional CD4<jats:sup>+<\/jats:sup> T cells which produced interferon gamma (IFN\u03b3), tumor necrosis factor alpha (TNF\u03b1), and interleukin (IL)-17 upon ex vivo antigenic stimulation. Cytokine-producing lung CD8<jats:sup>+<\/jats:sup> T cells were also found, albeit in lesser numbers. A significant, durable IFN\u03b3 response was observed in the lungs, spleen, and blood. Moreover, IFN\u03b3 secretion following ex vivo stimulation directly correlated with fungal control in the lungs. Thus, we have developed multivalent cryptococcal vaccines which protect mice from experimental cryptococcosis using an adjuvant which has been safely tested in humans. These preclinical studies suggest a path towards human cryptococcal vaccine trials.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012220","type":"journal-article","created":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T19:03:25Z","timestamp":1720465405000},"page":"e1012220","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Protection against experimental cryptococcosis elicited by Cationic Adjuvant Formulation 01-adjuvanted subunit vaccines"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3638-4582","authenticated-orcid":true,"given":"Ruiying","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1762-0076","authenticated-orcid":true,"given":"Lorena V. 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Guidelines for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV. Updated June 17, 2022. https:\/\/apps.who.int\/iris\/bitstream\/handle\/10665\/357088\/9789240052178-eng.pdf?sequence=1."},{"issue":"12","key":"ppat.1012220.ref004","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1016\/S1473-3099(22)00499-6","article-title":"The global burden of HIV-associated cryptococcal infection in adults in 2020: a modelling analysis","volume":"22","author":"R Rajasingham","year":"2022","journal-title":"Lancet Infect Dis"},{"issue":"4","key":"ppat.1012220.ref005","doi-asserted-by":"crossref","first-page":"e143","DOI":"10.1016\/S1473-3099(18)30493-6","article-title":"Leave no one behind: Response to new evidence and guidelines for the management of cryptococcal meningitis in low-income and middle-income countries","volume":"19","author":"A Loyse","year":"2019","journal-title":"Lancet Infect Dis"},{"key":"ppat.1012220.ref006","unstructured":"World Health Organization. WHO fungal priority pathogens list to guide research, development and public health action. 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