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6. Protection against experimental cryptococcosis elicited by Cationic Adjuvant Formulation 01-adjuvanted subunit vaccines.

Author

Wang, Ruiying, Oliveira, Lorena V. N., Hester, Maureen M., Carlson, Diana, Christensen, Dennis, Specht, Charles A., and Levitz, Stuart M.

Subjects
T cells, CRYPTOCOCCOSIS, VACCINE trials, CYTOTOXIC T cells, TUMOR necrosis factors, RESOURCE-limited settings
Abstract

The fungal infection, cryptococcosis, is responsible for >100,000 deaths annually. 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 Cryptococcus neoformans 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 C. neoformans had an influx of leukocytes into the lung including robust numbers of polyfunctional CD4+ T cells which produced Interferon gamma (IFNγ), tumor necrosis factor alpha (TNFα), and interleukin (IL)-17 upon ex vivo antigenic stimulation. Cytokine-producing lung CD8+ T cells were also found, albeit in lesser numbers. A significant, durable IFNγ response was observed in the lungs, spleen, and blood. Moreover, IFNγ 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. Author summary: Cryptococcosis is a fungal infection that poses great challenges to public health, especially in resource-limited regions with high HIV prevalence. Despite the urgent need, no licensed vaccines are currently available. In this study, we used a lethal mouse model of cryptococcosis to explore protection and immune responses elicited by vaccines consisting of recombinant cryptococcal proteins formulated with CAF01, an adjuvant that has an established safety and immunogenicity profile in human clinical vaccine trials. We discovered that while vaccines containing a single protein partially protected mouse strains, the protection was greatly augmented when the mice received vaccines formulated with multiple antigens. The lungs of vaccinated and infected mice had a robust influx of CD4+ T cells, many of which made the cytokines IFNγ and IL-17 when stimulated ex vivo. Moreover, we found the higher production of IFNγ directly correlated with better fungal control in the lungs. Cytotoxic CD8+ T cell responses were also observed, albeit in lesser numbers. Our promising findings from this preclinical research paves the way for future human cryptococcal vaccine trials. [ABSTRACT FROM AUTHOR]

Published
2024
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13. Immune evasion by Cryptococcus gattii in vaccinated mice coinfected with C. neoformans.

Author

Hester, Maureen M., Carlson, Diana, Lodge, Jennifer K., Levitz, Stuart M., and Specht, Charles A.

Subjects
VACCINE effectiveness, VACCINATION, CRYPTOCOCCUS, FUNGAL virulence, CRYPTOCOCCUS neoformans, MICE
Abstract

Cryptococcus neoformans and C. gattii, the etiologic agents of cryptococcosis, cause over 100,000 deaths worldwide every year, yet no cryptococcal vaccine has progressed to clinical trials. In preclinical studies, mice vaccinated with an attenuated strain of C. neoformans deleted of three cryptococcal chitin deacetylases (Cn-cda1Δ2Δ3Δ) were protected against a lethal challenge with C. neoformans strain KN99. While Cn-cda1Δ2Δ3Δ extended the survival of mice infected with C. gattii strain R265 compared to unvaccinated groups, we were unable to demonstrate fungal clearance as robust as that seen following KN99 challenge. In stark contrast to vaccinated mice challenged with KN99, we also found that R265-challenged mice failed to induce the production of protectionassociated cytokines and chemokines in the lungs. To investigate deficiencies in the vaccine response to R265 infection, we developed a KN99-R265 coinfection model. In unvaccinated mice, the strains behaved in a manner which mirrored single infections, wherein only KN99 disseminated to the brain and spleen. We expanded the coinfection model to Cn-cda1Δ2Δ3Δ-vaccinated mice. Fungal burden, cytokine production, and immune cell infiltration in the lungs of vaccinated, coinfected mice were indicative of immune evasion by C. gattii R265 as the presence of R265 neither compromised the immunophenotype established in response to KN99 nor inhibited clearance of KN99. Collectively, these data indicate that R265 does not dampen a protective vaccine response, but rather suggest that R265 remains largely undetected by the immune system. [ABSTRACT FROM AUTHOR]

Published
2024
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17. The Genome of the Basidiomycetous Yeast and Human Pathogen Cryptococcus neoformans

Author

Loftus, Brendan J., Fung, Eula, Roncaglia, Paola, Rowley, Don, Amedeo, Paolo, Bruno, Dan, Vamathevan, Jessica, Miranda, Molly, Anderson, Iain J., Fraser, James A., Allen, Jonathan E., Bosdet, Ian E., Brent, Michael R., Chiu, Readman, Doering, Tamara L., Donlin, Maureen J., D'Souza, Cletus A., Fox, Deborah S., Grinberg, Viktoriya, Fu, Jianmin, Fukushima, Marilyn, Haas, Brian J., Huang, James C., Janbon, Guilhem, Koo, Hean L., Krzywinski, Martin I., Kwon-Chung, June K., Lengeler, Klaus B., Maiti, Rama, Marra, Marco A., Marra, Robert E., Mathewson, Carrie A., Mitchell, Thomas G., Pertea, Mihaela, Riggs, Florenta R., Salzberg, Steven L., Schein, Jacqueline E., Shvartsbeyn, Alla, Shin, Heesun, Shumway, Martin, Specht, Charles A., Suh, Bernard B., Tenney, Aaron, Utterback, Terry R., Wickes, Brian L., Wortman, Jennifer R., Wye, Natasja H., Kronstad, James W., Lodge, Jennifer K., Heitman, Joseph, Davis, Ronald W., Fraser, Claire M., and Hyman, Richard W.

Published
2005

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