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Vaccine-Mediated Protection of Mice Against African and Asian Clinical Strains of Cryptococcus neoformans
Diana Carlson1, Ruiying Wang1, Zachary Hastings1
1Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
Abstract:
Infections with strains of the Cryptococcus neoformans species complex are responsible for over 100,000 deaths per year, predominantly due to meningitis in immunocompromised individuals. Despite much research, there are no licensed fungal vaccines available. Most experimental cryptococcal vaccine formulations have been tested in preclinical models using laboratory strains of C. neoformans, particularly H99 and KN99. However, to be effective, vaccines need to protect against the wide variety of cryptococcal isolates found worldwide, particularly in regions that have the highest burden of infections. Therefore, we explored vaccine-mediated protection of BALB/c mice against experimental cryptococcosis due to six C. neoformans strains originally isolated from patients with cryptococcal meningitis in Vietnam, Uganda, and Botswana. Two vaccines were tested: a live-attenuated C. neoformans vaccine lacking three chitin deacetylase genes, and a quadrivalent subunit protein vaccine adjuvanted with Cationic Adjuvant Formulation 01. When compared to unvaccinated mice, both vaccines provided significant protection against all six clinical strains. However, the degree of protection varied as a function of vaccine formulation and clinical strain. Lung leukocytes from vaccinated and infected mice had significantly increased antigen-stimulated interferon-gamma production compared with infected but unvaccinated mice. Thus, although the degree of protection varied, two cryptococcal vaccines significantly protected mice against experimental infection with cryptococcal strains representative of regions of the world that account for the majority of cryptococcal meningitis cases found globally. These data provide preclinical support for trialing vaccines in persons at high risk for developing cryptococcosis.
Insights
Two experimental fungal vaccines show significant protection against Cryptococcus neoformans meningitis strains in mice. These vaccines offer hope for preventing cryptococcosis, a major cause of death globally.
Area of Science:
- Mycology
- Immunology
- Vaccinology
Background:
- Cryptococcus neoformans infections cause over 100,000 deaths annually, primarily cryptococcal meningitis in immunocompromised individuals.
- No licensed fungal vaccines are currently available, necessitating the development of broadly protective strategies.
- Existing research often uses limited laboratory strains, potentially limiting vaccine efficacy against diverse clinical isolates.
Purpose of the Study:
- To evaluate the efficacy of two novel vaccine formulations against diverse clinical strains of Cryptococcus neoformans.
- To assess vaccine-induced protection in a preclinical mouse model using geographically distinct patient-derived isolates.
Main Methods:
- BALB/c mice were vaccinated with either a live-attenuated C. neoformans vaccine or a quadrivalent subunit protein vaccine.
- Mice were challenged with six C. neoformans strains isolated from meningitis patients in Vietnam, Uganda, and Botswana.
- Protection was assessed by survival rates and immunological responses, including interferon-gamma production by lung leukocytes.
Main Results:
- Both tested vaccines provided significant protection against experimental cryptococcosis caused by all six clinical C. neoformans strains.
- The degree of protection varied depending on the specific vaccine formulation and the clinical strain used for challenge.
- Vaccinated mice exhibited increased antigen-stimulated interferon-gamma production in lung leukocytes compared to unvaccinated controls.
Conclusions:
- Two distinct cryptococcal vaccine candidates demonstrate preclinical efficacy against diverse, clinically relevant C. neoformans strains.
- These findings support the potential of these vaccines for broader protection against cryptococcosis, particularly in high-burden regions.
- Further clinical trials are warranted to evaluate these vaccines in at-risk human populations.
