Induction of Broad-Spectrum Protective Immunity against Disparate Cryptococcus Serotypes

Abstract

Cryptococcosis is a fungal disease caused by multiple <i>Cryptococcus</i> serotypes; particularly <i>C. neoformans</i> (serotypes A and D) and <i>C. gattii</i> (serotypes B and C). To date, there is no clinically available vaccine to prevent cryptococcosis. Mice given an experimental pulmonary vaccination with a <i>C. neoformans</i> serotype A strain engineered to produce interferon-γ, denoted H99γ, are protected against a subsequent otherwise lethal experimental infection with <i>C. neoformans</i> serotype A. Thus, we determined the efficacy of immunization with <i>C. neoformans</i> strain H99γ to elicit broad-spectrum protection in BALB/c mice against multiple disparate <i>Cryptococcus</i> serotypes. We observed significantly increased survival rates and significantly decreased pulmonary fungal burden in H99γ immunized mice challenged with <i>Cryptococcus</i> serotypes A, B, or D compared to heat-killed H99γ (HKH99γ) immunized mice. Results indicated that prolonged protection against <i>Cryptococcus</i> serotypes B or D in H99γ immunized mice was CD4⁺ T cell dependent and associated with the induction of predominantly Th1-type cytokine responses. Interestingly, immunization with H99γ did not elicit greater protection against challenge with the <i>Cryptococcus</i> serotype C tested either due to low overall virulence of this strain or enhanced capacity of this strain to evade host immunity. Altogether, these studies provide "proof-of-concept" for the development of a cryptococcal vaccine that provides cross-protection against multiple disparate serotypes of <i>Cryptococcus</i>.