Vaccination with a ZNF2(oe) Strain of Cryptococcus Provides Long-Lasting Protection against Cryptococcosis and Is Effective in Immunocompromised Hosts

Systemic cryptococcosis is fatal without treatment. Even with the current antifungal therapies, this disease kills 180,000 of 225,000 infected people annually. Exposure to the causative environmental fungus Cryptococcus neoformans is universal. Either reactivation of a latent infection or an acute infection after high exposure to cryptococcal cells can result in cryptococcosis. Currently, there is no vaccine to prevent cryptococcosis. Previously, we discovered that Znf2, a transcription factor that directs Cryptococcus yeast-to-hypha transition, profoundly affects cryptococcal interaction with the host. Overexpression of ZNF2 drives filamentous growth, attenuates cryptococcal virulence, and elicits protective host immune responses. Importantly, immunization with cryptococcal cells overexpressing ZNF2, in either live or heat-inactivated form, offers significant protection to the host from a subsequent challenge by the otherwise lethal clinical isolate H99. In this study, we found that the heat-inactivated ZNF2(oe) vaccine offered long-lasting protection with no relapse upon challenge with the wild-type H99. Vaccination with heat-inactivated ZNF2(oe) cells provides partial protection in hosts with preexisting asymptomatic cryptococcal infection. Importantly, once animals have been vaccinated with heat-inactivated or live short-lived ZNF2(oe) cells, they are protected against cryptococcosis even when their CD4(+) T cells are depleted at the time of fungal challenge. Remarkably, vaccination with live, short-lived ZNF2(oe) cells in CD4-depleted hosts still provides strong protection to these hosts with preexisting immunodeficiency at the time of vaccination. This work raises hope for developing effective vaccines with long-lasting protection for individuals who are immunocompromised or could become immunocompromised later in life.