Biosciences Research Seminar - Cryptococcus neoformans delta¬sgl1 is a promising vaccine candidate against cryptococcosis

Vaccines are one of the greatest medical accomplishments to date, yet no fungal vaccines are currently available in humans mainly because opportunistic mycoses generally occur during immunodeficiencies necessary for vaccine protection. In previous studies, a live, attenuated Cryptococcus neoformans delta-sgl1 mutant accumulating sterylglucosides was found to be avirulent and protected mice from a subsequent lethal infection even in absence of CD4+ T cells, a condition most associated with cryptococcosis (e.g., HIV). Here, we tested three strategies of vaccination against cryptococcosis. First, in our preventative model, protection was achieved even after a 3-fold increase of the vaccination window. Second, because live C. neoformans delta-sgl1-vaccinated mice challenged more than once with wild-type (WT) strain had a significant decrease in lung fungal burden, we tested C. neoformans delta-sgl1 as an immunotherapeutic. We found that therapeutic administrations of heat- killed (HK) C. neoformans delta-sgl1 post WT challenge significantly improves the lung fungal burden. Similarly, therapeutic administration of HK C. neoformans delta-sgl1 post WT challenge resulted in 100% or 70% survival depending on the time of vaccine administration, suggesting that HK delta-sgl1 is a robust immunotherapeutic option. Third, we investigated a novel model of vaccination in preventing reactivation from lung granuloma using C. neoformans delta-sgl1. Remarkably, we show that administration of HK delta-sgl1 prevents mice from reactivating delta-sgl1 upon inducing immunosuppression with corticosteroids or by depleting CD4+ T cells. Our results suggest that HK delta-sgl1 represents a clinically relevant, efficacious vaccine that confers robust host protection in three models of vaccination against cryptococcosis even during CD4-deficiency.