The morbidity associated with invasive fungal infections (IFIs) is high and IFIs are highly intractable to treatment once these opportunistic pathogens gain a foothold. There is a rapidly rising incidence in hospital- acquired nosocomial infections which are likely have an increasing impact on health care. Compounding the serious nature of IFIs is the relative lack of antifungal drugs, the emergence of triazole-resistant fungal strains, one of the few classes of effective anti-fungal agents, and the lack of any licensed anti-fungal vaccine. The long-term goal of this project is to provide new active vaccination and passive protection strategies that provide more optimal prevention and treatment for personnel at risk for IFI. We are proposing a novel approach that involves vaccination with immunogens expressing epitopes shared by Aspergillus fumigatus and other fungi with bacteria. This strategy will circumvent the low responsivity of the immune response to surface fungal antigens which normally leads to a lack of protective immunity in fungal infections. This approach, to develop active immunity against IFI, is based on findings that (i) immunization of mice with whole heat-killed strains of streptococci induced protection against invasive aspergillosis and (ii) anti-A. fumigatus Abs are induced in humans by conjugate vaccines that have been used to vaccinate humans against streptococcal infections. Repurposing of prophylactic conjugate vaccines and availability of passive monoclonal antibodies for protection against IFI by multiple fungal species would have a high impact and provide much needed treatments for patients at risk for, or suffering from IFIs.
Immunomodulatory therapeutics for invasive fungal infections are backed by scientific rationale and a large body of experimental work in vitro and in animal models. Given the bleak outlook for novel drug classes to combat fungal infections and the rising prevalence of fungi resistance to currently used antifungals, there is an urgent need to facilitate the developmental pipeline for clinical application of antifungal immunotherapeutics. This proposal explores the possibility of repurposing anti-bacterial vaccines for at-risk patients and as adjuncts to conventional antifungal treatment in patients with invasive fungal infections.
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