Vaccines for human fungal diseases: close but still a long way to go

Abstract

Despite the substantial global burden of human fungal infections, there are no approved fungal vaccines to protect at risk individuals. Here, we review the progress that has been made and the challenges that lie ahead in the quest towards efficacious fungal vaccines. In mouse studies, protection has been achieved with vaccines directed against fungal pathogens, including species of Candida, Cryptococcus, and Aspergillus, that most commonly cause life-threatening human disease. Encouraging results have been obtained with vaccines composed of live-attenuated and killed fungi, crude extracts, recombinant subunit formulations, and nucleic acid vaccines. Novel adjuvants that instruct the immune system to mount the types of protective responses needed to fight mycotic infections are under development. Candidate vaccines include those that target common antigens expressed on multiple genera of fungi thereby protecting against a broad range of mycoses. Encouragingly, three vaccines have reached human clinical trials. Still, formidable obstacles must be overcome before we will have fungal vaccines licensed for human use.

Fig. 1. Schematic model of the fungal cell wall.

This model shows the three basic components of the cell wall present in almost all fungal pathogens. Mannoproteins have polymers of mannose that decorate the proteins through O-linkages or N-linkages and are predominately found in the outer portion of cell wall. β-glucans are the most abundant constituent of the cell wall and tend to be in the middle with β-1,3-glucans forming the scaffold and β-1,6-glucans forming the branches, while chitin is found in the inner portion of the cell wall and linked to β-1,3-glucan. Other components of the cell wall in some fungi include α-glucan, galactomannan, chitosan, and melanin. In addition, the cryptococcal capsule is linked to the cell wall. Figure created with BioRender.com.

Fig. 2. Examples of the diversity in fungal morphology in human tissue from patients with mycoses.

a Tissue Gram stain of C. albicans from a patient with endocarditis. Hyphae (elongated cells), pseudo-hyphae (sausage-shaped cells) and yeasts (oval cells, some with buds) stain deep purple. Candida cells average 2–8 microns in diameter. b Mucicarmine stain of C. neoformans in the lungs of a patient with pulmonary cryptococcosis. Budding yeast cells with capsules that stain rose red are present. Yeast cells average about 5 microns in diameter without capsule. Capsular thickness is variable, typically ranging from 1 to 10 microns. c Grocott’s methenamine silver stain of A. fumigatus from a patient with invasive pulmonary aspergillosis. Septate hyphae with “Y”-shaped branching that stain silvery black are present. Average hyphal diameter is about 3 microns. d Periodic acid-Schiff stain of C. immitis from a patient with coccidioidomycosis. Three spherules, each containing endospores, are present. Spherules and endospores range in diameter from 10 to 100 microns and 2 to 5 microns, respectively. A single spherule can contain hundreds of endospores. Photo image credits. a, b, and d: Centers for Disease Control Public Health Image Library. c: Wikimedia Commons.