9 - Antifungal glycoconjugate vaccines

Abstract

Fungal infections are a serious threat for human beings, especially for those who are considered at risk due to underline diseases or medical treatments that weaken their immunological status or facilitate tissues invasion by fungal pathogens. The available antifungal drugs are characterized by severe adverse effects; in addition, new and antimicrobial-resistant strains are emerging making their effective treatment more problematic. Alternative strategies like effective immunoprophylaxis are increasingly needed. Carbohydrates dominate the fungal cell wall (CW) are exposed on their surface and, therefore, represent a logical target for antifungal vaccines development. Since they are T-cell independent, they are poorly immunogenic in infants and do not induce immunological memory and high affinity antibodies which limits their applicability in all classes of age. Conjugation to protein carriers has solved this drawback. Accordingly, carbohydrate-based antifungal vaccines approached are based on conjugation of selected glycan antigens to protein carriers. Antifungal glycoconjugate vaccines are being explored at preclinical level for at least three of the major fungal pathogens: Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans. Glycoconjugates against C. albicans are the more advanced in terms of preclinical evidence, and different glycans have been tested (e.g., α- and β-mannosides, β-glucans, poly-N-acetyl-(1→6)-α-glucosamine). Efforts to develop a glycoconjugate vaccine against C. neoformans are also ongoing and deserve a lot of attention. One of the main challenges is to identify and reproduce, by chemical synthesis, those epitopes located in the structure of the capsular polysaccharide glucuronoxylomannan (GXM) able to elicit protective antibodies. More effort is needed to investigate the protective role of carbohydrate antigens from Aspergillus CW although some preliminary evidence has been reported for β-(1→3) and increasing interest is being given to α-(1→3)-glucans. Since besides glycans, fungal pathogens display also other virulence and potentially protective factors like proteins, it seems reasonable that an optimal vaccine should simultaneously target both class of antigens. In this regard, glycoconjugate vaccines of selected fungal glycans and protein antigens appear an attractive perspective.