6-O-Branched Oligo-ß-glucan-Based Antifungal Glycoconjugate Vaccines.

ABSTRACT

With the rapid growth in fungal infections and drug-resistant fungal strains, antifungal vaccines have become an especially attractive strategy to tackle this important health problem. ß-Glucans, a class of extracellular carbohydrate antigens abundantly and consistently expressed on fungal cell surfaces, are intriguing epitopes for antifungal vaccine development. ß-Glucans have a conserved ß-1,3-glucan backbone with sporadic ß-1,3- or ß-1,6-linked short glucans as branches at the 6-O-positions, and the branches may play a critical role in their immunologic functions. To study the immunologic properties of branched ß-glucans and develop ß-glucan-based antifungal vaccines, three branched ß-glucan oligosaccharides with 6-O-linked ß-1,6-tetraglucose, ß-1,3-diglucose, and ß-1,3-tetraglucose branches on a ß-1,3-nonaglucan backbone, which mimic the structural epitopes of natural ß-glucans, were synthesized and coupled with keyhole limpet hemocyanin (KLH) to form novel synthetic conjugate vaccines. These glycoconjugates were proved to elicit strong IgG antibody responses in mice. It was also discovered that the number, size, and structure of branches linked to the ß-glucan backbone had a significant impact on the immunologic property. Moreover, antibodies induced by the synthetic oligosaccharide-KLH conjugates were able to recognize and bind to natural ß-glucans and fungal cells. Most importantly, these conjugates elicited effective protection against systemic Candida albicans infection in mice. Thus, branched oligo-ß-glucans were identified as functional epitopes for antifungal vaccine design and the corresponding protein conjugates as promising antifungal vaccine candidates.