6-O-Branched Oligo-β-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. β-Glucans, a class of extracellular carbohydrate antigens abundantly and consistently expressed on fungal cell surfaces, are intriguing epitopes for antifungal vaccine development. β-Glucans have a conserved β-1,3-glucan backbone with sporadic β-1,3- or β-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 β-glucans and develop β-glucan-based antifungal vaccines, three branched β-glucan oligosaccharides with 6-O-linked β-1,6-tetraglucose, β-1,3-diglucose, and β-1,3-tetraglucose branches on a β-1,3-nonaglucan backbone, which mimic the structural epitopes of natural β-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 β-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 β-glucans and fungal cells. Most importantly, these conjugates elicited effective protection against systemic Candida albicans infection in mice. Thus, branched oligo-β-glucans were identified as functional epitopes for antifungal vaccine design and the corresponding protein conjugates as promising antifungal vaccine candidates.

Dectin-1 Facilitates IL-18 Production for the Generation of Protective Antibodies Against Candida albicans

“…Furthermore, we found that the high titer of IgG antibody was maintained for a long time after gpi7 mutant-vaccination, which suggests the longevity of the protective effects of this vaccination against IC ( Supplementary Figure S6 ). Previous studies have been demonstrated that purified glucan could enhance innate antifungal immune response ( Quintin et al, 2012 ; Cheng et al, 2014 ) and glucan-based vaccine could increase resistance of experimental animal to invasive candidiasis ( Bromuro et al, 2010 ; Liao et al, 2015 , 2016 ). Heat inactivated cell wall β-glucan of C. albicans was exposed, but the protein on the cell wall surface was denatured.…”

Recent Advances in the Synthesis of Glycoconjugates for Vaccine Development

“…More recently, Liao et al [ 249 ] reported similar immunological studies of fragments 323a – 325a containing the dominant linear octasaccharide and β-(1-6) and β-(1-3) branches with different chain length ( Figure 35 ). KLH conjugates 323b and 324b were more immunogenic than 325b but the majority of elicited Abs were against the common β-glucan motif.…”

Potential targets for next generation antimicrobial glycoconjugate vaccines

“… 2013 ; Liao et al. 2015 , 2016 ). β-Glucans are immunostimulator molecules through Dectin-1 activation (Donadei et al.…”