In-cell depolymerization of polysaccharide antigens. Exploring the processing pathways of glycans and why some glycoconjugate vaccines are less effective than expected: A review

Microbial polysaccharides are depolymerized within antigen-presenting cells by reactive nitrogen and reactive oxygen species with no obvious structure alterations. The exact chemical mechanisms of the in-cell processes vary with the structural features of the complex polymers. Free amine-containing carbohydrates are highly susceptible to action of reactive nitrogen species and acid sensitive linkages are prone to hydrolysis. The endosomal processing of glycoconjugates can modify the structure to a variable degree that correlates with ability to T-cell activation and immunogenicity of the antigen. The processed structures may direct innate and adaptive immune responses through modulation of polysaccharide-specific T cell response. During the in-cell processing of the glycoconjugate the immunodominant epitopes can be lost, leading to suboptimal antigenic properties. Consequently, the protective efficacy of the vaccine antigens can be altered. This may explain a differing effectiveness of vaccines, when the glycoconjugates are prepared from native or intact microbial glycans. The properties of both glycan and protein carrier should be considered in the design of optimal antigens, maximizing the glycopeptide specific T cell help and booster response. In this review, we highlight the importance of a prior knowledge of the carbohydrate structural features and present current understanding of the in-cell processing of glycoconjugates. [Display omitted]