Fig. 4: A hypothetical model of the role of chain length in the interaction of glycoconjugates with antigen-presenting B cells (APC) and T helper cells.

The necessary steps for glycoconjugate vaccines to engender B cell maturation and production of glycan-specific antibodies are enumerated in the central blue segment. Glycoconjugate construct (a) contains medium-sized glycan chains that are excessively cross-linked and therefore not sufficiently accessible to be optimally recognized by the B cell receptors (BCRs). Instead, functional vaccines can be achieved by rational design of linkage sites and chain lengths in the vaccine molecule. Appropriate levels of cross-linking of long-chain polysaccharides (construct b) or end-linked chemistries for medium-sized oligosaccharides (construct c) can lead to protective glycoconjugate vaccines. In those settings, T-helper cells recognize the MHCII-bound peptide complexes and become activated. With T-helper cell support, cognate B cells mature to memory B cells and produce glycan-specific antibodies. However, excessively long glycan stretches (construct d) may act similar to unconjugated PS and cross-link BCRs, generating mainly T cell-independent immune responses resulting in hyporesponsiveness. Without T-helper cell support, B cells become temporarily activated but proceed to undergo apoptosis, impeding the production of long-lasting memory B cells and long-lived plasma cells⁸¹.