Structure-guided design of a Group B Streptococcus type III synthetic glycan-conjugate vaccine

We recently mapped the structural epitope of the capsular polysaccharide from type III Group B Streptococcus (GBSIII), a major cause of invasive disease in newborns, by using a dimer fragment obtained by depolymerization complexed with a protective mAb. While literature data had suggested a highly complex epitope contained in a helical structure composed of more than four repeating units, we showed that such dimer conjugated to a carrier protein with a high glycodensity elicited functional antibodies comparably to the full-length conjugated polysaccharide. Here, starting from the X-ray crystallographic structure of the polysaccharide fragment-mAb complex, we designed and synthesized a hexasaccharide comprising exclusively the relevant positions involved in binding. Combining competitive Surface Plasmon Resonance, Saturation Transfer Difference NMR and in silico modelling, we demonstrated that the synthetic hexasaccharide recognized the mAb similarly to the dimer and, conjugated to CRM₁₉₇ (a mutant of diphtheria toxin), elicited a functional immune response non inferior to the conjugated polysaccharide, indicating to suffice as vaccine antigen