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 antigenWe thank Alessio Corrado, Riccardo De Ricco, Maria Michelina Raso, Daniela Proietti and Barbara Brogioni for contributing to the work. This study was sponsored by GSK group of companies. We acknowledge the Horizon 2020 research and innovation programme of the European Union for support through the Marie Skłodowska-Curie grant agreement Glycovax No 675671. The group at CIC bioGUNE thank Agencia Estatal de Investigación (Spain) for Grant CTQ2015-68756-R, and for the Severo Ochoa Excellence Accreditation (SEV-2016-0644). J.J.-B. also thanks the European Research Council (RECGLYCANMR, Advanced Grant 788143). D.O., L.D.B., F.C., P.R.M.H., F.A., M.M.R., F.B., I.M. and R.A. are employees of GSK groups companies. L.D.B., F.C., F.B., I.M. and R.A. are inventors of patents related to the topic. F.B., I.M. and R.A. are owners of GSK stocks