A conserved glycan motif induces broadly reactive functional antibodies against the zoonotic pathogen <i>Streptococcus suis</i>

<i>Streptococcus suis</i> is a largely neglected but emerging bacterial zoonotic pathogen of global concern for animal welfare, antibiotic resistance development, and human health. No effective vaccines are now available. Here, we identified and characterized the function and structure of two cell wall polysaccharide variants in pathogenic <i>S. suis</i> strains using genetic deletion and (heterologous) complementation, lectin staining, glycan composition analysis, and specialized NMR spectroscopy. Both glycan variants were anionic polymers that differed in the presence of glucose in the side chain as a result of allelic variation in a glycosyltransferase gene. Deletion of this variable glycosyltransferase revealed an identical glycan "core" and affected <i>S. suis</i> morphology and lysozyme resistance. Immunization of pigs with this core domain elicited antibodies that recognized antigenically diverse pathogenic <i>S. suis</i> strains and induced complement deposition on encapsulated pathogenic <i>S. suis</i> strains. This study provides valuable insights for developing next-generation glycoconjugate vaccines, whereby a single-glycan target could protect against the emerging zoonotic pathogen <i>S. suis</i>.