Evaluation of vaccine-induced anti-lipopolysaccharide antibodies against clinically relevant Klebsiella pneumoniae strains to inform vaccine design

Klebsiella pneumoniae is a leading cause of neonatal sepsis in low- and middle-income countries and is increasingly multi-drug resistant, highlighting the need for vaccines. Putative vaccine targets include the lipopolysaccharide (O antigen) and capsular polysaccharide (K antigen), but capsule may mask O antigen and limit antibody-mediated opsonophagocytosis. We evaluated the activity of O antigen-specific antibodies induced by a tetravalent bioconjugate vaccine against 146 clinical isolates representing 17 prevalent capsule types associated with neonatal sepsis. Susceptibility to antibody-mediated killing varied by capsule type: four were consistently susceptible, six showed heterogeneous responses, and seven were resistant despite remaining susceptible to K antigen-specific antibodies. Killing of susceptible strains was predominantly mediated by anti-O1 antibodies, as demonstrated by competitive inhibition with purified polysaccharides. Collectively, these findings support an antigen-sparing vaccine design strategy, in which susceptible capsule types may be replaced by a single O type, reducing vaccine complexity while maintaining broad functional coverage.