Capsular polysaccharide inhibits vaccine-induced O-antigen antibody binding and function across both classical and hypervirulent K2:O1 strains ofKlebsiella pneumoniae

Abstract

AbstractKlebsiella pneumoniaepresents as two circulating pathotypes: classicalK. pneumoniae(cKp) and hypervirulentK. pneumoniae(hvKp). Classical isolates are considered urgent threats due to their antibiotic resistance profiles, while hvKpisolates have historically been antibiotic susceptible. Recently, however, increased rates of antibiotic resistance have been observed in both hvKpand cKp, further underscoring the need for preventive and effective immunotherapies. Two distinct surface polysaccharides have gained traction as vaccine candidates againstK. pneumoniae: capsular polysaccharide and the O-antigen of lipopolysaccharide. While both targets have practical advantages and disadvantages, it remains unclear which of these antigens included in a vaccine would provide superior protection against matchedK. pneumoniaestrains. Here, we report the production of two bioconjugate vaccines, one targeting the K2 capsular serotype and the other targeting the O1 O-antigen. Using murine models, we investigated whether these vaccines induced specific antibody responses that recognize K2:O1K. pneumoniaestrains. While each vaccine was immunogenic in mice, both cKpand hvKpstrains exhibited decreased O-antibody binding in the presence of capsule. Further, O1 antibodies demonstrated decreased killing in serum bactericidal assays with encapsulated strains, suggesting that the presence ofK. pneumoniaecapsule blocks O1-antibody binding and function. Finally, the K2 vaccine outperformed the O1 vaccine against both cKpand hvKpin two different murine infection models. These data suggest that capsule-based vaccines may be superior to O-antigen vaccines for targeting hvKpand some cKpstrains, due to capsule blocking the O-antigen.Significance StatementCurrently there are no licensed vaccines targetingK. pneumoniae, but several are in development. Two prominentK. pneumoniaesurface polysaccharides (capsule and O-antigen) represent attractive vaccine targets; however, the relative efficacy of these potential vaccines againstK. pneumoniaestrains has not been directly compared. To inform future vaccine development, we evaluate two bioconjugate vaccines (targeting either capsule or O-antigen) demonstrating that each are immunogenic in murine models. However, we find thatK. pneumoniaecapsule largely inhibits recognition by antibodies raised against O-antigen. Further, we demonstrate that a capsule-based vaccine outperforms an O-antigen vaccine against both cKpand hvKpin murine models of pneumonia and bacteremia, suggesting that capsule-based vaccines offer superior protection from someK. pneumoniaeinfections.