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

Abstract

Klebsiella pneumoniae presents as two circulating pathotypes: classical K. pneumoniae (cKp) and hypervirulent K. pneumoniae (hvKp). Classical isolates are considered urgent threats due to their antibiotic resistance profiles, while hvKp isolates have historically been antibiotic susceptible. Recently, however, increased rates of antibiotic resistance have been observed in both hvKp and cKp, further underscoring the need for preventive and effective immunotherapies. Two distinct surface polysaccharides have gained traction as vaccine candidates against K. 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 matched K. pneumoniae strains. 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:O1 K. pneumoniae strains. While each vaccine was immunogenic in mice, both cKp and hvKp strains 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 of K. pneumoniae capsule blocks O1-antibody binding and function. Finally, the K2 vaccine outperformed the O1 vaccine against both cKp and hvKp in two different murine infection models. These data suggest that capsule-based vaccines may be superior to O-antigen vaccines for targeting hvKp and some cKp strains, due to capsule blocking the O-antigen. Significance StatementCurrently there are no licensed vaccines targeting K. pneumoniae, but several are in development. Two prominent K. pneumoniae surface polysaccharides (capsule and O-antigen) represent attractive vaccine targets; however, the relative efficacy of these potential vaccines against K. pneumoniae strains 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 that K. pneumoniae capsule largely inhibits recognition by antibodies raised against O-antigen. Further, we demonstrate that a capsule-based vaccine outperforms an O-antigen vaccine against both cKp and hvKp in murine models of pneumonia and bacteremia, suggesting that capsule-based vaccines offer superior protection from some K. pneumoniae infections.