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.

Geographical distribution, disease association and diversity ofKlebsiella pneumoniaeKL and O antigens in India: roadmap for vaccine development

“…A recent study reported a heptavalent O-antigen bioconjugate vaccine [56] which exhibits promising efficacy against some, but not all, K. pneumoniae isolates. While some studies [57] say that O antigen is accessible by antibodies irrespective of the capsule type other studies are highlighting that hyperproduction of CPS may inhibit the vaccine-induced O-antigen antibody binding [57]; [58]. A more recent study evaluating monoclonal antibodies against K. pneumoniae ST147 NDM-1 , concluded that highly bactericidal anti O-antigen antibodies are not protective against this hypervirulent and pan drug-resistant strain ( [45]).…”

Antibody responses inKlebsiella pneumoniaebloodstream infection: a cohort study

“…OPS is a candidate vaccine antigen for Kpn 5,14,15 and is immunogenic in mice and rabbits [24][25][26] OPS vaccines have variable efficacy in animal models, with protection dependent on the type of model (e.g. the type of animal, the type of immunization, the route of infection, and the type of challenge strain 9,[27][28][29] ). In contrast, there are scant data on the immunogenicity of OPS in humans.…”

“…14 However, there are gaps in our understanding of the role of OPS antibody responses in immunity to Kpn. First, while OPS-based vaccines are protective in some mouse models of invasive Kpn, 9 human antibody responses to OPS have not been characterized. Whether Kpn OPS is immunogenic in humans at risk for invasive Kpn is highly relevant to vaccine development.…”

Longitudinal analysis within one hospital in sub-Saharan Africa over 20 years reveals repeated replacements of dominant clones ofKlebsiella pneumoniaeand stresses the importance to include temporal patterns for vaccine design considerations

“…Selection pressure might not directly drive evolution given that Kpn is not human restricted but could likely select for strains with currently less abundant O-types to increase in prevalence. Further, there remains an open question of how accessible the O-antigens are to antibodies, which a recent study calls into question(46); we currently have very limited understanding what drives the extent of capsule expression per cell in non-hypermucoid isolates and how different stages of the infection impact this. It is known from in vitro studies that capsule expression even in the same experimental setting can differ widely within clonal lineages, which also impacts the bacterial ability to escape the complement system(47).…”