A heptavalent O-antigen bioconjugate vaccine exhibits differential functional antibody responses against diverse Klebsiella pneumoniae isolates

Klebsiella pneumoniae is a concerning pathogen that is now the leading cause of neonatal sepsis and is increasingly difficult to treat due to heightened antibiotic resistance. Thus, there is an urgent need for preventive and effective immunotherapies targeting K. pneumoniae. Vaccination represents a tractable approach to combat this resistant bacterium in some settings; however, there is currently not a licensed K. pneumoniae vaccine available. K. pneumoniae surface polysaccharides, including the terminal O-antigen polysaccharides of lipopolysaccharide, have long been attractive candidates for vaccine inclusion. Herein we describe the generation of a bioconjugate vaccine targeting seven of the predominant O-antigen subtypes in K. pneumoniae. Each of the seven bioconjugates were immunogenic in isolation, with limited cross-reactivity among subtypes. Vaccine-induced antibodies demonstrated varying degrees of binding to a wide variety of K. pneumoniae strains, including suspected hypervirulent strains, all expressing different O-antigen and capsular polysaccharide combinations. Further, sera from vaccinated mice induced complement-mediated killing of many of these K. pneumoniae strains. Finally, we found that increased quantity of capsule interferes with O-antigen antibodies ability to bind and mediate killing of some K. pneumoniae strains, including those carrying hypervirulence-associated genes. Taken together, these data indicate that this novel heptavalent O-antigen bioconjugate vaccine formulation exhibits promising efficacy against some, but not all, K. pneumoniae isolates.