A heptavalent O-antigen bioconjugate vaccine exhibits differential functional antibody responses against diverseKlebsiella pneumoniaeisolates

Abstract

Klebsiella pneumoniaeis 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 targetingK. pneumoniae. Vaccination represents a tractable approach to combat this resistant bacterium in some settings; however, there is currently not a licensedK. pneumoniaevaccine available.K. pneumoniaesurface 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 inK. 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 ofK. pneumoniaestrains, 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 theseK. pneumoniaestrains. Finally, we found that increased quantity of capsule interferes with O-antigen antibodies’ ability to bind and mediate killing of someK. pneumoniaestrains, 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. pneumoniaeisolates.

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

“…Studies have highlighted the importance of targeting specific O types, such as O1, O2, and O3b, in vaccine development strategies due to their high prevalence and association with disease manifestation [13]. 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].…”

Klebsiella pneumoniae O-polysaccharide biosynthesis highlights the diverse organization of catalytic modules in ABC transporter-dependent glycan assembly

“…In addition, the development of glycoengineering strategies to produce glycans for biomedical and other applications in heterologous hosts is greatly facilitated by understanding the classes of proteins and functions required to generate the authentic glycan product. Glycoengineering is currently being employed to pursue immunotherapeutic approaches exploiting capsular polysaccharides ( 78 ) and OPSs ( 18 , 79 ) from K. pneumoniae . The work described here will facilitate the application of such strategies to a broader range of K. pneumoniae serotypes.…”

“…Certain serotypes are highly represented in clinical isolates, with recent assessments estimating that serotype O1, the O2 and O3 serogroups (groups of serotypes possessing related OPS structures with some shared epitopes), together with serotype O5, constitute at least 75% of global isolates ( 5 , 8 , 9 , 10 , 11 ). Immunotherapeutic strategies targeting individual O antigens, and combinations of O antigens have proved effective in animal challenge experiments and serum killing tests with some isolates ( 12 , 13 , 14 , 15 , 16 , 17 , 18 ). However, capsular polysaccharides reduce protection from OPS-directed antibodies, particularly in hypervirulent isolates and antibodies against selected capsular types are protective in animal models ( 19 , 20 ).…”

Geographical distribution, disease association and diversity of Klebsiella pneumoniae K/L and O antigens in India: roadmap for vaccine development

“…Studies have highlighted the importance of targeting specific O types, such as O1, O2, and O3b, in vaccine development strategies due to their high prevalence and association with disease manifestation [20]. A recent study reported a heptavalent O-antigen bioconjugate vaccine [68] which exhibits promising efficacy against some, but not all, K. pneumoniae isolates. While some studies [69] 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 [69, 70].…”