Antibody mediated immunity against Klebsiella pneumoniae

PROJECT SUMMARY Klebsiella pneumoniae has emerged as a critical human pathogen in the United States and globally. In the United States, K. pneumoniae is the third most common cause of hospital-acquired infections and accounts for 20% of deaths attributable to antibiotic-resistant bacteria. In low- and middle-income countries, K. pneumoniae is a leading cause of childhood mortality and neonatal sepsis. Despite the rising importance of this pathogen, there are no U.S. Food and Drug Administration or World Health Organization-approved vaccines for K. pneumoniae. Our project is designed to address three critical knowledge gaps related to the development of Klebsiella vaccines. First, although a quadrivalent O-antigen vaccine for K. pneumoniae has been proposed, there is insufficient evidence to show that the inclusion of only four O-types would provide sufficient protection against the nine structural subtypes of these K. pneumoniae O-antigens. To address this knowledge gap, we will determine whether human infection with each K. pneumoniae O-antigen subtype results in cross-specific antibody responses against other K. pneumoniae subtypes. This research will provide new and detailed information on the specificity of human O-antigen responses to K. pneumoniae and inform the antigenic composition of a K. pneumoniae O-antigen vaccine. Second, our proposed experiments will determine which K. pneumoniae antigens contribute to functional human antibody responses the bacterium. Specifically, we will determine whether antibody responses to both the capsular (K-) and O-antigens the bacteria through interactions with phagocytic cells and complement. This is important because such functional responses are likely to mediate protection against K. pneumoniae infection. Third, we will determine which types of antibodies are associated with protection against intestinal colonization with K. pneumoniae. If we identify antibodies that are correlated with protection against K. pneumoniae, this will represent a groundbreaking finding and aid in the development of vaccines for this important pathogen. In summary, we expect the proposed studies to generate fundamental insights into immunity against this pathogen and aid in the development and assessment of K. pneumoniae vaccines. Our proposed work will provide critical data to inform the antigenic composition of K. pneumoniae vaccines and new proxy measures to assess vaccine efficacy in pre-clinical and early phase vaccine trials. These insights are urgently needed to address the growing global threat of antibiotic-resistant K. pneumoniae.