Vaccines for Klebsiella

The goal of Research Project 3 in the "Immunization against Multidrug-resistant Pathogens: Activating T Cell Immunity" Center of Excellence for Translational Research (IMPACT-CETR) is to develop a quadrivalent Klebsiella pneumoniae vaccine based on conserved proteins that elicit protective Th17 cells and antibodies. K. pneumoniae is the third leading cause of hospital-acquired pneumonia and the second leading cause of bloodstream infections, with a high incidence of serious infections in patients who are immunocompromised individuals (e.g., diabetics, solid organ transplant recipients) or who require mechanical ventilation. This team was the first group to identify lymphocyte-derived IL-17 as a major cytokine mediating lung immunity to Gram- negative bacteria such as K. pneumoniae. This confirmed that Th17 cells provide immunity against clades of organisms and thus may serve as major targets for novel and effective vaccine strategies. Advancing a vaccine candidate into the clinic requires optimizing adjuvant-antigen combinations, and routes of delivery, that generate Th17 responses in the nose/lung. Mucosal delivery of recombinant OMPs from serotype 2 K. pneumoniae, along with the unique LT-based adjuvant LTA1, confers serotype-independent Th17 immunity against hypervirulent K1 K. pneumoniae. Four K. pneumoniae OMP candidate antigens are immunogenic in mice and elicit both Th17 and IgA/IgG antibody responses. The objective of this project is to identify the best delivery route and the best adjuvant to prevent both lung infection and bacteremia in pre-clinical murine and non-human primate (NHP) models. The hypothesis is that the development of multivalent OMP combinatorial vaccine with LTA1 adjuvant will elicit mucosal Th17 memory cells that confer serotype-independent immunity to K. pneumoniae. Aim 1 is to compare immunization routes and adjuvants of the lead quadrivalent antigen formulation in murine models. Aim 2 is to test the role of humoral and type 17 immunity in protection in wild- type mice and transgenic/knock-out models of transplant immunosuppression. Aim 3 is to test immunogenicity and vaccine effect in an established NHP model of K. pneumoniae infection. Successful completion of this project will provide important evidence in support of a data package for a potential FDA IND application for a quadrivalent K. pneumoniae vaccine that can move forward to human clinical trials.