Immunization against Multidrug-resistant Pathogens: Activating T Cell Immunity (IMPACT-CETR)

Overall Project Abstract The overall focus of the “Immunization against Multidrug-resistant Pathogens: Activating T Cell Immunity” Center of Excellence for Translational Research (IMPACT-CETR) is to advance promising multicomponent vaccines for Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae. These are among the most important bacterial pathogens that cause severe clinical disease and death and yet are becoming increasingly resistant to the most effective antibiotics. The overarching goal of this IMPACT-CETR is to harness the collaborative team’s complementary expertise in immunology, bacteriology, bioinformatics, primatology, vaccine development, and antigen-adjuvant formulations to achieve three deliverables: 1) novel multicomponent vaccines optimized for bacterial proteins and/or polysaccharides that elicit broad and potent serotype- independent protection against S. aureus, P. aeruginosa, and K. pneumoniae infections, including with resistant and MDR clinical isolates; 2) defined key mechanisms of host protection and biomarkers of vaccine efficacy; and 3) nonhuman primate (NHP) models to characterize immunogenicity and surrogate markers of protection. The proposed vaccine components are well-characterized, some are chemically defined, and all are designed for feasible scale-up and manufacture. The three research projects in this CETR are bonded by the theme that tissue-resident memory T cell responses, particularly tissue-resident Th17 cells, are critical for protective vaccines against these pathogens. The translational research projects will develop countermeasures to prevent/reduce disease caused by key resistant and MDR bacterial pathogens. Project 1 addresses a multicomponent S. aureus vaccine formulated with conserved protein antigens using the new and innovative Multiple Antigen Presenting System (MAPS) platform wherein fusion proteins of the avidin derivative rhizavidin with conserved S. aureus protein antigens are complexed to a biotinylated polysaccharide to generate protective B- and T-cells. Project 2 addresses a multicomponent P. aeruginosa MAPS vaccine based on the serotype- independent P. aeruginosa biofilm polysaccharide Psl and its critical lipid epitope, combined with conserved protein antigens including the Th17-eliciting antigen PopB. Project 3 addresses a quadrivalent K. pneumoniae vaccine based on conserved proteins that elicit protective Th17 cells and antibodies. Vaccine candidates will be tested in wild-type and transgenic and/or knock-out mice and in non-human primates. These projects will be supported by an administrative core and three scientific cores that focus on bioinformatics, transgenic mouse models for mechanistic studies, and NHP studies. The expected milestone for each project is the development of a preclinical data package that would pave the way for subsequent IND applications and clinical trials.