Saturday, November 23, 2024
11/23/2024
PROJECT SUMMARY Vaccination is the greatest public health achievement of our time. With an explosion of antibiotic resistance, new vaccines against multi-drug resistant (MDR) bacterial pathogens are more important than ever. Pseudomonas aeruginosa (Pa) is an opportunistic human pathogen that causes severe infections in patients with cystic fibrosis (CF), burns, severe wounds, pneumonia, as well as critically ill patients who require intubation or catheterization. Clearing Pa has become problematic as it has become increasingly antibiotic resistant. This is exacerbated by the fact that the biggest risk factor for negative outcomes associated with MDR Pa is advanced age. After 60, there is a significant increase in morbidity and mortality resulting from MDR Pa. While there are Pa vaccines in development, none are licensed. Like many Gram-negative pathogens, Pa strains of the PAO1/PA14-clades possess a type III secretion system (T3SS), a virulence factor that allows avoidance of host innate immunity and is required for the onset of infection. Structurally resembling a molecular syringe with an external needle, the T3SS apparatus (T3SA) provides an energized conduit from the bacterial cytoplasm into the host cell for transporting effector proteins that mediate key aspects of infection. A needle tip protein and the first of two translocator proteins localize to the distal end of the T3SA needle to mediate host cell contact. These proteins, PcrV and PopB, respectively, are required for pathogenesis and are 95-98% conserved among Pa. We have fused PcrV and PopB to give PaF. After demonstrating the protective efficacy of PaF, we genetically fused LTA1, the active moiety of labile toxin from ETEC, to the N-terminus of PaF (L-PaF). L-PaF reduces mouse and rat lung burdens significantly. When compared to PBS-vaccinated mice, L-PaF-vaccinated mice possessed significantly higher OPK activity in the sera and elevated levels of IL-17 were secreted from lung cells. Recently, Pa outliers have been identified that are devoid of the T3SS entirely and use ExlA to disrupt host cell membranes. Thus, we have added ExlA to our L-PaF (L-PaFE) emulsion and have demonstrated protection in PAO1/14/7 clades when delivered intranasally. Furthermore, we have added BECC438, a novel monophosphoryl lipid A (MPL) biosimilar (a TLR4 agonist), to increase OPK activity (L-PaFEB438). The goal of the R01 is to continue to develop our broadly protective Pa vaccine formulation by assessing the protective immune response in rodent models. Knowing the vaccine efficacy and immune response in these models will allow us to finalize the vaccine formulation and the demonstrate the potential utility of that formulation in humans.
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