An intranasal bivalent vaccine induces antigen-specific humoral and Th1/Th17 cellular immunity and protects young and aged mice against MRSA and Pseudomonas aeruginosa skin and soft tissue infections

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(MRSA) and carbapenem-resistant PA have rendered standard antibiotics less effective. Unfortunately, there are currently no licensed vaccines for either pathogen. To address this need, we developed a bivalent intranasal (IN) vaccine formulation combining L-PaF, a fusion of PA T3SS proteins PcrV and PopB, with the mucosal adjuvant LTA1, NEAT2 (N2), the protective heme-transporting domain of SA IsdB protein, and a novel TLR-4 agonist, which is a detoxified lipid A analog designated Bacterial Enzymatic Combinatorial Chemistry 438 (BECC438b), formulated in an oil-in-water medImmune emulsion (ME). Mice immunized with L-PaF/ME/N2/BECC438b generated robust antigen-specific IgG and IgA responses, which correlated with strong opsonophagocytic killing of both MRSA and PA strains. Vaccination also induced interleukin IL-17A, IL-2, and IL-22 responses in spleen cells from both young and elderly mice, supporting Th1/Th17-mediated immunity. In stringent murine SSTI models, immunized animals exhibited significantly reduced dermonecrosis, abscess volume, and bacterial burden, with approximately a 10-fold reduction in abscess CFUs compared to non-immunized controls. Notably, significant protection was observed in both young and elderly mice despite age-related immunosenescence, with elderly vaccinated animals showing substantially reduced abscess formation and bacterial burden relative to non-immunized controls. These results suggest that the bivalent L-PaF/ME/N2/BECC438b formulation has potential as a broad-spectrum vaccine against both MRSA- and PA-mediated SSTIs across different age groups.