Vaccine, 25 July 2013, Vol.31(34), pp.3417-3426
► Transcutaneous immunization with chimV4+ dmLT resolved ongoing NTHI-induced experimental OM. ► Significant reduction in signs of OM, NTHI concentration and mucosal biofilms in the middle ear was achieved. ► Activated DCs, polyfunctional T-cells and host defense peptide contributed to rapid resolution. ► Immunogen-specific IgG in middle ear fluids also contributed to eradication of NTHI. ► Transcutaneous immunization is a simple strategy to induce efficacious immune responses. Transcutaneous immunization (TCI) is a simple and needle-free method with which to induce protective immune responses. Using a chinchilla model of nontypeable (NTHI)-induced otitis media (OM), we examined the efficacy afforded by TCI with a novel chimeric immunogen called ‘chimV4’ which targets two critical adhesins expressed by NTHI, outer membrane protein P5 and the majority subunit of NTHI Type IV pilus, PilA. Experimental OM was first established in cohorts of animals, and then TCI performed via a therapeutic immunization regime by rubbing vaccine formulations on hydrated pinnae. The kinetics of resolution of established experimental disease was evaluated by clinically-relevant assessments of OM, bacterial culture of planktonic and adherent NTHI within the middle ear and gross examination of the relative amount of NTHI mucosal biofilms within the middle ear space. Within seven days after primary TCI, a significant reduction in the signs of OM, significantly fewer NTHI adherent to the middle ear mucosa and significant resolution of mucosal biofilms was detected in animals that received chimV4+ the adjuvant LT(R192G-L211A), compared to animals administered LT(R192G-L211A) alone or saline by TCI ( 〈 0.05) with eradication of NTHI within an additional seven days. The mechanism for rapid disease resolution involved efflux of activated dermal dendritic cells from the pinnae after TCI, secretion of factors chemotactic for CD4 T-cells, induction of polyfunctional IFNγ- and IL-17-producing CD4 T-cells and secretion of host defense peptide within the middle ear. These data support TCI as a therapeutic intervention against experimental NTHI-induced OM and begin to elucidate the host response to immunization by this noninvasive regimen.
Chimv4 ; Omp P5 ; Type IV Pilus ; Chinchilla ; Mucosal Biofilm ; Dendritic Cell ; Dmlt ; Medicine ; Biology ; Veterinary Medicine ; Pharmacy, Therapeutics, & Pharmacology
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