Kinetic analysis and evaluation of the mechanisms involved in the resolution of experimental nontypeable Haemophilus influenzae-induced otitis media after transcutaneous immunization.

Transcutaneous immunization (TCI) is a simple and needle-free method with which to induce protective immune responses. Using a chinchilla model of nontypeable Haemophilus influenzae (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.

Respiratory syncytial virus promotes Moraxella catarrhalis-induced ascending experimental otitis media.

Otitis media (OM) is a polymicrobial disease wherein prior or concurrent infection with an upper respiratory tract virus plays an essential role, predisposing the middle ear to bacterial invasion. In episodes of acute bacterial OM, respiratory syncytial virus (RSV) is the most commonly isolated virus and thus serves as an important co-pathogen. Of the predominant bacterial agents of OM, the pathogenesis of disease due to Moraxella catarrhalis is the least well understood.

Bacterial biofilms in the upper airway - evidence for role in pathology and implications for treatment of otitis media.

Understanding the nature of the biofilm component in the pathogenesis of otitis media [OM] will likely have a meaningful influence on the development of novel strategies to prevent and/or treat this highly prevalent pediatric disease. The design of vaccine candidates for OM that currently focus on preventing colonization are predicated on the assumption that by reducing the burden of bacteria present in the pediatric nasopharynx, one could reduce or eliminate the likelihood of retrograde ascension of the Eustachian tube by bacteria from the nasopharynx to the middle ear. If effective, this strategy could prevent biofilms from ever forming in the middle ear.

Transcutaneous immunization as preventative and therapeutic regimens to protect against experimental otitis media due to nontypeable Haemophilus influenzae.

We have developed three nontypeable Haemophilus influenzae (NTHI) adhesin-derived immunogens that are significantly efficacious against experimental otitis media (OM) due to NTHI when delivered parenterally. We now expanded our preventative immunization strategies to include transcutaneous immunization (TCI) as a less invasive, but potentially equally efficacious, regimen to prevent OM due to NTHI. Additionally, we examined the potential of TCI as a therapeutic immunization regimen to resolve ongoing experimental OM.

Epitope mapping immunodominant regions of the PilA protein of nontypeable Haemophilus influenzae (NTHI) to facilitate the design of two novel chimeric vaccine candidates.

We designed and tested three PilA-derived vaccine candidates in a chinchilla model of ascending nontypeable Haemophilus influenzae (NTHI)-induced otitis media (OM). Delivery of antiserum directed against each immunogen conferred varying degrees of protection. Presentation of a B-cell epitope derived from the OMP P5 adhesin at the N-terminus of recombinant soluble PilA protein (as opposed to the C-terminus), resulted in a protective chimeric immunogen that combined epitopes from two distinct NTHI adhesins (type IV pili and OMP P5).

A member of the cathelicidin family of antimicrobial peptides is produced in the upper airway of the chinchilla and its mRNA expression is altered by common viral and bacterial co-pathogens of otitis media.

Cationic antimicrobial peptides (AMPs), a component of the innate immune system, play a major role in defense of mucosal surfaces against a wide spectrum of microorganisms such as viral and bacterial co-pathogens of the polymicrobial disease otitis media (OM). To further understand the role of AMPs in OM, we cloned a cDNA encoding a cathelicidin homolog (cCRAMP) from upper respiratory tract (URT) mucosae of the chinchilla, the predominant host used to model experimental OM. Recombinant cCRAMP exhibited alpha-helical secondary structure and killed the three main bacterial pathogens of OM.