Otitis media (OM), or middle ear infection, is a highly prevalent pediatric disease worldwide, ranking first in reasons why children make physician's office and emergency room visits, undergo surgery requiring general anesthesia, and experience hearing loss. The widely held practice of prescribing of broad-spectrum antibiotics to treat OM has been a major driving force behind the sobering emergence of multiple antibiotic resistant strains of bacteria among those that cause OM. Since the recent licensure of a 7-valent vaccine directed against Streptococcus pneumoniae, the relative proportion of cases of OM due to our studied microorganism (nontypeable Haemophilus influenzae or NTHI) has increased significantly. NTHI are now credited with approximately 40% of all cases of acute OM, yet remain the predominant causative agent of chronic OM, recurrent OM, and OM in children who fail treatment. There is thus a pressing need to develop better methods to manage OM, preferably via the development of vaccines to prevent middle ear infections due to NTHI. We have designed and extensively tested vaccine candidates for the prevention of NTHI-induced OM that have been derived from primarily two bacterial adhesins/virulence determinants: the OMP P5-homologous adhesin (or OMP P5) and the type IV twitching pilus (or Tfp). These candidates have shown significant promise to date in pre-clinical efficacy trials, however, there are as yet a few gaps in the understanding required to complete their development. Thereby, herein, we propose two complementary specific aims to gain this needed enhanced understanding, as well as a third integrated specific aim designed to translate the success realized to date using traditional immunization approaches for these vaccine candidates to methods of delivery that are novel and non-invasive, and thereby have a significant opportunity to improve the health of children worldwide.
In Specific Aim 1, we will determine niche-specific and concordant vs. discordant expression of our targeted virulence determinants, as well as define the cognate receptor(s) for these ligands and determine their relative spatial distribution in the uppermost airway.
In Specific Aim 2, we will determine the biological mechanisms by which these candidate antigens have induced significant protection against experimental NTHI-induced OM when delivered parenterally (e.g. the correlates of immune protection).
In Specific Aim 3, we will develop and assess three novel non-invasive delivery methods (intranasal, transcutaneous and sublingual) for these promising vaccine candidates and determine their relative protective efficacy when delivered via each of these routes.
In 1990, there were 24.5 million physician's office visits made for middle ear infections [or otitis media (OM)] in The United States alone, representing a greater than 200% increase over that reported a decade prior. Moreover, worldwide it is reported that between 65 and 330 million children suffer from chronic secretory OM, 60% of which have an associated hearing loss from this disease state which is characterized by chronically draining ears and can extend over years. The most cost-effective way to manage this highly prevalent pediatric disease, and have a transformational effect on the health of children worldwide, is through the development of novel vaccines to prevent OM, which is the long-standing focus of our research program.
|Mokrzan, Elaine M; Novotny, Laura A; Brockman, Kenneth L et al. (2018) Antibodies against the Majority Subunit (PilA) of the Type IV Pilus of Nontypeable Haemophilus influenzae Disperse Moraxella catarrhalis from a Dual-Species Biofilm. MBio 9:|
|Brockman, Kenneth L; Azzari, Patrick N; Branstool, M Taylor et al. (2018) Epigenetic Regulation Alters Biofilm Architecture and Composition in Multiple Clinical Isolates of Nontypeable Haemophilus influenzae. MBio 9:|
|Novotny, Laura A; Clements, John D; Goodman, Steven D et al. (2017) Transcutaneous Immunization with a Band-Aid Prevents Experimental Otitis Media in a Polymicrobial Model. Clin Vaccine Immunol 24:|
|Das, Jayajit; Mokrzan, Elaine; Lakhani, Vinal et al. (2017) Extracellular DNA and Type IV Pilus Expression Regulate the Structure and Kinetics of Biofilm Formation by Nontypeable Haemophilus influenzae. MBio 8:|
|Mokrzan, Elaine M; Ward, Michael O; Bakaletz, Lauren O (2016) Type IV Pilus Expression Is Upregulated in Nontypeable Haemophilus influenzae Biofilms Formed at the Temperature of the Human Nasopharynx. J Bacteriol 198:2619-30|
|Novotny, Laura A; Bakaletz, Lauren O (2016) Intercellular adhesion molecule 1 serves as a primary cognate receptor for the Type IV pilus of nontypeable Haemophilus influenzae. Cell Microbiol 18:1043-55|
|Brockman, Kenneth L; Jurcisek, Joseph A; Atack, John M et al. (2016) ModA2 Phasevarion Switching in Nontypeable Haemophilus influenzae Increases the Severity of Experimental Otitis Media. J Infect Dis 214:817-24|
|Shimoyama, Mary; Smith, Jennifer R; De Pons, Jeff et al. (2016) The Chinchilla Research Resource Database: resource for an otolaryngology disease model. Database (Oxford) 2016:|
|Atack, John M; Winter, Linda E; Jurcisek, Joseph A et al. (2015) Selection and Counterselection of Hia Expression Reveals a Key Role for Phase-Variable Expression of Hia in Infection Caused by Nontypeable Haemophilus influenzae. J Infect Dis 212:645-53|
|Novotny, Laura A; Jurcisek, Joseph A; Ward Jr, Michael O et al. (2015) Antibodies against the majority subunit of type IV Pili disperse nontypeable Haemophilus influenzae biofilms in a LuxS-dependent manner and confer therapeutic resolution of experimental otitis media. Mol Microbiol 96:276-92|
Showing the most recent 10 out of 37 publications