{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T23:39:33Z","timestamp":1788910773861,"version":"build-2803163510"},"reference-count":334,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T00:00:00Z","timestamp":1706054400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>Otitis media is an inflammatory disorder of the middle ear caused by airways-associated bacterial or viral infections. It is one of the most common childhood infections as globally more than 80% of children are diagnosed with acute otitis media by 3\u2009years of age and it is a common reason for doctor\u2019s visits, antibiotics prescriptions, and surgery among children. Otitis media is a multifactorial disease with various genetic, immunologic, infectious, and environmental factors predisposing children to develop ear infections. <jats:italic>Streptococcus pneumoniae, Haemophilus influenzae,<\/jats:italic> and <jats:italic>Moraxella catarrhalis<\/jats:italic> are the most common culprits responsible for acute otitis media. Despite the massive global disease burden, the pathogenesis of otitis media is still unclear and requires extensive future research. Antibiotics are the preferred treatment to cure middle ear infections, however, the antimicrobial resistance rate of common middle ear pathogens has increased considerably over the years. At present, pneumococcal and influenza vaccines are administered as a preventive measure against otitis media, nevertheless, these vaccines are only beneficial in preventing carriage and\/or disease caused by vaccine serotypes. Otitis media caused by non-vaccine serotype pneumococci, non-typeable <jats:italic>H. influenza,<\/jats:italic> and <jats:italic>M. catarrhalis<\/jats:italic> remain an important healthcare burden. The development of multi-species vaccines is an arduous process but is required to reduce the global burden of this disease. Many novel vaccines against <jats:italic>S. pneumoniae,<\/jats:italic> non-typeable <jats:italic>H. influenza,<\/jats:italic> and <jats:italic>M. catarrhalis<\/jats:italic> are in preclinical trials. It is anticipated that these vaccines will lower the disease burden and provide better protection against otitis media. To study disease pathology the rat, mouse, and chinchilla are commonly used to induce experimental acute otitis media to test new therapeutics, including antibiotics and vaccines. Each of these models has its advantages and disadvantages, yet there is still a need to develop an improved animal model providing a better correlated mechanistic understanding of human middle ear infections, thereby underpinning the development of more effective otitis media therapeutics. This review provides an updated summary of current vaccines against otitis media, various animal models of otitis media, their limitations, and some future insights in this field providing a springboard in the development of new animal models and novel vaccines for otitis media.<\/jats:p>","DOI":"10.3389\/fmicb.2024.1345027","type":"journal-article","created":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T04:42:58Z","timestamp":1706071378000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":26,"title":["Otitis media: recent advances in otitis media vaccine development and model systems"],"prefix":"10.3389","volume":"15","author":[{"given":"Ayesha","family":"Zahid","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer C.","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I. 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Med. Microbiol."},{"key":"ref7","first-page":"362","article-title":"Pattern of bacterial isolates in the middle ear discharge of patients with chronic suppurative otitis media in a tertiary hospital in north Central Nigeria","volume":"12","author":"Afolabi","year":"2012","journal-title":"Afr. Health Sci."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"e00385","DOI":"10.1016\/j.btre.2019.e00385","article-title":"Protective responses of an engineered PspA recombinant antigen against Streptococcus pneumoniae","volume":"24","author":"Akbari","year":"2019","journal-title":"Biotechnol. Rep."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"5683","DOI":"10.1128\/iai.62.12.5683-5688.1994","article-title":"Immunization of mice with pneumolysin toxoid confers a significant degree of protection against at least nine serotypes of Streptococcus pneumoniae","volume":"62","author":"Alexander","year":"1994","journal-title":"Infect. Immun."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/0165-5876(91)90001-r","article-title":"What is an 'otitis-prone' child?","volume":"21","author":"Alho","year":"1991","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1080\/23744235.2018.1463451","article-title":"Antibody responses against Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in children with acute respiratory infection with or without nasopharyngeal bacterial carriage","volume":"50","author":"Andrade","year":"2018","journal-title":"Infect. Dis."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1016\/S2213-2600(21)00502-6","article-title":"Non-typeable Haemophilus influenzae\u2013Moraxella catarrhalis vaccine for the prevention of exacerbations in chronic obstructive pulmonary disease: a multicentre, randomised, placebo-controlled, observer-blinded, proof-of-concept, phase 2b trial","volume":"10","author":"Andreas","year":"2022","journal-title":"Lancet Respir. Med."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1128\/mBio.01401-18","article-title":"Nontypeable Haemophilus influenzae Lipooligosaccharide expresses a terminal Ketodeoxyoctanoate in vivo, which can be used as a target for bactericidal antibody","volume":"9","author":"Apicella","year":"2018","journal-title":"MBio"},{"key":"ref14","first-page":"1835","article-title":"Pathogenesis of Sendai virus infection in mice","volume":"32","author":"Appell","year":"1971","journal-title":"Am. J. Vet. Res."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1128\/mBio.00102-10","article-title":"Indirect pathogenicity of Haemophilus influenzae and Moraxella catarrhalis in polymicrobial otitis media occurs via interspecies quorum signaling","volume":"1","author":"Armbruster","year":"2010","journal-title":"MBio"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"5924","DOI":"10.1016\/j.vaccine.2022.08.053","article-title":"A detailed analysis of possible efficacy signals of NTHi-Mcat vaccine against severe COPD exacerbations in a previously reported randomised phase 2b trial","volume":"40","author":"Arora","year":"2022","journal-title":"Vaccine"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.ijporl.2010.09.024","article-title":"The effects of methylprednisolone, montelukast and indomethacine in experimental otitis media with effusion","volume":"75","author":"Aynali","year":"2011","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"3564","DOI":"10.1093\/hmg\/ddw202","article-title":"Ectodysplasin signalling deficiency in mouse models of hypohidrotic ectodermal dysplasia leads to middle ear and nasal pathology","volume":"25","author":"Azar","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.micpath.2016.06.033","article-title":"Recombinant C-terminal 311 amino acids of HapS adhesin as a vaccine candidate for nontypeable Haemophilus influenzae: a study on immunoreactivity in Balb\/C mouse","volume":"98","author":"Bafroee","year":"2016","journal-title":"Microb. Pathog."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"23403","DOI":"10.1074\/jbc.M114.579714","article-title":"Structure of pneumococcal peptidoglycan hydrolase LytB reveals insights into the bacterial cell wall remodeling and pathogenesis","volume":"289","author":"Bai","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1586\/erv.09.63","article-title":"Chinchilla as a robust, reproducible and polymicrobial model of otitis media and its prevention","volume":"8","author":"Bakaletz","year":"2009","journal-title":"Expert Rev. Vaccines"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"2746","DOI":"10.1128\/IAI.67.6.2746-2762.1999","article-title":"Protection against development of otitis media induced by nontypeable Haemophilus influenzae by both active and passive immunization in a chinchilla model of virus-bacterium superinfection","volume":"67","author":"Bakaletz","year":"1999","journal-title":"Infect. Immun."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"2765","DOI":"10.1128\/IAI.00079-07","article-title":"Moraxella catarrhalis strain O35E expresses two filamentous hemagglutinin-like proteins that mediate adherence to human epithelial cells","volume":"75","author":"Balder","year":"2007","journal-title":"Infect. Immun."},{"key":"ref24","article-title":"Vaccination with Moraxella catarrhalis MhaB1\/B2 proteins enhance clearance in a chinchilla nasopharyngeal colonization model","volume-title":"American Society for Microbiology general meeting","author":"Balder","year":"2011"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1093\/infdis\/jit242","article-title":"A new human colonization model for nontypeable Haemophilus influenzae","volume":"208","author":"Barenkamp","year":"2013","journal-title":"J. Infect. Dis."},{"key":"ref26","doi-asserted-by":"crossref","first-page":"S51","DOI":"10.1177\/0194599816639028","article-title":"Panel 4: report of the microbiology panel","volume":"156","author":"Barenkamp","year":"2017","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1016\/j.micpath.2017.07.025","article-title":"Recombinant truncated E protein as a new vaccine candidate against nontypeable H. influenzae: its expression and immunogenic evaluation","volume":"110","author":"Behrouzi","year":"2017","journal-title":"Microb. Pathog."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"417","DOI":"10.18502\/ijm.v12i5.4602","article-title":"Evaluation of immunological responses against outer membrane vesicles (OMV) of nontypeable Haemophilus influenzae using MPLA-CpG adjuvant as a vaccine candidate","volume":"12","author":"Behrouzi","year":"2020","journal-title":"Iran. J. Microbiol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"2264","DOI":"10.1016\/j.vaccine.2021.03.032","article-title":"Nasopharyngeal carriage of otitis media pathogens in infants receiving 10-valent non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10), 13-valent pneumococcal conjugate vaccine (PCV13) or a mixed primary schedule of both vaccines: a randomised controlled trial","volume":"39","author":"Beissbarth","year":"2021","journal-title":"Vaccine"},{"key":"ref30","doi-asserted-by":"crossref","DOI":"10.1093\/ofid\/ofz359.181","article-title":"2903. Post PCV13 dynamics of NonVaccine serotype (NVT): disproportionate increase of the additional PCV20 candidate serotypes in respiratory and invasive disease in young children","volume-title":"Open forum infectious diseases","author":"Ben-Shimol","year":"2019"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"1724","DOI":"10.1093\/cid\/ciu683","article-title":"Near-elimination of otitis media caused by 13-valent pneumococcal conjugate vaccine (PCV) serotypes in southern Israel shortly after sequential introduction of 7-valent\/13-valent PCV","volume":"59","author":"Ben-Shimol","year":"2014","journal-title":"Clin. Infect. Dis."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"1304","DOI":"10.1086\/382508","article-title":"Intranasal vaccination with recombinant P6 protein and adamantylamide dipeptide as mucosal adjuvant confers efficient protection against otitis media and lung infection by nontypeable Haemophilus influenzae","volume":"189","author":"Bertot","year":"2004","journal-title":"J. Infect. Dis."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"2668","DOI":"10.1128\/iai.65.7.2668-2675.1997","article-title":"Antigenic characterization and analysis of the human immune response to outer membrane protein E of Branhamella catarrhalis","volume":"65","author":"Bhushan","year":"1997","journal-title":"Infect. Immun."},{"key":"ref34","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1177\/0194599812449986","article-title":"Mouse models of otitis media: strengths and limitations","volume":"147","author":"Bhutta","year":"2012","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12866-019-1660-y","article-title":"The Moraxella catarrhalis phase-variable DNA methyltransferase ModM3 is an epigenetic regulator that affects bacterial survival in an in vivo model of otitis media","volume":"19","author":"Blakeway","year":"2019","journal-title":"BMC Microbiol."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/S0165-5876(97)00147-X","article-title":"Epidemiology and pathogenesis of chronic suppurative otitis media: implications for prevention and treatment","volume":"42","author":"Bluestone","year":"1998","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"7461","DOI":"10.1016\/j.vaccine.2012.10.076","article-title":"Safety and immunogenicity of pneumococcal protein vaccine candidates: monovalent choline-binding protein a (PcpA) vaccine and bivalent PcpA\u2013pneumococcal histidine triad protein D vaccine","volume":"30","author":"Bologa","year":"2012","journal-title":"Vaccine"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1097\/QCO.0b013e3283531b0f","article-title":"Use of pneumococcal polysaccharide vaccine in children: what is the evidence?","volume":"25","author":"Borrow","year":"2012","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1128\/IAI.68.2.796-800.2000","article-title":"Intranasal immunization of mice with a mixture of the pneumococcal proteins PsaA and PspA is highly protective against nasopharyngeal carriage of Streptococcus pneumoniae","volume":"68","author":"Briles","year":"","journal-title":"Infect. Immun."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"1694","DOI":"10.1086\/317602","article-title":"Immunization of humans with recombinant pneumococcal surface protein a (rPspA) elicits antibodies that passively protect mice from fatal infection with Streptococcus pneumoniae bearing heterologous PspA","volume":"182","author":"Briles","year":"","journal-title":"J. Infect. Dis."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"e40088","DOI":"10.1371\/journal.pone.0040088","article-title":"Respiratory syncytial virus promotes Moraxella catarrhalis-induced ascending experimental otitis media","volume":"7","author":"Brockson","year":"2012","journal-title":"PLoS One"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/j.anaerobe.2008.12.002","article-title":"The role of anaerobic bacteria in chronic suppurative otitis media in children: implications for medical therapy","volume":"14","author":"Brook","year":"2008","journal-title":"Anaerobe"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"1836","DOI":"10.1080\/21645515.2015.1039210","article-title":"Passive protection of mice against Streptococcus pneumoniae challenge by naturally occurring and vaccine-induced human anti-PhtD antibodies","volume":"11","author":"Brookes","year":"2015","journal-title":"Hum. Vaccin. Immunother."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"4610","DOI":"10.1016\/j.vaccine.2015.06.078","article-title":"Safety and immunogenicity of a trivalent recombinant PcpA, PhtD, and PlyD1 pneumococcal protein vaccine in adults, toddlers, and infants: a phase I randomized controlled study","volume":"33","author":"Brooks","year":"2015","journal-title":"Vaccine"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"5127","DOI":"10.1128\/IAI.73.8.5127-5136.2005","article-title":"Hag directly mediates the adherence of Moraxella catarrhalis to human middle ear cells","volume":"73","author":"Bullard","year":"2005","journal-title":"Infect. Immun."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1128\/iai.55.4.882-887.1987","article-title":"Antigenic diversity of lipooligosaccharides of nontypable Haemophilus influenzae","volume":"55","author":"Campagnari","year":"1987","journal-title":"Infect. Immun."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1097\/INF.0b013e3181c1bc48","article-title":"New patterns in the otopathogens causing acute otitis media six to eight years after introduction of pneumococcal conjugate vaccine","volume":"29","author":"Casey","year":"2010","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/S0165-5876(01)00641-3","article-title":"Histopathologic differences due to bacterial species in acute otitis media","volume":"63","author":"Cay\u00e9-Thomasen","year":"2002","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref49","year":"2019"},{"key":"ref50","year":"2020"},{"key":"ref51","first-page":"18","article-title":"Next generation vaccines: development of a novel Streptococcus pneumoniae multivalent protein vaccine","volume":"14","author":"Cecchini","year":"2015","journal-title":"Bioprocess. J."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.1128\/aac.42.6.1361","article-title":"In vivo efficacies of amoxicillin and cefuroxime against penicillin-resistant Streptococcus pneumoniae in a gerbil model of acute otitis media","volume":"42","author":"Cenjor","year":"1998","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"e0084618a","DOI":"10.1128\/IAI.00846-18a","article-title":"Corrected and republished from: \"a novel, multiple-antigen pneumococcal vaccine protects against lethal Streptococcus pneumoniae challenge\"","volume":"90","author":"Chan","year":"2022","journal-title":"Infect. Immun."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"1628","DOI":"10.1016\/j.vaccine.2010.12.076","article-title":"Novel method for non-invasive induction of a middle-ear biofilm in the rat","volume":"29","author":"Chaney","year":"2011","journal-title":"Vaccine"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"1900","DOI":"10.1128\/iai.64.6.1900-1905.1996","article-title":"Evaluation of purified UspA from Moraxella catarrhalis as a vaccine in a murine model after active immunization","volume":"64","author":"Chen","year":"1996","journal-title":"Infect. Immun."},{"key":"ref56","first-page":"204","article-title":"Cholesteatoma: spontaneous occurrence in the Mongolian gerbil Meriones unguiculatis","volume":"2","author":"Chole","year":"1981","journal-title":"Otol. Neurotol."},{"key":"ref57","doi-asserted-by":"publisher","first-page":"2161","DOI":"10.1001\/jama.2010.1651","article-title":"Diagnosis, microbial epidemiology, and antibiotic treatment of acute otitis media in children: a systematic review","volume":"304","author":"Coker","year":"2010","journal-title":"JAMA"},{"key":"ref58","doi-asserted-by":"publisher","first-page":"6148","DOI":"10.1016\/j.vaccine.2016.11.001","article-title":"Immunization with LytB protein of Streptococcus pneumoniae activates complement-mediated phagocytosis and induces protection against pneumonia and sepsis","volume":"34","author":"Corsini","year":"2016","journal-title":"Vaccine"},{"key":"ref59","doi-asserted-by":"publisher","first-page":"e1006969","DOI":"10.1371\/journal.pgen.1006969","article-title":"A mutation in Nischarin causes otitis media via LIMK1 and NF-\u03baB pathways","volume":"13","author":"Crompton","year":"2017","journal-title":"PLoS Genet."},{"key":"ref60","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1086\/344233","article-title":"Immunization with Haemophilus influenzae hap adhesin protects against nasopharyngeal colonization in experimental mice","volume":"186","author":"Cutter","year":"2002","journal-title":"J. Infect. Dis."},{"key":"ref61","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12864-019-6195-y","article-title":"ReVac: a reverse vaccinology computational pipeline for prioritization of prokaryotic protein vaccine candidates","volume":"20","author":"D\u2019Mello","year":"2019","journal-title":"BMC Genomics"},{"key":"ref62","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.heares.2008.05.010","article-title":"Change of middle ear transfer function in otitis media with effusion model of guinea pigs","volume":"243","author":"Dai","year":"2008","journal-title":"Hear. Res."},{"key":"ref63","article-title":"Change of cochlear mechanics in acute otitis media and otitis media with effusion","volume-title":"Association for Research in otolaryngology (ARO)-midwinter meeting","author":"Dai","year":"2009"},{"key":"ref64","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1016\/j.ijporl.2009.09.006","article-title":"Epidemiology, natural history, and risk factors: panel report from the ninth international research conference on otitis media","volume":"74","author":"Daly","year":"2010","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref65","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1177\/000348948209100118","article-title":"Comparative anatomy of eustachian tube and middle ear cavity in animal models for otitis media","volume":"91","author":"Daniel","year":"1982","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref66","doi-asserted-by":"publisher","first-page":"1416","DOI":"10.1016\/j.ijporl.2012.06.013","article-title":"Bacterial involvement in otitis media with effusion","volume":"76","author":"Daniel","year":"2012","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref67","doi-asserted-by":"publisher","first-page":"e01466","DOI":"10.1128\/mBio.01466-17","article-title":"Extracellular DNA and type IV pilus expression regulate the structure and kinetics of biofilm formation by nontypeable Haemophilus influenzae","volume":"8","author":"Das","year":"2017","journal-title":"MBio"},{"key":"ref68","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/j.anorl.2017.06.013","article-title":"Animal models of acute otitis media\u2013a review with practical implications for laboratory research","volume":"135","author":"Davidoss","year":"2018","journal-title":"Eur. Ann. Otorhinolaryngol. Head Neck Dis."},{"key":"ref69","doi-asserted-by":"publisher","first-page":"e36617","DOI":"10.5812\/jjm.36617","article-title":"Immunization with protein D from non-Typeable Haemophilus influenzae (NTHi) induced cytokine responses and bioactive antibody production","volume":"9","author":"Davoudi Vijeh Motlagh","year":"2016","journal-title":"Jundishapur J. Microbiol."},{"key":"ref70","article-title":"Pneumococcal conjugate vaccines for preventing acute otitis media in children","volume":"11","author":"de S\u00e9vaux","year":"2020","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref71","doi-asserted-by":"publisher","first-page":"100124","DOI":"10.1016\/j.jvacx.2021.100124","article-title":"Long-term immunogenicity and safety of a non-typeable Haemophilus influenzae-Moraxella catarrhalis vaccine: 4-year follow-up of a phase 1 multicentre trial","volume":"9","author":"De Smedt","year":"2021","journal-title":"Vaccine X"},{"key":"ref72","doi-asserted-by":"publisher","first-page":"5187","DOI":"10.1128\/iai.64.12.5187-5192.1996","article-title":"Immunization with outer membrane protein P6 from nontypeable Haemophilus influenzae induces bactericidal antibody and affords protection in the chinchilla model of otitis media","volume":"64","author":"DeMaria","year":"1996","journal-title":"Infect. Immun."},{"key":"ref73","doi-asserted-by":"publisher","first-page":"1128","DOI":"10.1128\/iai","article-title":"Otitis media and nasopharyngeal colonization in ccl3\u2212\/\u2212 mice","volume":"85","author":"Deniffel","year":"2017","journal-title":"Infect. 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Invest."},{"key":"ref76","doi-asserted-by":"publisher","first-page":"e1007696","DOI":"10.1371\/journal.ppat.1007696","article-title":"A model of chronic, transmissible otitis media in mice","volume":"15","author":"Dewan","year":"2019","journal-title":"PLoS Pathog."},{"key":"ref77","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1177\/000348949810701010","article-title":"Treatment of chronic suppurative otitis media with topical ciprofloxacin","volume":"107","author":"Dohar","year":"1998","journal-title":"Ann. Otol. Rhinol. 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Dis."},{"key":"ref192","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1097\/01.idc.0000121024.62151.c9","article-title":"Pneumococcal disease: pathogenesis, treatment, and prevention","volume":"12","author":"McDaniel","year":"2004","journal-title":"Infect. Dis. Clin. Pract."},{"key":"ref193","doi-asserted-by":"publisher","first-page":"5761","DOI":"10.1128\/AAC.00990-15","article-title":"Noninvasive pneumococcal clones associated with antimicrobial nonsusceptibility isolated from children in the era of conjugate vaccines","volume":"59","author":"McElligott","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref194","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1177\/000348949910800105","article-title":"Immunologic and histologic observations in Reo virus-induced otitis Media in the Mouse","volume":"108","author":"Meek","year":"1999","journal-title":"Ann. Otol. Rhinol. 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Otol."},{"key":"ref197","doi-asserted-by":"publisher","first-page":"e02423","DOI":"10.1128\/mBio.02423-18","article-title":"Antibodies against the majority subunit (PilA) of the type IV pilus of Nontypeable Haemophilus influenzae disperse Moraxella catarrhalis from a dual-species biofilm","volume":"9","author":"Mokrzan","year":"2018","journal-title":"MBio"},{"key":"ref198","doi-asserted-by":"publisher","first-page":"2619","DOI":"10.1128\/JB.01022-15","article-title":"Type IV pilus expression is upregulated in nontypeable Haemophilus influenzae biofilms formed at the temperature of the human nasopharynx","volume":"198","author":"Mokrzan","year":"2016","journal-title":"J. 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Immun."},{"key":"ref323","doi-asserted-by":"publisher","first-page":"3793","DOI":"10.1128\/IAI.67.8.3793-3799.1999","article-title":"Analysis of the immunological responses to transferrin and lactoferrin receptor proteins from Moraxella catarrhalis","volume":"67","author":"Yu","year":"1999","journal-title":"Infect. Immun."},{"key":"ref324","doi-asserted-by":"publisher","first-page":"1589","DOI":"10.3892\/etm.2013.1036","article-title":"Effect of glucocorticoids on aquaporin-1 in guinea pigs with otitis media with effusion","volume":"5","author":"Yu","year":"2013","journal-title":"Exp. Ther. Med."},{"key":"ref325","doi-asserted-by":"publisher","first-page":"2790","DOI":"10.1128\/IAI.73.5.2790-2796.2005","article-title":"Synthesis and characterization of lipooligosaccharide-based conjugate vaccines for serotype B Moraxella catarrhalis","volume":"73","author":"Yu","year":"2005","journal-title":"Infect. Immun."},{"key":"ref326","doi-asserted-by":"publisher","first-page":"2974","DOI":"10.1128\/IAI.01915-06","article-title":"Biological and immunological characteristics of lipooligosaccharide-based conjugate vaccines for serotype C Moraxella catarrhalis","volume":"75","author":"Yu","year":"2007","journal-title":"Infect. Immun."},{"key":"ref327","doi-asserted-by":"publisher","first-page":"5261","DOI":"10.1128\/IAI.68.9.5261-5268.2000","article-title":"Lipooligosaccharide Pk (Gal\u03b11-4Gal\u03b21-4Glc) epitope of Moraxella catarrhalis is a factor in resistance to bactericidal activity mediated by normal human serum","volume":"68","author":"Zaleski","year":"2000","journal-title":"Infect. Immun."},{"key":"ref328","doi-asserted-by":"publisher","first-page":"e0122572","DOI":"10.1371\/journal.pone.0122572","article-title":"Lipopolysaccharide-induced middle ear inflammation disrupts the cochlear intra-strial fluid-blood barrier through down-regulation of tight junction proteins","volume":"10","author":"Zhang","year":"2015","journal-title":"PLoS One"},{"key":"ref329","doi-asserted-by":"publisher","first-page":"635","DOI":"10.2147\/JIR.S338598","article-title":"IL-17 is a potential therapeutic target in a rodent model of otitis media with effusion","volume":"15","author":"Zhang","year":"2022","journal-title":"J. Inflamm. Res."},{"key":"ref330","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.brainres.2006.01.046","article-title":"Mouse models as a tool to unravel the genetic basis for human otitis media","volume":"1091","author":"Zheng","year":"2006","journal-title":"Brain Res."},{"key":"ref331","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1007\/s10162-022-00838-2","article-title":"gom1 mutant mice as a model of otitis","volume":"23","author":"Zheng","year":"2022","journal-title":"Media"}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2024.1345027\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T04:43:14Z","timestamp":1706071394000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2024.1345027\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,24]]},"references-count":334,"alternative-id":["10.3389\/fmicb.2024.1345027"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2024.1345027","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,24]]},"article-number":"1345027"}}