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Current licensed vaccines have been incompletely ineffective at reducing the global burden of AOM, underscoring a major unmet medical need. The complex etiology of AOM presents additional challenges for vaccine development, as it can stem from multiple bacterial species including Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. As such, targeting multiple pathogens simultaneously may be required to significantly impact the overall disease burden. Methods: In this study, we aim to overcome this challenge by engineering a live-attenuated vaccine platform based on an attenuated mutant of S. pneumoniae that expresses H. influenzae and M. catarrhalis surface epitopes to induce protective immunity against all three pathogens. Results: The trivalent live-attenuated vaccine conferred significant protection against all three bacterial otopathogens as measured by seroconversion and the development of AOM, with the inclusion of the additional epitopes providing unexpected synergy and enhanced protection against S. pneumoniae. Conclusions: These data demonstrate a novel mechanism of introducing non-native immunogenic antigens into a live-attenuated vaccine platform to engender protection against AOM from multiple pathogenic species.<\/jats:p>","DOI":"10.3390\/vaccines12121432","type":"journal-article","created":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T06:50:44Z","timestamp":1734591044000},"page":"1432","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Trivalent Live Vaccine Elicits Cross-Species Protection Against Acute Otitis Media in a Murine Model"],"prefix":"10.3390","volume":"12","author":[{"given":"Haley","family":"Echlin","sequence":"first","affiliation":[{"name":"Department of Host-Microbe Interactions, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Iverson","sequence":"additional","affiliation":[{"name":"Department of Host-Microbe Interactions, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail","family":"McKnight","sequence":"additional","affiliation":[{"name":"Department of Host-Microbe Interactions, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1798-1760","authenticated-orcid":false,"given":"Jason W.","family":"Rosch","sequence":"additional","affiliation":[{"name":"Department of Host-Microbe Interactions, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,19]]},"reference":[{"key":"ref_1","unstructured":"(2024, December 11). 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