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Adv."],"published-print":{"date-parts":[[2026,8,7]]},"abstract":"<jats:p>\n                    Existing licensed pneumococcal vaccines, including Prevnar-13 and its higher-valency successors, have played a major role in reducing invasive pneumococcal disease worldwide. However, their effectiveness is increasingly threatened by the rise of multidrug-resistant strains and the shift in circulating serotypes toward those not targeted by current vaccines\u2014a trend known as serotype replacement. These evolving challenges underscore the urgent need for next-generation vaccines with broader, serotype-independent protection\u2014long considered the holy grail of pneumococcal vaccine development. Here, we report the discovery and preclinical evaluation of ZPY-CpG-Ch, a broad-coverage protein-based pneumococcal vaccine formulation. We assessed the protective efficacy and immunogenicity of ZPY-CpG-Ch in translational murine models, using both adult and neonatal mice, and tested various adjuvants, protein combinations, and doses, followed by challenge experiments with both vaccine- and non\u2013vaccine-covered serotypes. Prevnar-13 was included as a benchmark. While Prevnar-13\n                    <jats:sup>\u00ae<\/jats:sup>\n                    demonstrated robust efficacy, our results show that ZPY-CpG-Ch achieves greater cross-serotype protection. We attribute this enhanced efficacy primarily to T\n                    <jats:sub>H<\/jats:sub>\n                    17 (T helper 7)\u2013biased immune responses. Together, these findings highlight the promise of genome-guided, protein-based vaccines in overcoming the limitations of current serotype-based approaches and represent a meaningful step toward a truly universal pneumococcal vaccine.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aee7981","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T17:59:18Z","timestamp":1786125558000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["ZPY-CpG-Ch, a broad coverage vaccine against\n                    <i>Streptococcus pneumoniae<\/i>"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0773-7685","authenticated-orcid":true,"given":"Teerawit","family":"Audshasai","sequence":"first","affiliation":[{"name":"Department of Clinical Infection Microbiology &amp; Immunology, Institute of Infection, Veterinary &amp; Ecological Sciences, University of Liverpool, The Ronald Ross Building, 8 West Derby St., Liverpool L69 7BE, UK."},{"name":"Department of Microbiology, Faculty of Pharmacy, Mahidol University, 447, Thanon Si Ayutthaya, Khwaeng Thung Phaya Thai, Khet Ratchathewi, Bangkok 10400, Thailand."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9972-5068","authenticated-orcid":true,"given":"Stavros","family":"Panagiotou","sequence":"additional","affiliation":[{"name":"Department of Clinical Infection Microbiology &amp; Immunology, Institute of Infection, Veterinary &amp; Ecological Sciences, University of Liverpool, The Ronald Ross Building, 8 West Derby St., Liverpool L69 7BE, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2390-4750","authenticated-orcid":true,"given":"Lisa","family":"Crossman","sequence":"additional","affiliation":[{"name":"SequenceAnalysis.co.uk, Norwich Research Park, Norwich NR4 7UG, UK."},{"name":"School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8895-0303","authenticated-orcid":true,"given":"Rong","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Clinical Infection Microbiology &amp; Immunology, Institute of Infection, Veterinary &amp; Ecological Sciences, University of Liverpool, The Ronald Ross Building, 8 West Derby St., Liverpool L69 7BE, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6492-6708","authenticated-orcid":true,"given":"Lynn","family":"Verheijen","sequence":"additional","affiliation":[{"name":"Department of Clinical Infection Microbiology &amp; Immunology, Institute of Infection, Veterinary &amp; Ecological Sciences, University of Liverpool, The Ronald Ross Building, 8 West Derby St., Liverpool L69 7BE, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2108-1757","authenticated-orcid":true,"given":"Chrispin","family":"Chaguza","sequence":"additional","affiliation":[{"name":"Host-Microbe Interactions Dept. at St Jude Children\u2019s Research Hospital, Danny Thomas Place, Memphis, TN 38105, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3104-2150","authenticated-orcid":true,"given":"Marie","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"Department of Clinical Infection Microbiology &amp; Immunology, Institute of Infection, Veterinary &amp; Ecological Sciences, University of Liverpool, The Ronald Ross Building, 8 West Derby St., Liverpool L69 7BE, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1137-6321","authenticated-orcid":true,"given":"Aras","family":"Kadioglu","sequence":"additional","affiliation":[{"name":"Department of Clinical Infection Microbiology &amp; Immunology, Institute of Infection, Veterinary &amp; Ecological Sciences, University of Liverpool, The Ronald Ross Building, 8 West Derby St., Liverpool L69 7BE, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30925-9"},{"key":"e_1_3_2_3_2","unstructured":"European Centre for Disease Prevention and Control (ECDC) Invasive pneumococcal disease \u2013 Annual Epidemiological Report for 2022. 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