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The availability of massive omic data and novel algorithms may improve antigen selection to develop effective prophylactic strategies. Up to 133 exposed proteins in the core proteomes, between 516 and 8666 genome samples, of the six most relevant MDR clonal groups (CGs) carried conserved B-cell epitopes, suggesting minimized future evasion if utilized for vaccination. Antigens showed a range of epitopicity, functional constraints, and potential side effects. Eleven antigens, including three sugar porins, were represented in all MDR-CGs, constitutively expressed, and showed limited reactivity with gut microbiota. Some of these antigens had important interactomic interactions and may elicit adhesion-neutralizing antibodies. Synergistic bivalent to pentavalent combinations that address expression conditions, interactome location, virulence activities, and clone-specific proteins may overcome the limiting protection of univalent vaccines. The combination of five central antigens accounted for 41% of all non-redundant interacting partners of the antigen dataset. Specific antigen mixtures represented in a few or just one MDR-CG further reduced the chance of microbiota interference. Rational antigen selection schemes facilitate the design of high-coverage and \u201cmagic bullet\u201d multivalent vaccines against recalcitrant K. pneumoniae lineages.<\/jats:p>","DOI":"10.3390\/ijms25189837","type":"journal-article","created":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T10:33:01Z","timestamp":1726050781000},"page":"9837","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Deep Intraclonal Analysis for the Development of Vaccines against Drug-Resistant Klebsiella pneumoniae Lineages"],"prefix":"10.3390","volume":"25","author":[{"given":"Ana","family":"Tajuelo","sequence":"first","affiliation":[{"name":"Intrahospital Infections Unit, National Centre for Microbiology, Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain"},{"name":"Universidad Nacional de Educaci\u00f3n a Distancia (UNED), 28015 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1662-514X","authenticated-orcid":false,"given":"Eva","family":"Gato","sequence":"additional","affiliation":[{"name":"Intrahospital Infections Unit, National Centre for Microbiology, Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3327-8263","authenticated-orcid":false,"given":"Jes\u00fas","family":"Oteo-Iglesias","sequence":"additional","affiliation":[{"name":"Reference and Research Laboratory for Antibiotic Resistance and Health Care Infections, National Centre for Microbiology, Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain"},{"name":"CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"P\u00e9rez-V\u00e1zquez","sequence":"additional","affiliation":[{"name":"Reference and Research Laboratory for Antibiotic Resistance and Health Care Infections, National Centre for Microbiology, Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain"},{"name":"CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"McConnell","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio J.","family":"Mart\u00edn-Galiano","sequence":"additional","affiliation":[{"name":"Core Scientific and Technical Units, Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1809-3332","authenticated-orcid":false,"given":"Astrid","family":"P\u00e9rez","sequence":"additional","affiliation":[{"name":"Intrahospital Infections Unit, National Centre for Microbiology, Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"12868","DOI":"10.1073\/pnas.1717157115","article-title":"Antimicrobial Resistance and the Role of Vaccines","volume":"115","author":"Bloom","year":"2018","journal-title":"Proc. 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