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To overcome this limitation, we present Functional Genomic Vaccinology (FGV), a high-throughput antigen discovery platform integrating genome-wide antigen prediction, proteome-scale screening, and experimental immunogenicity validation to identify protective bacterial antigens. Using FGV, 222 conserved\n                    <jats:italic>S. pneumoniae<\/jats:italic>\n                    proteins are expressed in vitro, incorporated into a protein microarray, and coupled to magnetic beads for mouse vaccination. Protein array analysis shows significant IgG responses in 40% of the screened proteins. Antigen-specific responses measured in human sera guide the prioritisation of 22 candidates, which undergo further studied for their serological and Th17 responses. Four antigens combined in a multicomponent vaccine induces protection from pneumonia and sepsis in mice, with epitope mapping revealing potential protective sites for each protein. These results establish FGV as a scalable, experimentally driven approach for bacterial vaccine discovery and demonstrate its applicability in developing protective pneumococcal vaccines.\n                  <\/jats:p>","DOI":"10.1038\/s41467-026-75848-2","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:24:58Z","timestamp":1784593498000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["High-throughput antigen discovery using Functional Genomic Vaccinology (FGV) identifies protective Streptococcus pneumoniae vaccine candidates"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7326-1680","authenticated-orcid":false,"given":"Giuseppe","family":"Ercoli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0803-2755","authenticated-orcid":false,"given":"Elisa","family":"Ramos-Sevillano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3317-6534","authenticated-orcid":false,"given":"Samantha","family":"Palethorpe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trisha","family":"Kerai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7042-8609","authenticated-orcid":false,"given":"Timothy","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael R.","family":"de Assis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aarti","family":"Jain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Algis","family":"Jasinskas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rie","family":"Nakajima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiin","family":"Felgner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2182-0222","authenticated-orcid":false,"given":"Stephanie W.","family":"Lo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6140-9489","authenticated-orcid":false,"given":"Brendan W.","family":"Wren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Felgner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5650-5361","authenticated-orcid":false,"given":"Jeremy S.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"75848_CR1","doi-asserted-by":"publisher","first-page":"2221","DOI":"10.1016\/S0140-6736(22)02185-7","volume":"400","author":"KS Ikuta","year":"2022","unstructured":"Ikuta, K. 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