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Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>BNT162b2 immunogenicity wanes with time and we investigated association between gut microbiota and longer-term immunogenicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This cohort study prospectively recruited adult BNT162b2 two-dose recipients from three vaccination centers in Hong Kong. Blood samples were collected at baseline and day 180 after first dose, and tested for neutralizing antibodies (NAb) against receptor-binding domain (RBD) of wild type SARS-CoV-2 virus using chemiluminescence immunoassay. Shotgun DNA metagenomic sequencing was performed to characterize baseline stool microbiome. Baseline metabolites were measured by gas and liquid chromatography-tandem mass spectrometry (GC-MS\/MS and LC-MS\/MS). Primary outcome was persistent high NAb response (defined as top 25% of NAb level) at day 180. Putative bacterial species and metabolic pathways were identified using linear discriminant analysis [LDA] effect size analysis. Multivariable logistic regression adjusting for clinical factors was used to derive adjusted odds ratio (aOR) of outcome with bacterial species and metabolites.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Of 242 subjects (median age: 50.2 years [IQR:42.5-55.6]; male:85 [35.1%]), 61 (25.2%) were high-responders while 33 (13.6%) were extreme-high responders (defined as NAb\u2265200AU\/mL). None had COVID-19 at end of study. <jats:italic>Ruminococcus bicirculans<\/jats:italic> (log<jats:sub>10<\/jats:sub>LDA score=3.65), <jats:italic>Parasutterella excrementihominis<\/jats:italic> (score=2.82) and <jats:italic>Streptococcus salivarius<\/jats:italic> (score=2.31) were enriched in high-responders, while <jats:italic>Bacteroides thetaiotaomicron<\/jats:italic> was enriched in low-responders (score=-3.70). On multivariable analysis, bacterial species (<jats:italic>R. bicirculans<\/jats:italic>\u2013aOR: 1.87, 95% CI: 1.02-3.51; <jats:italic>P. excrementihominis<\/jats:italic>\u2013aOR: 2.2, 95% CI: 1.18-4.18; S. <jats:italic>salivarius<\/jats:italic>\u2013aOR: 2.09, 95% CI: 1.13-3.94) but not clinical factors associated with high response. <jats:italic>R. bicirculans<\/jats:italic> positively correlated with most metabolic pathways enriched in high-responders, including superpathway of L-cysteine biosynthesis (score=2.25) and L-isoleucine biosynthesis I pathway (score=2.16) known to benefit immune system. Baseline serum butyrate (aOR:10.00, 95% CI:1.81-107.2) and isoleucine (aOR:1.17, 95% CI:1.04-1.35) significantly associated with extreme-high vaccine response.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Certain gut bacterial species, metabolic pathways and metabolites associate with longer-term COVID-19 vaccine immunogenicity.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1534787","type":"journal-article","created":{"date-parts":[[2025,2,27]],"date-time":"2025-02-27T07:11:13Z","timestamp":1740640273000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Gut microbiota is associated with persistence of longer-term BNT162b2 vaccine immunogenicity"],"prefix":"10.3389","volume":"16","author":[{"given":"Ho Yu","family":"Ng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunshi","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching Lung","family":"Cheung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiqi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwok Hung","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wai-Kay","family":"Seto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wai K.","family":"Leung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan F. 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