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System-level analyses of multiomics datasets measuring six modalities and serological data revealed that poor responders lacked time-dependent changes in response to vaccination as observed in responders, suggestive of systemic dysregulation in poor responders. Multiomics integration revealed key molecules and their likely role in vaccination response. High prevaccination plasma interleukin-15 (IL-15) concentrations negatively associated with antibody production, further supported by experimental validation in mice revealing an IL-15\u2013driven natural killer cell axis explaining the suppressive role in vaccine-induced antibody production as observed in poor responders. We propose a subset of long-chain fatty acids as modulators of persistent inflammation in poor responders. Our findings provide a potential link between low-grade chronic inflammation and poor vaccination response and open avenues for possible pharmacological interventions to enhance vaccine responses.<\/jats:p>","DOI":"10.1126\/sciadv.adq7006","type":"journal-article","created":{"date-parts":[[2024,9,27]],"date-time":"2024-09-27T17:59:07Z","timestamp":1727459947000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":12,"title":["Systemic dysregulation and molecular insights into poor influenza vaccine response in the aging population"],"prefix":"10.1126","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9481-1944","authenticated-orcid":true,"given":"Saumya","family":"Kumar","sequence":"first","affiliation":[{"name":"Centre for Individualised Infection Medicine (CiiM), a joint venture between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany."},{"name":"TWINCORE, a 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