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Here we analyzed 66 cytokines across four inactivated influenza vaccine (IIV) cohorts over five seasons (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009581) and identified baseline serum interleukin (IL)-18 and interferon (IFN)-\u03b2 as correlates of day 28 antibody responses. To test causality, we evaluated 19 cytokines in human tonsil and spleen organoids and found that type I IFNs, IL-21 and IL-12, but not IL-18 or IFN\u03b3, enhanced antibody production. The addition of IFN\u03b2 to IIV recapitulated key features of the live-vaccine cytokine program. IL-12 and IL-21 defined a parallel pathway independent of type I IFNs, with IL-12 inducing IL-21 in humans, unlike in mice. Delivery of IL-21 or IFN\u03b2 via mRNA lipid nanoparticles in vivo promoted long-lived plasma cell formation. Together, these findings define parallel pathways that regulate vaccine immunity. Our approach unites high-throughput organoid testing and human cohort studies, establishing a human-centric platform to identify adjuvant candidates.\n                  <\/jats:p>","DOI":"10.1038\/s41590-026-02547-x","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T09:04:40Z","timestamp":1781255080000},"page":"1643-1652","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Human vaccine responses regulated by parallel cytokine 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