Human vaccine responses regulated by parallel cytokine pathways
Human vaccine responses vary widely, but the determinants remain incompletely defined. Here we analyzed 66 cytokines across four inactivated influenza vaccine (IIV) cohorts over five seasons (n = 581) and identified baseline serum interleukin (IL)-18 and interferon (IFN)-β 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 IFNγ, enhanced antibody production. The addition of IFNβ 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 IFNβ 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.
Authors
- Mingdian Tan (ORCID: https://orcid.org/0000-0003-3064-2189)
- Guangbo Chen (ORCID: https://orcid.org/0000-0003-2179-1174)
- Paul J. Utz (ORCID: https://orcid.org/0000-0003-1181-1565)
- Harry B. Greenberg (ORCID: https://orcid.org/0000-0002-2128-9080)
- Cornelia L. Dekker (ORCID: https://orcid.org/0000-0002-3871-918X)
- William H. Robinson (ORCID: https://orcid.org/0000-0003-4385-704X)
- Vamsee Mallajosyula (ORCID: https://orcid.org/0000-0002-0658-3652)
- Mark M. Davis (ORCID: https://orcid.org/0000-0001-6868-657X)
- Tyler R. Prestwood (ORCID: https://orcid.org/0000-0002-0971-5286)
- John E. Heath (ORCID: https://orcid.org/0000-0002-5004-2693)
- Ying Lu (ORCID: https://orcid.org/0000-0002-3545-1026)
- Elsa Solà (ORCID: https://orcid.org/0000-0001-6897-2760)
- Shai S. Shen-Orr (ORCID: https://orcid.org/0000-0002-6991-7736)
- Holden T. Maecker (ORCID: https://orcid.org/0000-0003-0795-9946)
- Azam Mohsin (ORCID: https://orcid.org/0000-0003-0021-3244)
- Catherine A. Blish (ORCID: https://orcid.org/0000-0001-6946-7627)
- Ahmad Salehi (ORCID: https://orcid.org/0000-0001-8257-3280)
- Purvesh Khatri (ORCID: https://orcid.org/0000-0002-4143-4708)
- Yueh‐hsiu Chien (ORCID: https://orcid.org/0000-0002-6014-1230)
- Lei Chen (ORCID: https://orcid.org/0000-0001-7864-8649)
- Jing Guo (ORCID: https://orcid.org/0000-0002-6616-2585)
- A. Sangaré
- Woo Joo Kwon (ORCID: https://orcid.org/0009-0005-5767-6559)
- Oviya Siva
- Philip Grant
- Tran T. Nguyen
- Ryan Furuichi Fong (ORCID: https://orcid.org/0009-0008-1320-0892)
- Karan R. Kathuria
- Cindy Padilla
- Ashley R. Smith (ORCID: https://orcid.org/0000-0001-5826-682X)
Institutions
- Technion – Israel Institute of Technology (IL)
- Palo Alto University (US)
- Medical College of Wisconsin (US)
- Biology of Infection (FR)
- Donor Network West (US)
- Versiti Blood Center of Wisconsin (US)
- Stanford Medicine (US)
- Stanford University (US)
Publication Details
- Journal
- Nature Immunology
- Published
- 2026-06-12
- DOI
- https://doi.org/10.1038/s41590-026-02547-x
- Primary Topic
- Immunotherapy and Immune Responses
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- Bill and Melinda Gates Foundation
- Eli Lilly and Company
- Medical College of Wisconsin
- Life Sciences Research Foundation
- Open Philanthropy Project
- National Institutes of Health
- National Institute on Aging
- National Institute of Allergy and Infectious Diseases