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Peer-reviewedCC BY-NC-NDNature Immunology

mRNA-based influenza vaccine expands the B cell response breadth in humans

  • Hanover C. Matz1
  • Tae-Geun Yu2
  • Kritika Dixit1
  • Caroline Kikawa3
  • Julian Q. Zhou1
  • Garazi Peña Alzua4,5
  • Lowrey Peyton6,2
  • Anders Madsen7,8
  • Fangjie Han1
  • Ariana Ghez Farrell9
  • Robert Hoelzl5
  • Aaron J. Schmitz1
15 more authors
  • Stephen C. Horvath1
  • Hunter K. Keplinger1
  • Benjamin S. Strnad10
  • Mark Jeffrey Hoegger10
  • William Dana Middleton10
  • Michael K. Klebert11
  • Nina Lin12
  • Raffael Nachbagauer12
  • Florian Krammer4,5,13,14,15
  • Robert Paris12
  • Jesse D. Bloom16,17
  • Jackson S. Turner1
  • Rachel M. Presti18,19,11,20
  • Jiwon Lee21,22,23
  • Ali H. Ellebedy24,25,26
26 affiliations
  1. 1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
  2. 2Thayer School of Engineering, Dartmouth College, Hanover, NH, USA
  3. 3Department of Genome Sciences, Medical Scientist Training Program, University of Washington, Seattle, WA, USA
  4. 4Center for Vaccine Research and Pandemic Preparedness (C-VaRPP), Icahn School of Medicine at Mount Sinai, New York, NY, USA
  5. 5Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  6. 6Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH, USA
  7. 7Department of Microbiology, Haukeland University Hospital, Bergen, Norway
  8. 8Influenza Centre, Department of Clinical Science, University of Bergen, Bergen, Norway
  9. 9Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, USA
  10. 10Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA
  11. 11Infectious Disease Clinical Research Unit, Washington University School of Medicine, St. Louis, MO, USA
  12. 12Moderna, Cambridge, MA, USA
  13. 13Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  14. 14Ignaz Semmelweis Institute, Interuniversity Institute for Infection Research, Medical University of Vienna, Vienna, Austria
  15. 15Ludwig Boltzmann Institute for Science Outreach and Pandemic Preparedness at the Medical University of Vienna, Medical University of Vienna, Vienna, Austria
  16. 16Fred Hutch Cancer Center, Seattle, WA, USA
  17. 17Howard Hughes Medical Institute, Seattle, WA, USA
  18. 18Center for Vaccines and Immunity to Microbial Pathogens, Washington University School of Medicine, St. Louis, MO, USA
  19. 19Division of Infectious Diseases, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
  20. 20The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA
  21. 21Department of Convergence Medicine, Korea University College of Medicine, Seoul, Republic of Korea. [email protected]
  22. 22Thayer School of Engineering, Dartmouth College, Hanover, NH, USA. [email protected]
  23. 23Vaccine Innovation Center, Korea University College of Medicine, Seoul, Republic of Korea. [email protected]
  24. 24Center for Vaccines and Immunity to Microbial Pathogens, Washington University School of Medicine, St. Louis, MO, USA. [email protected]
  25. 25Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. [email protected]
  26. 26The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA. [email protected]
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Abstract

Conventional influenza virus vaccines induce antibody responses of limited breadth. Whether mRNA-based influenza virus vaccines can induce a superior germinal center (GC) response in humans remains unclear. Here we assessed B cell responses in an observational study of cohorts of healthy young adults receiving a licensed, split-virion or investigative mRNA-based quadrivalent seasonal influenza virus vaccine over two consecutive seasons. mRNA-based vaccines consistently elicited higher antibody titers and frequencies of memory B cells. In the draining lymph nodes, mRNA vaccination stimulated sustained GC reactions that persisted for at least 26 weeks after vaccination in 5 of 13 participants across the two seasons. Proteomic analysis of serum IgG repertoire showed that mRNA vaccination increased the number of vaccine-elicited serum IgG clonotypes and promoted intraclonal expansion within pre-existing clonotypes. B cell lineage analyses further indicated that expanded serum clonotypes map to GC B cell-associated sub-branches, consistent with ongoing GC-driven evolution underlying intraclonal expansion. This repertoire remodeling was accompanied by increased binding breadth against antigenically divergent influenza viruses. These findings reveal a key role for persistent GC responses in broadening the repertoire of vaccine-induced antibodies. This study compares the humoral response of individuals who received inactivated influenza vaccines to that of individuals who received an mRNA-based quadrivalent influenza vaccine. The mRNA-based vaccine induced prolonged germinal center responses, more antibodies and increased numbers of memory B cells.

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Cite

BibTeXRIS
BibTeX
@article{matz2026mrnabased,
  title = {{mRNA-based influenza vaccine expands the B cell response breadth in humans}},
  author = {Hanover C. Matz and Tae-Geun Yu and Kritika Dixit and Caroline Kikawa and Julian Q. Zhou and Garazi Peña Alzua and Lowrey Peyton and Anders Madsen and Fangjie Han and Ariana Ghez Farrell and Robert Hoelzl and Aaron J. Schmitz and Stephen C. Horvath and Hunter K. Keplinger and Benjamin S. Strnad and Mark Jeffrey Hoegger and William Dana Middleton and Michael K. Klebert and Nina Lin and Raffael Nachbagauer and Florian Krammer and Robert Paris and Jesse D. Bloom and Jackson S. Turner and Rachel M. Presti and Jiwon Lee and Ali H. Ellebedy},
  journal = {Nature Immunology},
  year = {2026},
  month = jun,
  doi = {10.1038/s41590-026-02569-5},
  url = {https://doi.org/10.1038/s41590-026-02569-5},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - mRNA-based influenza vaccine expands the B cell response breadth in humans
AU  - Hanover C. Matz
AU  - Tae-Geun Yu
AU  - Kritika Dixit
AU  - Caroline Kikawa
AU  - Julian Q. Zhou
AU  - Garazi Peña Alzua
AU  - Lowrey Peyton
AU  - Anders Madsen
AU  - Fangjie Han
AU  - Ariana Ghez Farrell
AU  - Robert Hoelzl
AU  - Aaron J. Schmitz
AU  - Stephen C. Horvath
AU  - Hunter K. Keplinger
AU  - Benjamin S. Strnad
AU  - Mark Jeffrey Hoegger
AU  - William Dana Middleton
AU  - Michael K. Klebert
AU  - Nina Lin
AU  - Raffael Nachbagauer
AU  - Florian Krammer
AU  - Robert Paris
AU  - Jesse D. Bloom
AU  - Jackson S. Turner
AU  - Rachel M. Presti
AU  - Jiwon Lee
AU  - Ali H. Ellebedy
PY  - 2026
DA  - 2026/06/15
JO  - Nature Immunology
DO  - 10.1038/s41590-026-02569-5
UR  - https://doi.org/10.1038/s41590-026-02569-5
AB  - Conventional influenza virus vaccines induce antibody responses of limited breadth. Whether mRNA-based influenza virus vaccines can induce a superior germinal center (GC) response in humans remains unclear. Here we assessed B cell responses in an observational study of cohorts of healthy young adults receiving a licensed, split-virion or investigative mRNA-based quadrivalent seasonal influenza virus vaccine over two consecutive seasons. mRNA-based vaccines consistently elicited higher antibody titers and frequencies of memory B cells. In the draining lymph nodes, mRNA vaccination stimulated sustained GC reactions that persisted for at least 26 weeks after vaccination in 5 of 13 participants across the two seasons. Proteomic analysis of serum IgG repertoire showed that mRNA vaccination increased the number of vaccine-elicited serum IgG clonotypes and promoted intraclonal expansion within pre-existing clonotypes. B cell lineage analyses further indicated that expanded serum clonotypes map to GC B cell-associated sub-branches, consistent with ongoing GC-driven evolution underlying intraclonal expansion. This repertoire remodeling was accompanied by increased binding breadth against antigenically divergent influenza viruses. These findings reveal a key role for persistent GC responses in broadening the repertoire of vaccine-induced antibodies. This study compares the humoral response of individuals who received inactivated influenza vaccines to that of individuals who received an mRNA-based quadrivalent influenza vaccine. The mRNA-based vaccine induced prolonged germinal center responses, more antibodies and increased numbers of memory B cells.
SN  - 1529-2908
SN  - 1529-2916
ER  -