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Dartmouth College

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Nat. Immunol., 15 June 2026 | https://doi.org/10.1038/s41590-026-02569-5 mRNA-based influenza vaccine expands the B cell response breadth in humans

Hanover C. Matz^1,23, Tae-Geun Yu^2,23, Kritika Dixit¹, Caroline Kikawa³, Julian Q. Zhou¹, Garazi Pena Alzua^4,5, Lowrey Peyton^2,6, Anders Madsen^7,8, Fangjie Han¹, Ariana Ghez Farrell⁹, Robert Hoelzl⁴, Aaron J. Schmitz¹, Stephen C. Horvath¹, Hunter K. Keplinger¹, Benjamin S. Strnad¹⁰, Mark J. Hoegger¹⁰, William D. Middleton¹⁰, Michael K. Klebert¹¹, Nina H. Lin¹², Raffael Nachbagauer¹², Florian Krammer^4,5,13,14,15, Robert Paris¹², Jesse D. Bloom^16,17, Jackson S. Turner¹, Rachel M. Presti^11,18,19,20, Jiwon Lee^2,21,22,24 & Ali H. Ellebedy^1,19,20,24

¹Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
²Thayer School of Engineering, Dartmouth College, Hanover, NH, USA.
³Department of Genome Sciences, Medical Scientist Training Program, University of Washington, Seattle, WA, USA.
⁴Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵Center for Vaccine Research and Pandemic Preparedness (C-VaRPP), Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
⁷Influenza Centre, Department of Clinical Science, University of Bergen, Bergen, Norway.
⁸Department of Microbiology, Haukeland University Hospital, Bergen, Norway.
⁹Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, USA.
¹⁰Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
¹¹Infectious Disease Clinical Research Unit, Washington University School of Medicine, St. Louis, MO, USA.
¹²Moderna, Cambridge, MA, USA.
¹³Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴Ignaz Semmelweis Institute, Interuniversity Institute for Infection Research, Medical University of Vienna, Vienna, Austria.
¹⁵Ludwig Boltzmann Institute for Science Outreach and Pandemic Preparedness at the Medical University of Vienna, Medical University of Vienna, Vienna, Austria.
¹⁶Fred Hutch Cancer Center, Seattle, WA, USA.
¹⁷Howard Hughes Medical Institute, Seattle, WA, USA.
¹⁸Division of Infectious Diseases, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
¹⁹Center for Vaccines and Immunity to Microbial Pathogens, Washington University School of Medicine, St. Louis, MO, USA.
²⁰The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA.
²¹Department of Convergence Medicine, Korea University College of Medicine, Seoul, Republic of Korea.
²²Vaccine Innovation Center, Korea University College of Medicine, Seoul, Republic of Korea.
²³These authors contributed equally: Hanover C. Matz, Tae-Geun Yu.
²⁴These authors jointly supervised this work: Jiwon Lee, Ali H. Ellebedy.

Corresponding authors
Correspondence to Jiwon Lee or Ali H. Ellebedy.

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.

논문소개전체 설명

본 연구는 임상 3상을 진행중인 인플루엔자 mRNA 백신 (mRNA-1010)과 기존 egg-based vaccine (Fluarix)을 비교하여 mRNA-1010 접종 후 나타나는 강화된 germinal center반응이 어떤 혈청 항체의 변화를 이끌 수 있는지 밝혀낸 논문입니다. Blood에서 얻어진 peripheral B cell 들과 fine needle aspiration을 통해 얻어진 lymph node B cell을 통해 mRNA-1010 접종 이후 기존백신 대비 더 길게 유지되는 germinal center 반응을 정량하였고, Ig-Seq을 통해 이러한 cellular level 변화들이 serum antibody repertoire를 clonotypic level과 intraclonal level에서 다양화킨다는 점, 그리고 그 다양화의 결과로 여러 인플루엔자 바이러스 변이들을 인식할 수 있게 된다는 것을 밝혔습니다. 인플루엔자 바이러스의 경우 반복된 노출을 겪기때문에 새로운 항체들로 다양화되기보다는 원래 있었던 혈청항체가 우점하는 경향이 큰데, 본 연구에서는 인플루엔자 mRNA 백신 사례를 통해 더 지속적인 germinal center 반응을 유도할 경우 antibody repertoire가 다양화되며 업데이트된다는 것을 처음으로 측정하고 이러한 다양화의 결과로 여러 바이러스 변이들에 대한 저항성으로 연결되는 축을 보였다는 점이 의의가 있습니다.

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