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Vaccination-first immune priming shapes a sustained mRNA vaccine-induced IgG4 class switch that associates with SARS-CoV-2 breakthrough infection risk

Nature作者：Tamás Pongrácz2026年8月12日正文已收录本站
  • Article
  • Open access
  • Published:
  • Ulrika Marking1,
  • Oscar Bladh1,
  • Katherina Aguilera1,
  • Matilda Berkell1,2,
  • Sebastian Havervall1,
  • Nina Greilert-Norin1,
  • Jan Nouta3,
  • Steinar Gijze3,
  • Anna Wasynczuk3,
  • Mikael Åberg4,5,
  • Gestur Vidarsson6,7,
  • Youjia Zhong8,9,
  • David Falck3 na1 &
  • …
  • Charlotte Thålin1 na1 

Scientific Reports (2026) Cite this article

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Abstract

Repeated administration of mRNA vaccines against SARS-CoV-2 has been associated with qualitative changes in antibody responses, including the emergence of non-inflammatory IgG4 subclasses and changes in Fc glycosylation. While neutralizing antibody titers remain key correlates of protection, potential functional implications of these structural antibody features warrant further investigation across age groups and multiple mRNA vaccine boosters. We characterized spike-specific IgG responses—including subclasses and Fc glycosylation patterns—using a liquid chromatography—mass spectrometry-based approach across six mRNA vaccine doses in a Swedish healthcare worker cohort (n = 104) and across three mRNA doses in a Singaporean pediatric cohort (n = 18). Repeated mRNA vaccination induced an IgG4 class switch which was sustained across at least six doses. This response associated with an increased risk of breakthrough infection (HR = 1.83, p = 0.028) in infection-naïve individuals (n = 41) lacking mucosal IgA responses that would potentially confound the interpretation of systemic IgG4‑related infection outcomes. Moreover, the IgG4 class switch was preceded with high early IgG1 Fc fucosylation signatures. Notably, these IgG structural changes were observed primarily in individuals who were naïve to SARS-CoV-2 at the time of first vaccination. Similar IgG structural features were observed across three mRNA doses in the small infection-naive pediatric cohort. Our results illustrate an IgG4-dominated immunological signature in both adults and children and highlight that immune priming by prior infection may shape subsequent mRNA vaccine-induced antibody responses. While these findings do not call into question the efficacy or safety of the widely adapted mRNA vaccine platform, they may have implications that merit further investigation.

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Funding

Open access funding provided by Karolinska Institute. This work was funded by the Knut and Alice Wallenberg Foundation (KAW 2024.0108), the European Research Council (ERC) under the European Union’s Horizon Europe research and innovation programme (101164772-D-MAP), the Swedish Society for Medical Research (SSMF; CG-24-0191-B-H-01) and the National Bioinformatics Infrastructure Sweden (NBIS) at SciLifeLab.

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Author notes

  1. David Falck and Charlotte Thålin contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden

    Tamás Pongrácz, Ulrika Marking, Oscar Bladh, Katherina Aguilera, Matilda Berkell, Sebastian Havervall, Nina Greilert-Norin & Charlotte Thålin

  2. National Bioinformatics Infrastructure Sweden, Stockholm, Sweden

    Matilda Berkell

  3. Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands

    Jan Nouta, Steinar Gijze, Anna Wasynczuk & David Falck

  4. Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden

    Mikael Åberg

  5. Science for Life Laboratory, Uppsala University, Uppsala, Sweden

    Mikael Åberg

  6. Immunoglobulin Research Laboratory, Sanquin Research, Amsterdam, The Netherlands

    Gestur Vidarsson

  7. Department of Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences and Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands

    Gestur Vidarsson

  8. Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Youjia Zhong

  9. Khoo Teck Puat-National University Children’s Medical Institute, National University Health System (NUHS), Singapore, Singapore

    Youjia Zhong

Authors

  1. Tamás Pongrácz
  2. Ulrika Marking
  3. Oscar Bladh
  4. Katherina Aguilera
  5. Matilda Berkell
  6. Sebastian Havervall
  7. Nina Greilert-Norin
  8. Jan Nouta
  9. Steinar Gijze
  10. Anna Wasynczuk
  11. Mikael Åberg
  12. Youjia Zhong
  13. David Falck
  14. Charlotte Thålin

Corresponding authors

Correspondence to Tamás Pongrácz or Charlotte Thålin.

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Competing interests

The authors declare that the work has been construed in the absence of competing interests.

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Pongrácz, T., Marking, U., Bladh, O. et al. Vaccination-first immune priming shapes a sustained mRNA vaccine-induced IgG4 class switch that associates with SARS-CoV-2 breakthrough infection risk. Sci Rep (2026). https://doi.org/10.1038/s41598-026-64190-8

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  • DOI: https://doi.org/10.1038/s41598-026-64190-8

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