Spike-specific IgG4 generated post BNT162b2 mRNA vaccination is inhibitory when directly competing with functional IgG subclasses
Summary: COVID-19 vaccines proved vital in controlling the SARS-CoV-2 pandemic. Both neutralizing and effector-function activities of Spike-specific antibodies are important for their protective activity. Several studies have reported that COVID-19 mRNA vaccines can lead to elevated levels of Spike-...
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| Language: | English |
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Elsevier
2025-07-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725007715 |
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| author | Jerry C.H. Tam Abbie C. Sibayan Jeffrey Seow Carl Graham Ashwini Kurshan Blair Merrick Richard J. Stanton Katie J. Doores |
| author_facet | Jerry C.H. Tam Abbie C. Sibayan Jeffrey Seow Carl Graham Ashwini Kurshan Blair Merrick Richard J. Stanton Katie J. Doores |
| author_sort | Jerry C.H. Tam |
| collection | DOAJ |
| description | Summary: COVID-19 vaccines proved vital in controlling the SARS-CoV-2 pandemic. Both neutralizing and effector-function activities of Spike-specific antibodies are important for their protective activity. Several studies have reported that COVID-19 mRNA vaccines can lead to elevated levels of Spike-specific immunoglobulin G4 (IgG4), an anti-inflammatory subclass with reduced binding to Fcγ receptors. We show that Spike-specific IgG4 levels following BNT162b2 vaccination are impacted by the interval between and frequency of vaccine boosts, prior or post SARS-CoV-2 infection and bivalent vaccine boosters. Through expression of IgG1, IgG2, IgG3, and IgG4 subclasses of SARS-CoV-2 antibodies, we demonstrate that while IgG4 has reduced effector-function activity, including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent complement deposition (ADCD), and antibody-dependent cellular phagocytosis, IgG4 is only inhibitory when directly competing with functional IgG subclasses binding to overlapping epitopes. ADCC and ADCD activity in plasma was not depleted by adding a cocktail of Spike-specific IgG4 monoclonal antibodies, suggesting that the non-stimulatory effect of Spike-specific IgG4 may be hidden in polyclonal mixes. |
| format | Article |
| id | doaj-art-d7c716d5b899447fbc0c1f59bf767b04 |
| institution | OA Journals |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-d7c716d5b899447fbc0c1f59bf767b042025-08-20T02:36:46ZengElsevierCell Reports2211-12472025-07-0144711600010.1016/j.celrep.2025.116000Spike-specific IgG4 generated post BNT162b2 mRNA vaccination is inhibitory when directly competing with functional IgG subclassesJerry C.H. Tam0Abbie C. Sibayan1Jeffrey Seow2Carl Graham3Ashwini Kurshan4Blair Merrick5Richard J. Stanton6Katie J. Doores7Department of Infectious Diseases, School of Immunology & Microbial Sciences, King’s College London, London, UKDepartment of Infectious Diseases, School of Immunology & Microbial Sciences, King’s College London, London, UKDepartment of Infectious Diseases, School of Immunology & Microbial Sciences, King’s College London, London, UKDepartment of Infectious Diseases, School of Immunology & Microbial Sciences, King’s College London, London, UKDepartment of Infectious Diseases, School of Immunology & Microbial Sciences, King’s College London, London, UKCentre for Clinical Infection and Diagnostics Research, Department of Infectious Diseases, Guy’s and St Thomas’ NHS Foundation Trust, London, UKDivision of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UKDepartment of Infectious Diseases, School of Immunology & Microbial Sciences, King’s College London, London, UK; Corresponding authorSummary: COVID-19 vaccines proved vital in controlling the SARS-CoV-2 pandemic. Both neutralizing and effector-function activities of Spike-specific antibodies are important for their protective activity. Several studies have reported that COVID-19 mRNA vaccines can lead to elevated levels of Spike-specific immunoglobulin G4 (IgG4), an anti-inflammatory subclass with reduced binding to Fcγ receptors. We show that Spike-specific IgG4 levels following BNT162b2 vaccination are impacted by the interval between and frequency of vaccine boosts, prior or post SARS-CoV-2 infection and bivalent vaccine boosters. Through expression of IgG1, IgG2, IgG3, and IgG4 subclasses of SARS-CoV-2 antibodies, we demonstrate that while IgG4 has reduced effector-function activity, including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent complement deposition (ADCD), and antibody-dependent cellular phagocytosis, IgG4 is only inhibitory when directly competing with functional IgG subclasses binding to overlapping epitopes. ADCC and ADCD activity in plasma was not depleted by adding a cocktail of Spike-specific IgG4 monoclonal antibodies, suggesting that the non-stimulatory effect of Spike-specific IgG4 may be hidden in polyclonal mixes.http://www.sciencedirect.com/science/article/pii/S2211124725007715CP: Immunology |
| spellingShingle | Jerry C.H. Tam Abbie C. Sibayan Jeffrey Seow Carl Graham Ashwini Kurshan Blair Merrick Richard J. Stanton Katie J. Doores Spike-specific IgG4 generated post BNT162b2 mRNA vaccination is inhibitory when directly competing with functional IgG subclasses Cell Reports CP: Immunology |
| title | Spike-specific IgG4 generated post BNT162b2 mRNA vaccination is inhibitory when directly competing with functional IgG subclasses |
| title_full | Spike-specific IgG4 generated post BNT162b2 mRNA vaccination is inhibitory when directly competing with functional IgG subclasses |
| title_fullStr | Spike-specific IgG4 generated post BNT162b2 mRNA vaccination is inhibitory when directly competing with functional IgG subclasses |
| title_full_unstemmed | Spike-specific IgG4 generated post BNT162b2 mRNA vaccination is inhibitory when directly competing with functional IgG subclasses |
| title_short | Spike-specific IgG4 generated post BNT162b2 mRNA vaccination is inhibitory when directly competing with functional IgG subclasses |
| title_sort | spike specific igg4 generated post bnt162b2 mrna vaccination is inhibitory when directly competing with functional igg subclasses |
| topic | CP: Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725007715 |
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