Post-vaccination IgG4 and IgG2 class switch associates with increased risk of SARS-CoV-2 infections - 08/04/25

Doi : 10.1016/j.jinf.2025.106473

Carla Martín Pérez ^a,^b,^{^{1
Shared authorships.}}, Sílvia Ruiz-Rius ^a,^b,^{^{1
Shared authorships.}}, Anna Ramírez-Morros ^c, Marta Vidal ^a,^b, D. Herbert Opi ^d,^e,^f, Pere Santamaria ^g,^h, Julià Blanco ^i,^j,^k,^l, Josep Vidal-Alaball ^c,^k,^m, James G. Beeson ^d,^e,^f, Luis M. Molinos-Albert ^a,^b, Ruth Aguilar ^a,^b, Anna Ruiz-Comellas ^c,^k,^m,^n,^{^{1
Shared authorships.}}, Gemma Moncunill ^a,^b,^j,^⁎,^{^{1
Shared authorships.}} , Carlota Dobaño ^a,^b,^j,^⁎,^{^{1
Shared authorships.}}
^a ISGlobal, Barcelona, Catalonia, Spain
^b Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain
^c Unitat de Suport a la Recerca de la Catalunya Central, Fundació Institut Universitari per a la Recerca a l′Atenció Primària de Salut Jordi Gol i Gurina, Manresa, Spain
^d Burnet Institute, Melbourne, Australia
^e Department of Infectious Diseases, University of Melbourne, Australia
^f School of Translational Medicine, Monash University, Australia
^g Institut d′Investigacions Biomèdiques August Pi Sunyer, Barcelona, Spain
^h Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
ⁱ IrsiCaixa, Badalona, Spain
^j CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Barcelona, Spain
^k Department of Medicine. Faculty of Medicine. Universitat de Vic-Central de Catalunya, UVic-UCC, Vic, Spain
^l Institut Germans Trias I Pujol, IGTP, Badalona, Spain
^m Health Promotion in Rural Areas Research Group, Gerència d′Atenció Primària i a la Comunitat Catalunya Central, Institut Català de la Salut, Manresa, Spain
ⁿ Centre d′Atenció Primària (CAP) Sant Joan de Vilatorrada, Gerència d′Atenció Primària i a la Comunitat Catalunya Central, Institut Català de la Salut, Spain

^⁎Correspondence to: ISGlobal, Carrer del Rosselló, 153, 08036 Barcelona, Spain.ISGlobalCarrer del Rosselló, 153Barcelona08036Spain

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Summary

Objectives

Repeated COVID-19 mRNA vaccinations increase SARS-CoV-2 IgG4 antibodies, indicating extensive IgG class switching following the first booster dose. This shift in IgG subclasses raises concerns due to the limited ability of IgG4 to mediate Fc-dependent effector functions.

Methods

To assess the impact of IgG4 induction on protective immunity, we analyzed longitudinal SARS-CoV-2 IgG subclasses, C1q and FcγR responses, and neutralizing activity in a well-characterized cohort of healthcare workers in Spain.

Results

Elevated IgG4 levels and higher ratios of non-cytophilic to cytophilic antibodies after booster vaccination were significantly associated with an increased risk of breakthrough infections (IgG4 HR[10-fold increase]=1.8, 95% CI=1.2–2.7; non-cytophilic to cytophilic ratio HR[10-fold increase]=1.5, 95% CI=1.1–1.9). Moreover, an increased non-cytophilic to cytophilic antibody ratio correlated with reduced functionality, including neutralization.

Conclusions

These findings suggest a potential association between IgG4 induction by mRNA vaccination and a higher risk of breakthrough infection, warranting further investigation into vaccination strategies to ensure sustained protection.

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Highlights

•	IgG4 and IgG2 levels increase markedly after the third mRNA dose against SARS-CoV-2.
•	Elevated IgG4 levels after booster vaccination associate with an increased risk of infections.
•	Increased non-cytophilic to cytophilic antibody ratio correlates with reduced functionality.

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Keywords : SARS-CoV-2, Humoral immunity, COVID-19 mRNA vaccines, SARS-CoV-2-specific antibodies, Fc effector function

Plan

Introduction

Materials and methods

Study design and setting

Quantification of IgG subclasses

Quantification of FcγR-binding antibodies

Quantification of C1q-binding antibodies

Neutralizing activity of plasma

Statistical analysis

Results

Kinetics of IgG subclasses, and FcγR and C1q-binding antibodies

Correlation of the ratio of non-cytophilic to cytophilic antibodies with antibody functionality

Association of IgG subclasses and ratio of non-cytophilic to cytophilic antibodies with risk of SARS-COV-2 infection

Discussion

Funding

Author contributions

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Vol 90 - N° 4

Article 106473- avril 2025 Retour au numéro

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Post-vaccination IgG4 and IgG2 class switch associates with increased risk of SARS-CoV-2 infections - 08/04/25

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