Journal Article Ahead of print
PubMed: 42343025 DOI: 10.1038/s43856-026-01723-2
First exposure to SARS-CoV-2 shapes IgG subclass switching after mRNA vaccination.
Commun Med (Lond)
Authors: Carla Martin Pérez, Sílvia Ruiz-Rius, Anna Ramírez-Morros, Marta Vidal, Alfons Jiménez, Luis Izquierdo, Pere Santamaria, Josep Vidal-Alaball, James G Beeson, Luis M Molinos-Albert, Ruth Aguilar, Anna Ruiz-Comellas, Gemma Moncunill, Carlota Dobaño
Affiliations
- ISGlobal, Barcelona, Catalonia, Spain.
- Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain.
- 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.
- CIBER Epidemiologia y Salud Pública (CIBERESP), Barcelona, Spain.
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Barcelona, Spain.
- Institut d'Investigacions Biomèdiques August Pi Sunyer, Barcelona, Spain.
- Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
- Department of Medicine, Faculty of Medicine, Universitat de Vic-Central de Catalunya, UVic-UCC, Vic, Spain.
- Health Promotion in Rural Areas Research Group, Gerència d'Atenció Primària i a la Comunitat Catalunya Central, Institut Català de la Salut, Manresa, Spain.
- Burnet Institute, Melbourne, VIC, Australia.
- Department of Infectious Diseases, University of Melbourne, Melbourne, VIC, Australia.
- School of Translational Medicine, Monash University, Melbourne, VIC, Australia.
- Centre d'Atenció Primària (CAP) Sant Joan de Vilatorrada, Gerència d'Atenció Primària i a la Comunitat Catalunya Central, Institut Català de la Salut, Sant Joan de Vilatorrada, Spain.
- ISGlobal, Barcelona, Catalonia, Spain.
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Barcelona, Spain.
- ISGlobal, Barcelona, Catalonia, Spain.
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Barcelona, Spain.
Abstract
BACKGROUND
mRNA vaccines against SARS-CoV-2 have proven highly effective in reducing severe disease and death, but repeated administration induces an unusual shift in IgG subclasses. In particular, increases in IgG2 and IgG4 raise questions about their regulation, persistence, and implications for protective immunity.
METHODS
To investigate the longitudinal dynamics and factors influencing IgG subclasses and their impact on protective immunity, we analyzed the levels of IgG1-4 subclasses, C1q, and FcγR-binding IgG against antigens from multiple SARS-CoV-2 variants in a well-characterized cohort of healthcare workers in Spain.
RESULTS
Our findings indicate that subclass responses are shaped by exposure history, with infection before vaccination limiting the extent of IgG2 and IgG4 class switching relative to infection after vaccination. IgG4 exhibits broader reactivity to Omicron variants than IgG1, and both IgG2 and IgG4 show slower decay of circulating antibody levels than IgG1. IgG4 levels correlate with FcγR- and C1q-binding antibodies only in participants with lower IgG1, suggesting competition between subclasses. During Omicron predominance, elevated IgG2 and IgG4 are linked to increased risk of breakthrough infection in vaccinees, whereas levels of IgG1 and FcγR- and C1q-binding antibodies are associated with protection.
CONCLUSIONS
Our findings highlight marked differences in IgG subclass profiles according to first exposure history and suggest that IgG subclass distribution and persistence may influence antibody-mediated immunity following mRNA vaccination. Further studies are warranted to clarify the mechanistic and clinical implications of IgG subclass shift for long-term protection.
MeSH
Sars-Cov-2, Vaccines, Antibodies, Rna, Messenger, Vaccination, Immunity, Severe Acute Respiratory Syndrome-Related Coronavirus, History, Infections