First exposure to SARS-CoV-2 shapes IgG subclass switching after mRNA vaccination

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. 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. 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. 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. COVID-19 mRNA vaccines are very effective at preventing severe illness, but repeated doses can change the subtype of protective molecules, called ‘antibodies’, that our bodies produce. This study examined how these different antibody types evolve over time and what factors influence them, as well as how they relate to protection against infection. Researchers followed healthcare workers in Spain over time, measuring different antibody types after vaccination and/or infection. They found that people’s first exposure to the virus components, whether by infection or vaccination, shaped their antibody responses. Some antibody types lasted longer but were linked to a higher risk of infection during Omicron waves, while others were associated with better protection. These findings suggest that not all antibodies work the same way, and future vaccines may need to consider antibody quality, not just quantity, to improve long-term protection. Martín Pérez et al. evaluated how IgG antibody subclasses evolve after SARS-CoV-2 vaccination or infection in healthcare workers. Infection as first exposure limited IgG2/IgG4 switching; IgG2/IgG4 levels had a slower decline than IgG1, and higher IgG4 was linked to increased infection risk, while IgG1 was associated with protection.