END-VOC researchers show that the antibody profile evolves with repeated mRNA vaccination, offering new clues about long-term protection against COVID-19
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Repeated doses of mRNA COVID-19 vaccines not only increase antibody levels but also change the types of antibodies that are produced over time, shows a new study led by END-VOC researchers at ISGlobal and IDIAPJG, Spain, in collaboration with the Institut Catalá de la Salut (ICS). The findings help explain how previous infection and vaccination history shape long-term immune responses and could inform the design of future vaccination strategies.
Since their introduction, mRNA vaccines against SARS-CoV-2 have saved millions of lives by dramatically reducing severe disease and death. However, the team led by ISGlobal researchers Carlota Dobaño and Gemma Moncunill had observed that repeated vaccination induces an unusual shift in antibody subclasses, particularly an increase in two types known as IgG2 and IgG4. “However, until now, little was known about what drives these changes or whether they affect protection against infection,” says Moncunill.
To investigate this, the researchers followed a well-characterised cohort of 93 healthcare workers recruited since the early days of the pandemic in Barcelona, Spain (CovidCatCentral). They analysed blood samples collected over time and measured four subclasses of IgG antibodies (IgG1 to IgG4) against different SARS-CoV-2 variants, as well as other immune functions involved in virus neutralisation and clearance.
First exposure leaves a lasting imprint
Consistent with their previous work, the researchers found that a person’s first exposure to the virus plays an important role in shaping these antibody responses. Participants who had been infected before receiving the vaccine developed lower levels of IgG2 and IgG4 than those whose first exposure was vaccination followed by infection. The researchers also found that IgG2 and IgG4 antibodies remained in circulation for longer than the more common IgG1 antibodies. In addition, IgG4 recognised a broader range of Omicron variants than IgG1, suggesting it may contribute to the immune response against new viral variants.
However, not all antibody subclasses appear to play the same role in protection. During the period when Omicron variants were circulating, higher levels of IgG2 and IgG4 were associated with an increased risk of breakthrough infections among vaccinated participants, while higher levels of IgG1 and antibodies capable of activating other immune defence mechanisms were linked to greater protection. “These findings suggest that the shift in antibody subclasses may somewhat hamper the protection provided by booster doses,” says Carla Martin, first author of the study. “However, boosters remain essential for maintaining protection against newly emerging SARS-CoV-2 variants.”
“Our study shows that the immune response after repeated mRNA vaccination is more complex than simply producing more antibodies,” explains Dobaño. In other words, the type of antibody produced, and how long it persists, also matters.
Overall, these results provide new insights into how antibody responses evolve after repeated vaccination and infection, and suggest that future vaccines may need to consider antibody quality, and not only quantity, to improve long-term protection.
Reference:
Martin Pérez, C., Ruiz-Rius, S., Ramírez-Morros, A. et al. First exposure to SARS-CoV-2 shapes IgG subclass switching after mRNA vaccination. Commun Med (2026). https://doi.org/10.1038/s43856-026-01723-2
