For over three years, ENDVOC researchers analysed the quantity and function of different antibody classes in a cohort of healthcare workers who received mRNA vaccine booster doses
During the COVID-19 pandemic, a variety of vaccines were developed, with mRNA vaccines leading the way in Western countries. These vaccines have played a vital role in protecting against severe disease and death. They have also provided a unique opportunity to study how the immune system responds to repeated vaccinations over time.
“Several studies have shown that repeated doses of COVID-19 mRNA vaccines lead to a shift toward a specific antibody subclass called IgG4, raising some concerns,” explains Carlota Dobaño, ENDVOC researcher at ISGlobal and co-senior author of the study, together with Gemma Moncunill. IgG4 and IgG2 antibodies are known to have a lower capacity to neutralise the virus and to activate other immune mechanisms, compared to IgG1 and IgG3.
In this study, Dobaño and her team investigated the consequences of this IgG4 shift in a well-characterised cohort of healthcare workers in Catalonia (CovidCatCentral cohort) who received 3, 4 or 5 doses of mRNA vaccine. Over nearly three years, the research team analysed the type, function and virus-neutralising capacity of the different IgG antibodies.
What did the study find?
The study revealed that booster doses led to elevated IgG4 levels and an increase in the ratio of IgG4 relative to total IgG. Among people who received 3 vaccine doses, those with higher IgG4 and IgG2 levels had a reduced capacity to neutralise the virus, decreased effector functions, and a higher risk of breakthrough infections compared to those with lower levels. The association between IgG4 levels and infection risk remained independently of IgG1 levels.
“Our results confirm previous research showing a sharp increase in IgG4 and IgG2 levels after three doses of mRNA vaccines,” explains Carla Martín, first co-author of the study alongside Sílvia Ruiz. “But we go a step further by linking this antibody shift to a decrease in functions and in protection against infection” adds Ruiz. However, the researchers note that this shift may help protect against severe disease by mitigating excessive inflammation.
What does this mean for future vaccines?
This switch to IgG4 is not observed with other COVID-19 vaccines, such as adenovirus or protein-based ones. However, something similar has been observed following repeated vaccinations against malaria, HIV, and pertussis.
“We do not conclude that additional vaccine doses increase infection risk,” says Moncunill. “Booster doses remain essential for protection. But our findings warrant further investigation and suggest the need to re-evaluate vaccine formulations or booster schedules to ensure sustained protection” she adds.
Looking at other END-VOC cohorts
The research team is now analysing IgG4 levels in samples from other END-VOC cohorts, starting by Mozambique and Brazil, where non-mRNA vaccines were predominantly used.
Reference
Marín-Pérez C, Ruiz-Rius S, Ramírez-Morros A et al. Post-vaccination IgG4 and IgG2 class switch associates with increased risk of SARS-CoV-2 infections. J Infection. 2025. DOI: 10.1016/j.jinf.2025.106473
