COVID-19 vaccination induces long-lasting antibody B-cell responses

Three doses of COVID-19 mRNA vaccination induce long-lasting antibody and memory B-cell responses, according to a study of 113 healthcare workers in Catalonia who were followed during three years. The study, led by ISGlobal in collaboration with the Fundación Privada Daniel Bravo Andreu (FPDBA) and published in Cell Reports, also shows that exposure to the virus prior to vaccination differentially imprints the immune systems without compromising the quality of the antibody response.

Memory B cells are essential for maintaining a long-term immune response: they rapidly proliferate upon antigen rencounter and differentiate into antibody secreting cells. “There is the belief that vaccine-induced antibodies to SARS-CoV-2 decay rather rapidly, but recent evidence suggests that they remain quite stable over time,” says Gemma Moncunill, senior co-author of the study, together with ISGlobal colleague Carlota Dobaño.

As part of the European END-VOC project, the research team evaluated the durability and quality of SARS-CoV-2 antibody and memory B-cell responses in 113 individuals from a cohort of healthcare workers (CovidCatCentral) who were followed over 3 years since the start of the pandemic.

Durable B-cell responses

The findings reveal that individuals -whether or not they had been infected by SARS-CoV-2 before their first vaccine dose- developed comparable antibody and memory B-cell responses nearly a year and a half after completing a three-dose mRNA vaccination.

“Over time, we saw a progressive increase in the proportion of memory B cells recognising the receptor-binding domain (RBD) of the Spike protein, pointing to their continuous selection upon exposure to evolving variants,” says Luis Molinos-Albert, first author of the study. Notably, these RBD-reactive B cells were associated with lower breakthrough infections in individuals who had not been infected before vaccination. Meanwhile, individuals who had been exposed to the virus prior to vaccination developed an atypical subset of memory B cells that remained stable over time. “This is probably due to the different environment generated by primary mRNA vaccination as compared with viral infection,” says Dobaño, “but we still do not know whether this subset is detrimental or beneficial,” she adds.

Overall, the study findings show that both groups (previously exposed or not exposed) could develop efficient memory responses, but that having been infected first leaves a distinct imprint on the immune system. “Our data highlight the durability of SARS-CoV-2 immune responses, but they also suggest that updated vaccines to target new variants could further enhance immunity, especially in those previously infected,” concludes Moncunill.  

Switch to IgG4 antibodies upon repeated vaccination

In a related study using the same cohort, the research team found an increase in a certain subclass of virus-specific antibodies known as IgG4 after three mRNA doses. Vaccinated people with the highest levels of IgG4 and IgG2 antibodies, which have a lower capacity to neutralise the virus and activate other immune functions, had a higher risk of breakthrough infections.

References

Molinos-Albert L, Rubio R, Martín-Pérez C et al. Long-lasting antibody B-cell responses to SARS-CoV-2 three years after the onset of the pandemic. Cell Reports. 2025. DOI: 10.1016/j.celrep.2025.115498

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