A new study analysing the immune response to COVID-19 in a Catalan cohort of health workers sheds light on an important question: does it matter whether a person was first infected or first vaccinated? According to the results, the order of the events does alter the outcome, at least when it comes to long-term protection against Omicron. The study, published in Nature Communications, was led by the Barcelona Institute for Global Health (ISGlobal) in collaboration with the Catalan Health Institute (ICS) and the Jordi Gol Institute (IDIAP JG), and with support from the Daniel Bravo Andreu Private Foundation (FPDBA).
Since the start of the pandemic, scientists have studied how the body responds to SARS-CoV-2, focusing on antibodies and on T-cell responses. Today, most people have what is known as hybrid immunity, meaning a combination of vaccination and infection. "Previous studies have shown that hybrid immunity provides stronger protection than either vaccination or infection alone," says ISGlobal researcher Carlota Dobaño, "but whether the order of these exposures affected the outcome remained an open question".
A unique four-year dataset
The study was conducted among healthcare professionals from ICS Central Catalonia, a group that was particularly exposed to SARS-CoV-2 throughout the different waves of the pandemic. The team led by Dobaño analysed blood samples collected repeatedly between 2020 and 2023 from 357 healthcare professionals in the CovidCatCentral cohort. Of these, 160 were vaccinated before becoming infected, while 197 were infected first. Among the latter, almost all (98%) were infected with the original Wuhan variant.
"This long-term follow-up has made it possible to build a solid and highly relevant database to analyse the immune response to COVID-19 over time," says Anna Ruiz-Comellas, a researcher at ICS–IDIAP Jordi Gol who led the fieldwork. Thanks to regular serological testing, it was possible to detect both symptomatic and asymptomatic infections. The team assessed antibody and T-cell responses to five different viral antigens
Stronger antibodies to Omicron in those vaccinated first
The study found that, compared to those initially infected, people who were first exposed to SARS-CoV-2 through vaccination developed higher levels of IgG and IgA antibodies against six Omicron lineages (particularly, to the receptor binding domain of the Spike protein). This difference became smaller as individuals accumulated more exposures to the virus.
"In contrast, those infected first mounted a somewhat stronger T-cell response, which may result from being exposed to a wider repertoire of antigens or higher viral loads," says ISGlobal researcher and senior co-author Gemma Moncunill . However, the authors note that the number of participants evaluated for T-cell immunity was limited, so these results should be interpreted with caution.
Antibody dynamics reflect clinical protection
These antibody differences were reflected in clinical protection over time. People infected first were better protected early in the pandemic, when variants were closer to the original strain. But with the arrival of Omicron, the advantage shifted: those vaccinated first were better protected from breakthrough infections.
"Our results provide new evidence that first exposure to SARS-CoV-2 antigens via vaccination strengthens the long-term protective effect of hybrid immunity," says Otavio Ranzani, first author of the study. Overall, the study highlights the role of the vaccination campaigns against SARS-CoV-2 by helping shape a strong immune response as new variants emerge.
This study is part of the EU-funded END-VOC project , which aims to support the response to COVID-19 and other pandemics.
Reference
Ranzani O., Martín Pérez C., Rubio R. et al. Primary SARS-CoV-2 exposure by vaccination or infection shapes immune responses to omicron variants among a Spanish cohort. Nat Commun (2025). https://doi.org/10.1038/s41467-025-67577-9
