A study led by IDIAPJGol and the Catalan Institute of Health (ICS) has confirmed that the first exposure to SARS-CoV-2 influences immunity against COVID-19. The research, published in the scientific journal Nature Communications, analyzed immune responses in several healthcare professionals who were followed for four years. The study concludes that the order in which infection and vaccination occur determines the long-term immune response and protection against variants such as Omicron.
Since the beginning of the pandemic, the scientific community has studied how the body responds to SARS-CoV-2, both through antibodies and T-cell responses. Currently, most of the population has what is known as hybrid immunity, resulting from the combination of vaccination and infection. “Previous studies have shown that hybrid immunity offers superior protection, but it remained unclear whether the order of these exposures affected the outcome,” explains Carlota Dobaño, an ISGlobal researcher who coordinated the study.
A long-term follow-up study of healthcare professionals
The fieldwork, led by Anna Ruiz-Comellas, a researcher at IDIAP Jordi Gol, included the periodic collection of biological samples and clinical follow-up of participants over four years. This long-term monitoring made it possible to build a solid and highly relevant database to analyze the evolution of immune responses to COVID-19.
The team analyzed blood samples repeatedly collected between 2020 and 2023 from 357 healthcare professionals. Thanks to periodic serological testing, it was possible to detect both symptomatic and asymptomatic infections. The team assessed antibody and T-cell responses against five different viral antigens.
Stronger antibodies against variants
These differences in antibody responses were also reflected in clinical protection over time. Individuals who were infected first were better protected at the beginning of the pandemic, when circulating variants were more similar to the original strain. However, with the arrival of Omicron, the advantage shifted, and those who were vaccinated first showed greater protection against subsequent infections.
The study highlights the key role of vaccination in strengthening long-term immunity. “Our results provide new evidence that first exposure to SARS-CoV-2 through vaccination enhances the long-term protective effect of hybrid immunity,” concludes Otavio Ranzani, first author of the study.
Article 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://www.nature.com/articles/s41467-025-67577-9
