Primary SARS-CoV-2 exposure by vaccination or infection shapes immune responses to omicron variants among a Spanish cohort.

The comparison between vaccine-induced and infection-acquired adaptive immunity, and their co-occurrence -referred to as "hybrid immunity"- is of great interest and remains an area with significant knowledge gaps. Given that most of the population already has hybrid immunity to COVID-19, a key question is whether the order of infection-acquired and vaccine-induced immunity affects the immune response. Here, we analyze the humoral and T-cell responses in a Spanish cohort with longitudinal blood sampling spanning 2020-2023. We observe higher anti-RBD antibody levels against Omicron in individuals initially exposed to SARS-CoV-2 antigens via vaccination compared to those first exposed through natural infection. This difference diminishes with an increasing number of exposures. The dynamics of antibody levels over time correlate with clinical protection: those first-infected have higher protection early on, whereas those first-vaccinated show greater protection later, especially with the arrival of the Omicron variant. This phenomenon may reflect immune imprinting. In contrast to the humoral response, the T-cell response is higher in individuals first exposed through infection, although T-cell findings may be underpowered because of limited sample size. Our study provides valuable insights into the impact of initial antigen exposure on humoral and cellular responses to SARS-CoV-2.