Longitudinal Immunoprofiling of the CD8+ T-Cell Response in SARS-CoV-2 mRNA Vaccinees and COVID-19 Patients

<b>Background</b>: SARS-CoV-2 was the causing agent of the COVID-19 pandemic, which resulted in millions of deaths worldwide and massive economic losses. Although there are already several vaccines licensed, as novel variants develop, understanding the immune response induced by vaccination and natural infection is key for the development of future vaccines. <b>Methods</b>: In this study, we have used flow cytometry and next-generation sequencing to assess the longitudinal CD8⁺ T-cell response against natural infection and vaccination in convalescent and vaccinated individuals, from early activation to immune memory establishment. Moreover, we have characterized the T-cell receptor clonality and diversity at different stages post-infection and post-vaccination. <b>Results</b>: We have found no significant differences in CD8⁺ T-cell activation during the first three weeks post-infection compared to the first three weeks after first vaccination. Conversely, natural infection resulted in sustained high levels of T-cell activation at four weeks post-infection, a point in which we observed a decline in T-cell activation post-vaccination despite boosting with a second vaccination shot. Moreover, additional vaccination did not result in enhanced T-cell activation. Of note, we have observed variations in the memory subset structure at every stage of disease and vaccination. Overall, both infection and immunization induced a highly diverse T-cell receptor repertoire, which was observed both between study groups and between patients inside a given group. <b>Conclusions</b>: These data contribute to expand our knowledge about the immune response to SARS-CoV-2 infection and vaccination and call for additional strategies to enhance T-cell responses by booster immunization.