Enhanced and long-lasting SARS-CoV-2 immune memory in individuals with common cold coronavirus cross-reactive T cell immunity

David Florian ¹ Michael A Bauer ¹ Amelie Popovitsch ¹ Ingrid Fae ¹ David N Springer ¹ Marianne Graninger ¹ Marianna Traugott ² Lukas Weseslindtner ¹ Stephan W Aberle ¹ Gottfried Fischer ¹ Michael Kundi ¹ Karin Stiasny ¹ Alexander Zoufaly ² Samuel J Landry ³ Judith H Aberle ^1*

• ¹ Medical University of Vienna, Vienna, Austria
• ² Kaiser-Franz-Josef-Spital, Vienna, Vienna, Austria
• ³ Tulane University, New Orleans, Louisiana, United States

With the continuous emergence of novel SARS-CoV-2 variants, long-lasting and broadly reactive cellular and humoral immunity is critical for durable protection from COVID-19. We investigated SARS-CoV-2-specific T cell immunity in relation to antibodies, infection outcome and disease severity and assessed its durability in a longitudinal cohort over a three-year time course. We identified preexisting T cells reactive to the seasonal coronavirus (CoV) OC43 that cross-react with the conserved SARS-CoV-2 spike S813-829 peptide. These cross-reactive T cells increased in frequency following SARS-CoV-2 infection or vaccination and correlated with enhanced spike-specific T cell responses and significantly reduced viral loads. Furthermore, our data revealed that CoV-cross-reactive T cells were maintained as part of the long-lasting memory response, contributing to increased T cell frequencies against omicron variants. These findings suggest a functional role of CoV-cross-reactive T cells that extends beyond the initial SARS-CoV-2 exposure, contributing to enhanced immunity against highly mutated SARS-CoV-2 variants.