Breakthrough SARS-COV-2 infection induces broad anti-viral T cell immunity

Vaccines have curtailed the devastation wrought by COVID-19. Nevertheless, emerging variants result in a high incidence of breakthrough infections. Here we assess the impact of vaccination and breakthrough infection on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) T cell immunity. We demonstrate that COVID-19 vaccination induces robust spike-specific T cell responses that, within the CD4⁺ compartment, display comparable IFN-γ responses to SARS-CoV-2 infection without vaccination. Vaccine-induced CD8⁺ IFN-γ responses however, were significantly greater than those primed by SARS-CoV-2 infection alone. This increased responsiveness is associated with induction of novel HLA-restricted CD8⁺ T cell epitopes not primed by infection alone (without vaccination). Despite these augmented responses, breakthrough infection still induced de novo T cell responses against additional SARS-CoV-2 CD8⁺ epitopes that display HLA-associated immunodominance hierarchies consistent with those in unvaccinated COVID-19 convalescent individuals. This study demonstrates the unique modulation of anti-viral T cell responses against multiple viral antigens following consecutive yet distinct priming events in COVID-19 vaccination and breakthrough infection.