Characterising the CD8+ T cell response to SARS-CoV-2 infection and vaccination

CD8+ T cells play a central role in protection against severe SARS-CoV-2 infection, particularly as antibody-mediated immunity wanes or is undermined by viral evolution. However, how different exposure histories shape the magnitude, phenotype, and development of SARS-CoV-2-specific CD8+ T cell responses remains incompletely understood. This thesis characterises SARS-CoV-2-specific CD8+ T cell immunity across exposure contexts, incorporating data from individuals with severe infection, mild infection, and vaccination primes, at a range of timepoints spanning multiple vaccine doses and breakthrough infections.
Using IFN-γ ELISpot as well as peptide:MHC multimer staining with multiparameter spectral flow cytometry, SARS-CoV-2-specific CD8+ T cell responses were quantified and characterised over time. Across cohorts, the nature of the priming exposure emerged as a dominant determinant of the response. Attainable population magnitude was determined by a priming-dependent homeostatic ceiling; infection priming induced larger populations, while vaccination-induced populations remained constrained even following breakthrough infection, although responses to both primes were durable and exhibited cytotoxic effector potential.
Beyond magnitude, priming exposure also determined a phenotypic differentiation trajectory that was established early and remained stable over time. Infection-primed spike-specific CD8+ T cells rapidly adopted a highly cytotoxic, terminally differentiated phenotype that persisted through vaccination, breakthrough infection, and long-term follow-up. Vaccine-primed spike-specific responses, however, did not converge on this phenotype, even after infection, indicating a durable imprint of the priming exposure. Non-spike-specific responses exhibited greater phenotypic flexibility and included stem cell-like and pre-effector populations consistent with long-term memory-associated phenotypes.
Together, these findings demonstrate that SARS-CoV-2-specific CD8+ T cell immunity is robust, long-lived, and strongly shaped by the immunological context of the primary exposure. Importantly, maximal cytotoxic differentiation and large population size are not required for effective protection, highlighting the efficiency and durability of vaccine-induced cellular immunity and informing future vaccination strategies in an endemic setting.