CD8⁺T-cell memory induced by successive SARS-CoV-2 mRNA vaccinations is characterized by clonal replacement

Abstract

mRNA vaccines against the Spike glycoprotein of severe acute respiratory syndrome type 2 coronavirus (SARS-CoV-2) elicit strong T-cell responses. However, it is unknown whether T cell clones induced by the first vaccination or newly generated T cell clones dominate responses to the secondary vaccination. Here, we analyzed the kinetic profile of Spike-reactive T-cell clones before the first dose, one week after the first and second dose, and four weeks after the second dose of the BNT162b mRNA vaccine. Interestingly, a new set of Spike-reactive CD8+ T cell clones exhibited the greatest expansion following secondary vaccination and replaced the clones that had responded to the primary vaccination. Single-cell mRNA/protein/TCR analysis revealed that the first-responder clones exhibited a terminally differentiated phenotype, whereas second-responder clones exhibited an actively proliferating phenotype. These results show that Spike-reactive T cell responses induced by repetitive mRNA vaccination are augmented and maintained by replacement with newly-generated clones with proliferative potential.

Early acquisition of S-specific Tfh clonotypes after SARS-CoV-2 vaccination is associated with the longevity of anti-S antibodies

“…These observations suggest that these cross-reactive T cells might have been developed to establish tolerance against less harmful microbes, and thus unlikely to efficiently contribute to the protective viral immunity. Vaccination may induce opposite tendencies on T cell clonotypes that recognize the same antigen [35], which is hardly detected by the bulk T cell analyses. The current study highlights the necessity of dynamic tracing of T cell responses in an epitope-specific clonotype resolution for the evaluation of vaccine-induced immunity.…”