The immunodominant pan-coronavirus epitope iCope spans amino acids 816–830 within the fusion domain of the SARS-CoV-2 spike glycoprotein. This region exhibits a comparatively low mutation rate, especially when contrasted with the receptor-binding domain (RBD). Antigen-specific T cell responses against iCope are detectable even in unexposed individuals, are modestly enhanced following SARS-CoV-2 infection, and are robustly boosted by two doses of the BNT162b2 vaccine (BioNTech/Pfizer). Strikingly, in individuals over 70 years of age, vaccination fails to enhance the quantity and quality (avidity) of the iCope-specific T cell response, likely due to a restricted TCR repertoire targeting this epitope. In contrast, iCope-specific antibody titers do not exhibit an age-dependent decline.
ABSTRACT
Immune evasion by escape mutations subverts immunity against SARS-CoV-2. A role of pan-coronavirus immunity for more durable protection is being discussed, but has remained understudied. We here investigated the effects of age, mutations, and homo-/heterologous vaccination regimens on the dominant pan-coronavirus-specific cellular and humoral epitope iCope after SARS-CoV-2 infection and vaccination in detail. In older individuals, the quantitatively and qualitatively reduced iCope-reactive CD4+ T cell responses with narrow TCR repertoires could not be enhanced by vaccination and were further compromised by emerging spike mutations. In contrast, pan-coronavirus-reactive humoral immunity was affected only by mutations and not by age. Our results reveal a distinct deficiency of the dichotomous layer of pan-coronavirus immunity in the older, critical for long-term protection against SARS-CoV-2 variants.