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 the older, 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. One-Sentence SummaryAging and viral evolution impair dominant pan-coronavirus immunity, a hallmark of efficient and broad immune competence against SARS-CoV-2