Targets and cross-reactivity of human T cell recognition of common cold coronaviruses

The coronavirus (CoV) family includes several viruses infecting humans, highlighting the importance of exploring pan-CoV vaccine strategies to provide broad adaptive immune protection. We analyze T cell reac-tivity against representative Alpha (NL63) and Beta (OC43) common cold CoVs (CCCs) in pre-pandemic sam-ples. S, N, M, and nsp3 antigens are immunodominant, as shown for severe acute respiratory syndrome 2 (SARS2), while nsp2 and nsp12 are Alpha or Beta specific. We further identify 78 OC43-and 87 NL63-specific epitopes, and, for a subset of those, we assess the T cell capability to cross-recognize sequences from repre-sentative viruses belonging to AlphaCoV, sarbecoCoV, and Beta-non-sarbecoCoV groups. We find T cell cross-reactivity within the Alpha and Beta groups, in 89% of the instances associated with sequence conser-vation >67%. However, despite conservation, limited cross-reactivity is observed for sarbecoCoV, indicating that previous CoV exposure is a contributing factor in determining cross-reactivity. Overall, these results pro-vide critical insights in developing future pan-CoV vaccines.