Profound CD8 T-cell responses towardsSARS-CoV-2 OFR1ab in COVID-19 patients

ABSTRACT

While there is accumulating evidence on the antibody response against SARS-CoV-2, we are only beginning toacquire knowledge regarding the SARS-CoV-2 specific CD8 T-cell response. Therefore, it is an urgent matter to gaina deeper insight into the virus specific CD8 T-cell response to both assist vaccine design and provide tools toevaluate the vaccine-induced T-cell responses. To address this issue, we have analyzed samples from 20 COVID-19 patients for CD8 T-cell recognition of 500 predicted SARS-CoV-2-derived epitopes restricted to 10 of the mostcommon HLA-A and HLA-B alleles. For each HLA allele, the top 50 epitopes were selected based on predictedbinding affinity and likelihood of successful proteasomal processing. In addition, SARS-CoV-2 epitope predictionsshared by the science community were considered. To probe for CD8 T-cell recognition of the selected epitopes, wemade use of our in-house technology based on multiplexing of peptide HLA (pHLA) multimers conjugated tofluorescent dyes. Our data demonstrated that CD8 T-cell reactivity against SARS-CoV-2 was common. Remarkably, a substantial fraction of the observed CD8 T-cell responses were directed towards the ORF1ab polyprotein 1ab.These CD8 T-cell responses were frequently of a profound magnitude. In particular, a CD8 T-cell response towardsa potentially immunodominant epitope (TTDPSFLGRY) restricted to the HLA-A∗0101 allele was found in all patientspositive for this allele. Interestingly, the fraction of SARS-CoV-2 specific CD8 T cells expressing the inhibitoryreceptor NKG2A was higher as compared to bulk CD8 T cells. In conclusion, the fact that a major part of theidentified SARS-CoV-2 specific CD8 T-cell response is directed against a part of the viral genome that is notincluded in the majority of vaccine candidates currently in development may potentially influence their clinical activityand toxicity profile.