A large global effort is ongoing to develop vaccines against SARS-CoV-2, the causative agent of COVID-19. While there is accumulating information on the antibody response against SARS-CoV-2, less is known about the SARS-CoV-2 antigens that are targeted by CD8 T cells. Such knowledge will be of high value to gain fundamental insights into the antigenic landscape of SARS-CoV-2 recognized by CD8 T cells, to develop tool allowing focused analysis of the SARS-CoV-2 specific T cell responses directly ex vivo, and to understand whether current vaccine designs are covering the CD8 T cell recognized antigens.
To address this issue, we have analyzed samples from 18 COVID-19 patients for CD8 T cell recognition of 500 predicted SARS-CoV-2-derived epitopes restricted to 10 common HLA-A and HLA-B alleles. For each HLA allele, the top 50 epitopes were selected based on predicted binding affinity and likelihood of successful proteasomal processing. To probe for CD8 T cell recognition of the selected epitope-HLA complexes, we made use of our in-house technology based on multiplexing of peptide HLA (pHLA) multimers conjugated to fluorescent dyes.
In addition to previous studies showing CD8 T cell reactivity towards epitopes derived from the spike protein of SARS-CoV-2, we have identified several CD8 T cell recognized epitopes derived from the ORF1ab, including one epitope displaying clear immunodominant properties across patients positive for HLA-A*01:01. Investigation of the functional status of part of the identified responses (including 4 responses specific for the immunodominant epitope) revealed that the T cell responses were highly dysfunctional. In addition the SARS-CoV-2 specific CD8 T cell responses displayed an increased expression of NKG2A in comparison with bulk CD8 T cells, which may explain their dysfunctional state.
Our data suggest that part of the ORF1ab encodes multiple CD8 T cell antigens including one immunodominant epitope. Noteworthy these epitopes were derived from a part of the viral genome that is not included in the majority of vaccine candidates in development, and this may potentially influence their clinical activity and safety profile.
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All authors have declared no conflicts of interest.