Identification and assessment of TCR-T cells targeting an epitope conserved in SARS-CoV-2 variants for the treatment of COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) continues to be a major global public health challenge, with the emergence of variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current vaccines or monoclonal antibodies may not well be protect against infection with new SARS-CoV-2 variants. Unlike antibody-based treatment, T cell-based therapies such as TCR-T cells can target epitopes that are highly conserved across different SARS-CoV-2 variants. Reportedly, T cell-based immunity alone can restrict SARS-CoV-2 replication. METHODS: In this study, we identified two TCRs targeting the RNA-dependent RNA polymerase (RdRp) protein in CD8 + T cells. Functional evaluation by transducing these TCRs into CD8 + or CD4 + T cells confirmed their specificity. RESULTS: Combinations of inflammatory and anti-inflammatory cytokines secreted by CD8 + and CD4 + T cells can help control COVID-19 in patients. Moreover, the targeted epitope is highly conserved in all emerged SARS-CoV-2 variants, including the Omicron. It is also conserved in the seven coronaviruses that infect humans and more broadly in the subfamily Coronavirinae. CONCLUSIONS: The pan-genera coverage of mutant epitopes from the Coronavirinae subfamily by the two TCRs highlights the unique strengths of TCR-T cell therapies in controlling the ongoing pandemic and in preparing for the next coronavirus outbreak.

Identification and assessment of TCR-T cells targeting an epitope conserved in SARS-CoV-2 variants for the treatment of COVID-19

Background Coronavirus disease 2019 (COVID-19) continues to be a major global public health challenge, with the emergence of variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current vaccines or monoclonal antibodies may not well be protect against infection with new SARS-CoV-2 variants. Unlike antibody-based treatment, T cell-based therapies such as TCR-T cells can target epitopes that are highly conserved across different SARS-CoV-2 variants. Reportedly, T cell-based immunity alone can restrict SARS-CoV-2 replication. Methods In this study, we identified two TCRs targeting the RNA-dependent RNA polymerase (RdRp) protein in CD8+ T cells. Functional evaluation by transducing these TCRs into CD8+ or CD4+ T cells confirmed their specificity. Results Combinations of inflammatory and anti-inflammatory cytokines secreted by CD8+ and CD4+ T cells can help control COVID-19 in patients. Moreover, the targeted epitope is highly conserved in all emerged SARS-CoV-2 variants, including the Omicron. It is also conserved in the seven coronaviruses that infect humans and more broadly in the subfamily Coronavirinae. Conclusions The pan-genera coverage of mutant epitopes from the Coronavirinae subfamily by the two TCRs highlights the unique strengths of TCR-T cell therapies in controlling the ongoing pandemic and in preparing for the next coronavirus outbreak.

Large-Scale Identification of T-Cell Epitopes Derived From Severe Acute Respiratory Syndrome Coronavirus 2 for the Development of Peptide Vaccines Against Coronavirus Disease 2019.

BACKGROUND: Coronavirus disease 2019 (COVID-19) continues to be a major public health challenge globally. The identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-derived T-cell epitopes is of critical importance for peptide vaccines or diagnostic tools of COVID-19. METHODS: In this study, several SARS-CoV-2-derived human leukocyte antigen (HLA)-I binding peptides were predicted by NetMHCpan-4.1 and selected by Popcover to achieve pancoverage of the Chinese population. The top 5 ranked peptides derived from each protein of SARS-CoV-2 were then evaluated using peripheral blood mononuclear cells from unexposed individuals (negative for SARS-CoV-2 immunoglobulin G). RESULTS: Seven epitopes derived from 4 SARS-CoV-2 proteins were identified. It is interesting to note that most (5 of 7) of the SARS-CoV-2-derived peptides with predicted affinities for HLA-I molecules were identified as HLA-II-restricted epitopes and induced CD4+ T cell-dependent responses. These results complete missing pieces of pre-existing SARS-CoV-2-specific T cells and suggest that pre-existing T cells targeting all SARS-CoV-2-encoded proteins can be discovered in unexposed populations. CONCLUSIONS: In summary, in the current study, we present an alternative and effective strategy for the identification of T-cell epitopes of SARS-CoV-2 in healthy subjects, which may indicate an important role in the development of peptide vaccines for COVID-19.