Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent COVID-19 patients
Peng Y., Mentzer AJ., Liu G., Yao X., Yin Z., Dong D., Dejnirattisai W., Rostron T., Supasa P., Liu C., Lopez-Camacho C., Slon-campos J., Zhao Y., Stuart D., Paeson G., Grimes J., Antson F., Bayfield OW., Hawkins DEDP., Ker D-S., Turtle L., Subramaniam K., Thomson P., Zhang P., Dold C., Ratcliff J., Simmonds P., de Silva T., Sopp P., Wellington D., Rajapaksa U., Chen Y-L., Salio M., Napolitani G., Paes W., Borrow P., Kessler B., Fry JW., Schwabe NF., Semple MG., Baillie KJ., Moore S., Openshaw PJM., Ansari A., Dunachie S., Barnes E., Frater J., Kerr G., Goulder P., Lockett T., Levin R., Cornall RJ., Conlon C., Klenerman P., McMichael A., Screaton G., Mongkolsapaya J., Knight JC., Ogg G., Dong T.
<jats:title>Abstract</jats:title><jats:p>COVID-19 is an ongoing global crisis in which the development of effective vaccines and therapeutics will depend critically on understanding the natural immunity to the virus, including the role of SARS-CoV-2-specific T cells. We have conducted a study of 42 patients following recovery from COVID-19, including 28 mild and 14 severe cases, comparing their T cell responses to those of 16 control donors. We assessed the immune memory of T cell responses using IFNγ based assays with overlapping peptides spanning SARS-CoV-2 apart from ORF1. We found the breadth, magnitude and frequency of memory T cell responses from COVID-19 were significantly higher in severe compared to mild COVID-19 cases, and this effect was most marked in response to spike, membrane, and ORF3a proteins. Total and spike-specific T cell responses correlated with the anti-Spike, anti-Receptor Binding Domain (RBD) as well as anti-Nucleoprotein (NP) endpoint antibody titre (p<0.001, <0.001 and =0.002). We identified 39 separate peptides containing CD4<jats:sup>+</jats:sup> and/or CD8<jats:sup>+</jats:sup> epitopes, which strikingly included six immunodominant epitope clusters targeted by T cells in many donors, including 3 clusters in spike (recognised by 29%, 24%, 18% donors), two in the membrane protein (M, 32%, 47%) and one in the nucleoprotein (Np, 35%). CD8+ responses were further defined for their HLA restriction, including B*4001-restricted T cells showing central memory and effector memory phenotype. In mild cases, higher frequencies of multi-cytokine producing M- and NP-specific CD8<jats:sup>+</jats:sup> T cells than spike-specific CD8<jats:sup>+</jats:sup> T cells were observed. They furthermore showed a higher ratio of SARS-CoV-2-specific CD8<jats:sup>+</jats:sup> to CD4<jats:sup>+</jats:sup> T cell responses. Immunodominant epitope clusters and peptides containing T cell epitopes identified in this study will provide critical tools to study the role of virus-specific T cells in control and resolution of SARS-CoV-2 infections. The identification of T cell specificity and functionality associated with milder disease, highlights the potential importance of including non-spike proteins within future COVID-19 vaccine design.</jats:p>