Broad and strong memory CD4+and CD8+T cells induced by SARS-CoV-2 in UK convalescent COVID-19 patients
Authors: Peng Yanchun , Mentzer Alexander J. , Liu Guihai , Yao Xuan , Yin Zixi , Dong Danning , Dejnirattisai Wanwisa , Rostron Timothy , Supasa Piyada , Liu Chang , Lopez-Camacho Cesar , Slon-campos Jose , Zhao Yuguang , Stuart Dave , Paeson Guido , Grimes Jonathan , Antson Fred , Bayfield Oliver W. , Hawkins Dorothy EDP. , Ker De-Sheng , Turtle Lance , Subramaniam Krishanthi , Thomson Paul , Zhang Ping , Dold Christina , Ratcliff Jeremy , Simmonds Peter , de Silva Thushan , Sopp Paul , Wellington Dannielle , Rajapaksa Ushani , Chen Yi-Ling , Salio Mariolina , Napolitani Giorgio , Paes Wayne , Borrow Persephone , Kessler Benedikt , Fry Jeremy W. , Schwabe Nikolai F. , Semple Malcolm G , Baillie Kenneth J. , Moore Shona , Openshaw Peter JM , Ansari Azim , Dunachie Susanna , Barnes Ellie , Frater John , Kerr Georgina , Goulder Philip , Lockett Teresa , Levin Robert ,   Oxford Immunology Network Covid-19 Response T cell Consortium, Cornall Richard J. , Conlon Chris , Klenerman Paul , McMichael Andrew , Screaton Gavin , Mongkolsapaya Juthathip , Knight Julian C. , Ogg Graham , Dong Tao 
Published: June 2020

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+and/or CD8+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+T cells than spike-specific CD8+T cells were observed. They furthermore showed a higher ratio of SARS-CoV-2-specific CD8+to CD4+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.