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Authors: Ferretti et al. 

Journal/ Pre-Print:Medrxirv 

Tags: Bioinformatics, Clinical, Immunology/Immunity 

Research Highlights  

  1. Mapping SARS-CoV-2 T cell epitopes presented by six of the most common Class I HLA types reveals that memory CD8+ T cells from recovered COVID-19 patient target a limited set of shared immunodominant epitopes (3-8 for each HLA type).  

  1. These epitopes are not on high variable regions and are largely unique to SARS-CoV-2. Only 10% of those correspond to spike protein (only 3 of the 29 epitopes). This highlights the need to design vaccines that mimic natural CD8+ T cell responses and tempers enthusiasm related to potential cross-reactivity with common cold coronaviruses 

  1. Single-cell sequencing revealed that many different T cell clones target the same epitope, although it is the same TCR Va region that targets these epitopes. 

Summary  

Ferretti et al. performed an unbiased and detailed genome-wide screen (T-Scan) on memory CD8+ T cells against SARS-CoV-2 epitopes from 25 convalescent COVID-19 patients, focusing on epitopes presented by the most commonly expressed Class I HLASARS-CoV-2 CD8+ T cell memory establishment appears to be dominated by few antigenic epitopes that are shared among the same HLA typeMoreover, analysis of one specific HLA type (A*02:01) confirmed the presence of memory CD8+ T cells and revealed that many different T clonotypes target the same epitope. Specific fragments were recurrently recognised by the T cells of multiple patients that shared the same dominant TCR Va geneThe epitopes were compared to SARS-CoV-1 and common cold hCoV epitopes but found to be largely unique to SARS-CoV-2 and not on high variable regions. As many other studies have recently shown, only a small proportion (10%) of these epitopes correspond to the spike protein, highlighting the importance of the immune response against other parts of the virus such ORF1ab and N protein. 

Impact for SARS-CoV2/COVID19 research efforts  

Understand the precise targets of the CD8+ cellular immune response establishing immune memory and epitope specificity and frequency to SARS-CoV2/COVID19 

Study Type  

  • Bioinformatics study 

  • Clinical Cohort study  

Strengths and limitations of the paper 

Novelty:  

Comprehensive mapping of the COVID-19 convalescent CD8+T memory response by prevalent HLA types. Shows an oligoclonal response- with the same Va fragmentthat largely targets a limited set of shared immunodominant epitopes.  

Standing in the field:  

Implications for vaccine development. In line with current literature for analysis of convalescent patients regarding immunodominance hierarchy (Griffoni et al. or Le Bert et al); and in contrast with in silico studies predicting epitopes presented by HLA alleles and other studies showing cross-reactivity to hCoV under different experimental setups  

Appropriate statistics: The data are well presented and mostly descriptive but there are no statistical tests for significance.  

Viral model used: Clinical samples of recovered COVID-19 patients 

Translatability: This study does not aim for translatability per se but provides important information to help direct vaccine strategiesMoreover, there may be the potential for testing the presence of SARS-CoV2 specific memory CD8+ T cell IFNg secretion after ex vivo stimulation to identify previous infection. 

Main limitations:  

  • While the study suggests that these specific epitopes are result in CD8+ T cell memory, this does not necessarily mean that they were the efficient effector clones during the immune response. It would be interesting to look at affinity for the recognised epitope. 

  • Statistics are not clearly shown