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Clonal dissection of immunodominance and cross-reactivity of the CD4+ T cell response to SARS-CoV-2

Jun Siong Low, Daniela Vaqueirinho, Federico Mele, Mathilde Foglierini, Michela Perotti, David Jarrossay, Sandra Jovic, Tatiana Terrot, Alessandra Franzetti Pellanda, Maira Biggiogero, Christian Garzoni, Paolo Ferrari, Alessandro Ceschi, Antonio Lanzavecchia, Antonino Cassotta, Federica Sallusto
doi: https://doi.org/10.1101/2021.03.23.436642
Jun Siong Low
1Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland
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Daniela Vaqueirinho
1Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland
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Federico Mele
1Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland
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Mathilde Foglierini
1Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland
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Michela Perotti
1Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland
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David Jarrossay
1Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland
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Sandra Jovic
1Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland
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Tatiana Terrot
2Trial Unit, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
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Alessandra Franzetti Pellanda
3Clinic of Internal Medicine and Infectious Diseases, Clinica Luganese Moncucco, 6900 Lugano, Switzerland
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Maira Biggiogero
3Clinic of Internal Medicine and Infectious Diseases, Clinica Luganese Moncucco, 6900 Lugano, Switzerland
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Christian Garzoni
3Clinic of Internal Medicine and Infectious Diseases, Clinica Luganese Moncucco, 6900 Lugano, Switzerland
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Paolo Ferrari
4Faculty of Biomedical Sciences, Università della Svizzera italiana, 6900 Lugano, Switzerland
5Department of Internal Medicine, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
6Prince of Wales Hospital Clinical School, University of New South Wales, Sydney, NSW 2052, Australia
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Alessandro Ceschi
2Trial Unit, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
4Faculty of Biomedical Sciences, Università della Svizzera italiana, 6900 Lugano, Switzerland
7Division of Clinical Pharmacology and Toxicology, Institute of Pharmacological Sciences of Southern Switzerland, Ente Ospedaliero Cantonale, 6900 Lugano, Switzerland
8Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, 8091 Zurich, Switzerland
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Antonio Lanzavecchia
9National Institute of Molecular Genetics, 20122 Milano, Italy
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Antonino Cassotta
1Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland
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  • For correspondence: federica.sallusto@irb.usi.ch antonino.cassotta@irb.usi.ch
Federica Sallusto
1Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland
10Institute of Microbiology, ETH Zürich, Switzerland
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  • For correspondence: federica.sallusto@irb.usi.ch antonino.cassotta@irb.usi.ch
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Abstract

The identification of CD4+ T cell epitopes is essential for the design of effective vaccines capable of inducing neutralizing antibodies and long-term immunity. Here we demonstrate in COVID-19 patients a robust CD4+ T cell response to naturally processed SARS-CoV-2 Spike and Nucleoprotein, including effector, helper and memory T cells. By characterizing 2,943 Spike-reactive T cell clones, we found that 34% of the clones and 93% of the patients recognized a conserved immunodominant region encompassing residues S346-365 in the RBD and comprising three nested HLA-DR and HLA-DP restricted epitopes. By using pre- and post-COVID-19 samples and Spike proteins from alpha and beta coronaviruses, we provide in vivo evidence of cross-reactive T cell responses targeting multiple sites in the SARS-CoV-2 Spike protein. The possibility of leveraging immunodominant and cross-reactive T helper epitopes is instrumental for vaccination strategies that can be rapidly adapted to counteract emerging SARS-CoV-2 variants.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 23, 2021.
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Clonal dissection of immunodominance and cross-reactivity of the CD4+ T cell response to SARS-CoV-2
Jun Siong Low, Daniela Vaqueirinho, Federico Mele, Mathilde Foglierini, Michela Perotti, David Jarrossay, Sandra Jovic, Tatiana Terrot, Alessandra Franzetti Pellanda, Maira Biggiogero, Christian Garzoni, Paolo Ferrari, Alessandro Ceschi, Antonio Lanzavecchia, Antonino Cassotta, Federica Sallusto
bioRxiv 2021.03.23.436642; doi: https://doi.org/10.1101/2021.03.23.436642
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Clonal dissection of immunodominance and cross-reactivity of the CD4+ T cell response to SARS-CoV-2
Jun Siong Low, Daniela Vaqueirinho, Federico Mele, Mathilde Foglierini, Michela Perotti, David Jarrossay, Sandra Jovic, Tatiana Terrot, Alessandra Franzetti Pellanda, Maira Biggiogero, Christian Garzoni, Paolo Ferrari, Alessandro Ceschi, Antonio Lanzavecchia, Antonino Cassotta, Federica Sallusto
bioRxiv 2021.03.23.436642; doi: https://doi.org/10.1101/2021.03.23.436642

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