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ResearchIn-Press PreviewCOVID-19Immunology Open Access | 10.1172/jci.insight.147386

IgV somatic mutation of human anti-SARS-CoV-2 monoclonal antibodies governs neutralization and breadth of reactivity

Mayara Garcia de Mattos Barbosa,1 Hui Liu,1 Daniel Huynh,1 Greg Shelley,2 Evan T. Keller,2 Brian T. Emmer,3 Emily J. Sherman,3 David Ginsburg,4 Andrew A. Kennedy,3 Andrew W. Tai,3 Christiane E. Wobus,5 Carmen Mirabelli,5 Thomas M. Lanigan,6 Milagros Samaniego,7 Wenzhao Meng,8 Aaron M. Rosenfeld,8 Eline T. Luning Prak,9 Jeffrey L. Platt,1 and Marilia Cascalho5

1Department of Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Urology, University of Michigan, Ann Arbor, United States of America

3Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Howard Hughes Medical Institute, University of Michigan, Ann Arbor, United States of America

5Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

6Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Medicine, Henry Ford Health Systems, Detroit, United States of America

8Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

9Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Garcia de Mattos Barbosa, M. in: JCI | PubMed | Google Scholar |

1Department of Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Urology, University of Michigan, Ann Arbor, United States of America

3Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Howard Hughes Medical Institute, University of Michigan, Ann Arbor, United States of America

5Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

6Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Medicine, Henry Ford Health Systems, Detroit, United States of America

8Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

9Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Liu, H. in: JCI | PubMed | Google Scholar

1Department of Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Urology, University of Michigan, Ann Arbor, United States of America

3Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Howard Hughes Medical Institute, University of Michigan, Ann Arbor, United States of America

5Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

6Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Medicine, Henry Ford Health Systems, Detroit, United States of America

8Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

9Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Huynh, D. in: JCI | PubMed | Google Scholar

1Department of Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Urology, University of Michigan, Ann Arbor, United States of America

3Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Howard Hughes Medical Institute, University of Michigan, Ann Arbor, United States of America

5Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

6Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Medicine, Henry Ford Health Systems, Detroit, United States of America

8Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

9Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Shelley, G. in: JCI | PubMed | Google Scholar

1Department of Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Urology, University of Michigan, Ann Arbor, United States of America

3Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Howard Hughes Medical Institute, University of Michigan, Ann Arbor, United States of America

5Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

6Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Medicine, Henry Ford Health Systems, Detroit, United States of America

8Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

9Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Keller, E. in: JCI | PubMed | Google Scholar |

1Department of Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Urology, University of Michigan, Ann Arbor, United States of America

3Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Howard Hughes Medical Institute, University of Michigan, Ann Arbor, United States of America

5Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

6Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Medicine, Henry Ford Health Systems, Detroit, United States of America

8Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

9Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Emmer, B. in: JCI | PubMed | Google Scholar |

1Department of Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Urology, University of Michigan, Ann Arbor, United States of America

3Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Howard Hughes Medical Institute, University of Michigan, Ann Arbor, United States of America

5Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

6Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Medicine, Henry Ford Health Systems, Detroit, United States of America

8Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

9Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Sherman, E. in: JCI | PubMed | Google Scholar |

1Department of Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Urology, University of Michigan, Ann Arbor, United States of America

3Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Howard Hughes Medical Institute, University of Michigan, Ann Arbor, United States of America

5Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

6Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Medicine, Henry Ford Health Systems, Detroit, United States of America

8Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

9Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America

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1Department of Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Urology, University of Michigan, Ann Arbor, United States of America

3Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Howard Hughes Medical Institute, University of Michigan, Ann Arbor, United States of America

5Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

6Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Medicine, Henry Ford Health Systems, Detroit, United States of America

8Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

9Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Kennedy, A. in: JCI | PubMed | Google Scholar |

1Department of Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Urology, University of Michigan, Ann Arbor, United States of America

3Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Howard Hughes Medical Institute, University of Michigan, Ann Arbor, United States of America

5Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

6Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Medicine, Henry Ford Health Systems, Detroit, United States of America

8Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

9Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Tai, A. in: JCI | PubMed | Google Scholar |

1Department of Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Urology, University of Michigan, Ann Arbor, United States of America

3Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Howard Hughes Medical Institute, University of Michigan, Ann Arbor, United States of America

5Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

6Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Medicine, Henry Ford Health Systems, Detroit, United States of America

8Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

9Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Wobus, C. in: JCI | PubMed | Google Scholar |

1Department of Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Urology, University of Michigan, Ann Arbor, United States of America

3Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Howard Hughes Medical Institute, University of Michigan, Ann Arbor, United States of America

5Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

6Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Medicine, Henry Ford Health Systems, Detroit, United States of America

8Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

9Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Mirabelli, C. in: JCI | PubMed | Google Scholar |

1Department of Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Urology, University of Michigan, Ann Arbor, United States of America

3Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Howard Hughes Medical Institute, University of Michigan, Ann Arbor, United States of America

5Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

6Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Medicine, Henry Ford Health Systems, Detroit, United States of America

8Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

9Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Lanigan, T. in: JCI | PubMed | Google Scholar

1Department of Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Urology, University of Michigan, Ann Arbor, United States of America

3Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Howard Hughes Medical Institute, University of Michigan, Ann Arbor, United States of America

5Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

6Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Medicine, Henry Ford Health Systems, Detroit, United States of America

8Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

9Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Samaniego, M. in: JCI | PubMed | Google Scholar |

1Department of Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Urology, University of Michigan, Ann Arbor, United States of America

3Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Howard Hughes Medical Institute, University of Michigan, Ann Arbor, United States of America

5Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

6Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Medicine, Henry Ford Health Systems, Detroit, United States of America

8Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

9Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Meng, W. in: JCI | PubMed | Google Scholar |

1Department of Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Urology, University of Michigan, Ann Arbor, United States of America

3Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Howard Hughes Medical Institute, University of Michigan, Ann Arbor, United States of America

5Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

6Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Medicine, Henry Ford Health Systems, Detroit, United States of America

8Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

9Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Rosenfeld, A. in: JCI | PubMed | Google Scholar |

1Department of Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Urology, University of Michigan, Ann Arbor, United States of America

3Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Howard Hughes Medical Institute, University of Michigan, Ann Arbor, United States of America

5Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

6Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Medicine, Henry Ford Health Systems, Detroit, United States of America

8Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

9Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Luning Prak, E. in: JCI | PubMed | Google Scholar |

1Department of Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Urology, University of Michigan, Ann Arbor, United States of America

3Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Howard Hughes Medical Institute, University of Michigan, Ann Arbor, United States of America

5Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

6Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Medicine, Henry Ford Health Systems, Detroit, United States of America

8Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

9Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Platt, J. in: JCI | PubMed | Google Scholar

1Department of Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Urology, University of Michigan, Ann Arbor, United States of America

3Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Howard Hughes Medical Institute, University of Michigan, Ann Arbor, United States of America

5Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

6Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Medicine, Henry Ford Health Systems, Detroit, United States of America

8Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

9Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Cascalho, M. in: JCI | PubMed | Google Scholar |

Published March 26, 2021 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.147386.
Copyright © 2021, Garcia de Mattos Barbosa et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published March 26, 2021 - Version history
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Abstract

Antibodies that neutralize SARS-CoV-2, are thought to provide the most immediate and effective treatment for those severely afflicted by this virus. Because coronavirus potentially diversifies by mutation, broadly neutralizing antibodies are especially sought. Here we report a novel approach to rapid generation of potent broadly neutralizing human anti-SARS-CoV-2 antibodies. We isolated SARS-CoV-2 Spike protein-specific memory B cells by panning from the blood of convalescent human subjects after infection with SARS-CoV-2, sequenced and expressed Ig genes from individual B cells as human monoclonal antibodies (mAbs). All of 43 human mAbs generated in this way neutralized SARS-CoV-2. Eighteen of the 43 human mAbs exhibited half-maximal inhibitory concentration (IC50s) of 6.7 x10-12 M to 6.7x10-15 M for spike pseudotyped virus. Seven of the human mAbs also neutralized with IC50<6.7 x10-12 M viruses pseudotyped with mutant spike proteins (including receptor binding domain mutants and the S1 C-terminal D614G mutant). Neutralization of the Wuhan Hu-1 founder strain and of some variants decreased when coding sequences were reverted to germline, suggesting that potency of neutralization was acquired by somatic hypermutation and selection of B cells. The results indicate that infection with SARS-CoV-2 evokes high affinity B cell responses, some products of which are broadly neutralizing and others highly strain-specific. We also identify variants that would potentially resist immunity evoked by infection with the Wuhan Hu-1 founder strain or by vaccines developed with products of that strain, suggesting evolutionary courses SARS-CoV-2 could take.

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