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The spike gene is a major determinant for the SARS-CoV-2 Omicron-BA.1 phenotype

View ORCID ProfileTuba Barut, View ORCID ProfileNico Joel Halwe, View ORCID ProfileAdriano Taddeo, View ORCID ProfileJenna N. Kelly, View ORCID ProfileJacob Schön, View ORCID ProfileNadine Ebert, View ORCID ProfileLorenz Ulrich, View ORCID ProfileChristelle Devisme, View ORCID ProfileSilvio Steiner, View ORCID ProfileBettina Salome Trüeb, View ORCID ProfileBernd Hoffmann, View ORCID ProfileInês Berenguer Veiga, View ORCID ProfileNathan Georges François Leborgne, View ORCID ProfileEtori Aguiar Moreira, View ORCID ProfileAngele Breithaupt, View ORCID ProfileClaudia Wylezich, View ORCID ProfileDirk Höper, View ORCID ProfileKerstin Wernike, Aurélie Godel, View ORCID ProfileLisa Thomann, Vera Flück, View ORCID ProfileHanspeter Stalder, View ORCID ProfileMelanie Brügger, Blandina I. Oliveira Esteves, Beatrice Zumkehr, Guillaume Beilleau, Annika Kratzel, Kimberly Schmied, Sarah Ochsenbein, Reto M. Lang, Manon Wider, View ORCID ProfileCarlos Machahua, Patrick Dorn, View ORCID ProfileThomas M. Marti, View ORCID ProfileManuela Funke-Chambour, View ORCID ProfileAndri Rauch, View ORCID ProfileMarek Widera, Sandra Ciesek, View ORCID ProfileRonald Dijkman, View ORCID ProfileDonata Hoffmann, View ORCID ProfileMarco P. Alves, View ORCID ProfileCharaf Benarafa, View ORCID ProfileMartin Beer, View ORCID ProfileVolker Thiel
doi: https://doi.org/10.1101/2022.04.28.489537
Tuba Barut
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Nico Joel Halwe
3Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany
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Adriano Taddeo
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Jenna N. Kelly
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
4Multidisciplinary Center for Infectious Diseases, University of Bern, Bern, Switzerland
5European Virus Bioinformatics Center, Jena, Germany
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Jacob Schön
3Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany
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Nadine Ebert
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Lorenz Ulrich
3Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany
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  • ORCID record for Lorenz Ulrich
Christelle Devisme
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Silvio Steiner
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Bettina Salome Trüeb
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Bernd Hoffmann
3Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany
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Inês Berenguer Veiga
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Nathan Georges François Leborgne
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Etori Aguiar Moreira
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Angele Breithaupt
6Department of Experimental Animal Facilities and Biorisk Management, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany
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Claudia Wylezich
3Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany
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Dirk Höper
3Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany
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Kerstin Wernike
3Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany
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Aurélie Godel
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Lisa Thomann
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Vera Flück
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Hanspeter Stalder
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Melanie Brügger
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Blandina I. Oliveira Esteves
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Beatrice Zumkehr
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Guillaume Beilleau
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
7Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
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Annika Kratzel
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Kimberly Schmied
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Sarah Ochsenbein
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Reto M. Lang
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
7Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
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Manon Wider
8Institute for Infectious Diseases, University of Bern, Bern, Switzerland
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Carlos Machahua
9Department of Pulmonary Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
10Department for Pulmonary Medicine, BioMedical Research, University of Bern, Bern, Switzerland
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Patrick Dorn
11Division of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
12Department for BioMedical Research, Inselspital, Bern University Hospital, University of Bern, Switzerland
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Thomas M. Marti
11Division of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
12Department for BioMedical Research, Inselspital, Bern University Hospital, University of Bern, Switzerland
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Manuela Funke-Chambour
9Department of Pulmonary Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
10Department for Pulmonary Medicine, BioMedical Research, University of Bern, Bern, Switzerland
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Andri Rauch
4Multidisciplinary Center for Infectious Diseases, University of Bern, Bern, Switzerland
13Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Switzerland
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Marek Widera
14Institute of Medical Virology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany
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Sandra Ciesek
14Institute of Medical Virology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany
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Ronald Dijkman
4Multidisciplinary Center for Infectious Diseases, University of Bern, Bern, Switzerland
5European Virus Bioinformatics Center, Jena, Germany
8Institute for Infectious Diseases, University of Bern, Bern, Switzerland
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  • ORCID record for Ronald Dijkman
Donata Hoffmann
3Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany
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  • ORCID record for Donata Hoffmann
Marco P. Alves
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
4Multidisciplinary Center for Infectious Diseases, University of Bern, Bern, Switzerland
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  • For correspondence: volker.thiel@vetsuisse.unibe.ch charaf.benarafa@vetsuisse.unibe.ch martin.beer@fli.de marco.alves@vetsuisse.unibe.ch
Charaf Benarafa
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
4Multidisciplinary Center for Infectious Diseases, University of Bern, Bern, Switzerland
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  • For correspondence: volker.thiel@vetsuisse.unibe.ch charaf.benarafa@vetsuisse.unibe.ch martin.beer@fli.de marco.alves@vetsuisse.unibe.ch
Martin Beer
3Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany
5European Virus Bioinformatics Center, Jena, Germany
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  • ORCID record for Martin Beer
  • For correspondence: volker.thiel@vetsuisse.unibe.ch charaf.benarafa@vetsuisse.unibe.ch martin.beer@fli.de marco.alves@vetsuisse.unibe.ch
Volker Thiel
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
4Multidisciplinary Center for Infectious Diseases, University of Bern, Bern, Switzerland
5European Virus Bioinformatics Center, Jena, Germany
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  • ORCID record for Volker Thiel
  • For correspondence: volker.thiel@vetsuisse.unibe.ch charaf.benarafa@vetsuisse.unibe.ch martin.beer@fli.de marco.alves@vetsuisse.unibe.ch
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Abstract

Variant of concern (VOC) Omicron-BA1 has achieved global predominance in early 2022. Therefore, surveillance and comprehensive characterization of Omicron-BA.1 in advanced primary cell culture systems and multiple animal models is urgently needed. Here, we characterized Omicron-BA.1 and recombinant Omicron-BA.1 spike gene mutants in comparison with VOC Delta in well-differentiated primary human nasal and bronchial epithelial cells in vitro, followed by in vivo fitness characterization in naïve hamsters, ferrets and hACE2-expressing mice, and in immunized hACE2-mice. We demonstrate a spike-mediated enhancement of early replication of Omicron-BA.1 in nasal epithelial cultures, but limited replication in bronchial epithelial cultures. In Syrian hamsters, Delta showed dominance over Omicron-BA.1 and in ferrets, Omicron-BA.1 infection was abortive. In mice expressing the authentic hACE2-receptor, Delta and a Delta spike clone also showed dominance over Omicron-BA.1 and an Omicron-BA.1 spike clone, respectively. Interestingly, in naïve K18-hACE2 mice, we observed Delta spike-mediated increased replication and pathogenicity and Omicron-BA.1 spike-mediated reduced replication and pathogenicity, suggesting that the spike gene is a major determinant of both Delta and Omicron-BA.1 replication and pathogenicity. Finally, the Omicron-BA.1 spike clone was less well controlled by mRNA-vaccination in K18-hACE2-mice and became more competitive compared to the progenitor and Delta spike clones, suggesting that spike gene-mediated immune evasion is another important factor that led to Omicron-BA.1 dominance.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵† These authors contributed equally to this work.

  • ‡ These authors jointly lead this work.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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The spike gene is a major determinant for the SARS-CoV-2 Omicron-BA.1 phenotype
Tuba Barut, Nico Joel Halwe, Adriano Taddeo, Jenna N. Kelly, Jacob Schön, Nadine Ebert, Lorenz Ulrich, Christelle Devisme, Silvio Steiner, Bettina Salome Trüeb, Bernd Hoffmann, Inês Berenguer Veiga, Nathan Georges François Leborgne, Etori Aguiar Moreira, Angele Breithaupt, Claudia Wylezich, Dirk Höper, Kerstin Wernike, Aurélie Godel, Lisa Thomann, Vera Flück, Hanspeter Stalder, Melanie Brügger, Blandina I. Oliveira Esteves, Beatrice Zumkehr, Guillaume Beilleau, Annika Kratzel, Kimberly Schmied, Sarah Ochsenbein, Reto M. Lang, Manon Wider, Carlos Machahua, Patrick Dorn, Thomas M. Marti, Manuela Funke-Chambour, Andri Rauch, Marek Widera, Sandra Ciesek, Ronald Dijkman, Donata Hoffmann, Marco P. Alves, Charaf Benarafa, Martin Beer, Volker Thiel
bioRxiv 2022.04.28.489537; doi: https://doi.org/10.1101/2022.04.28.489537
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The spike gene is a major determinant for the SARS-CoV-2 Omicron-BA.1 phenotype
Tuba Barut, Nico Joel Halwe, Adriano Taddeo, Jenna N. Kelly, Jacob Schön, Nadine Ebert, Lorenz Ulrich, Christelle Devisme, Silvio Steiner, Bettina Salome Trüeb, Bernd Hoffmann, Inês Berenguer Veiga, Nathan Georges François Leborgne, Etori Aguiar Moreira, Angele Breithaupt, Claudia Wylezich, Dirk Höper, Kerstin Wernike, Aurélie Godel, Lisa Thomann, Vera Flück, Hanspeter Stalder, Melanie Brügger, Blandina I. Oliveira Esteves, Beatrice Zumkehr, Guillaume Beilleau, Annika Kratzel, Kimberly Schmied, Sarah Ochsenbein, Reto M. Lang, Manon Wider, Carlos Machahua, Patrick Dorn, Thomas M. Marti, Manuela Funke-Chambour, Andri Rauch, Marek Widera, Sandra Ciesek, Ronald Dijkman, Donata Hoffmann, Marco P. Alves, Charaf Benarafa, Martin Beer, Volker Thiel
bioRxiv 2022.04.28.489537; doi: https://doi.org/10.1101/2022.04.28.489537

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