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SARS-CoV-2 Omicron spike mediated immune escape and tropism shift

Bo Meng, Isabella A.T.M Ferreira, Adam Abdullahi, Niluka Goonawardane, Akatsuki Saito, Izumi Kimura, Daichi Yamasoba, Pehuén Perera Gerba, Saman Fatihi, Surabhi Rathore, Samantha K Zepeda, Guido Papa, Steven A. Kemp, Terumasa Ikeda, Mako Toyoda, Toong Seng Tan, Jin Kuramochi, Shigeki Mitsunaga, Takamasa Ueno, Kotaro Shirakawa, Akifumi Takaori-Kondo, Teresa Brevini, Donna L. Mallery, Oscar J. Charles, CITIID-NIHR BioResource COVID-19 Collaboration, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Ecuador-COVID19 Consortium, John E Bowen, Anshu Joshi, Alexandra C. Walls, Laurelle Jackson, Sandile Cele, Darren Martin, Kenneth G.C. Smith, John Bradley, John A. G. Briggs, Jinwook Choi, Elo Madissoon, Kerstin Meyer, Petra Mlcochova, Lourdes Ceron-Gutierrez, Rainer Doffinger, Sarah Teichmann, Matteo Pizzuto, Anna de Marco, Davide Corti, Alex Sigal, Leo James, David Veesler, Myra Hosmillo, Joo Hyeon Lee, Fotios Sampaziotis, Ian G Goodfellow, Nicholas J. Matheson, Lipi Thukral, Kei Sato, View ORCID ProfileRavindra K. Gupta
doi: https://doi.org/10.1101/2021.12.17.473248
Bo Meng
1Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK
2Department of Medicine, University of Cambridge, Cambridge, UK
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Isabella A.T.M Ferreira
1Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK
2Department of Medicine, University of Cambridge, Cambridge, UK
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Adam Abdullahi
1Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK
2Department of Medicine, University of Cambridge, Cambridge, UK
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Niluka Goonawardane
1Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK
2Department of Medicine, University of Cambridge, Cambridge, UK
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Akatsuki Saito
3Department of Veterinary Science, Faculty of Agriculture, University of Miyazaki, Miyazaki 8892192, Japan
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Izumi Kimura
4Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, 1088639, Japan
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Daichi Yamasoba
5Division of Molecular Virology and Genetics, Joint Research Center for Human Retrovirus infection, Kumamoto University, Kumamoto 8600811, Japan
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Pehuén Perera Gerba
1Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK
2Department of Medicine, University of Cambridge, Cambridge, UK
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Saman Fatihi
6CSIR Institute of Genomics and Integrative Biology, Delhi, India
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Surabhi Rathore
6CSIR Institute of Genomics and Integrative Biology, Delhi, India
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Samantha K Zepeda
7Department of Biochemistry, University of Washington, Seattle, 98195 USA
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Guido Papa
8MRC – Laboratory of Molecular Biology, Cambridge, UK
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Steven A. Kemp
1Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK
2Department of Medicine, University of Cambridge, Cambridge, UK
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Terumasa Ikeda
5Division of Molecular Virology and Genetics, Joint Research Center for Human Retrovirus infection, Kumamoto University, Kumamoto 8600811, Japan
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Mako Toyoda
9Division of Infection and Immunity, Joint Research Center for Human Retrovirus infection, Kumamoto University, Kumamoto 8600811, Japan
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Toong Seng Tan
10Kuramochi Clinic Interpark, Utsunomiya, Tochigi 3210114, Japan
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Jin Kuramochi
10Kuramochi Clinic Interpark, Utsunomiya, Tochigi 3210114, Japan
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Shigeki Mitsunaga
11Human Genetics Laboratory, National Institute of Genetics, Mishima, Shizuoka 4118540, Japan
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Takamasa Ueno
9Division of Infection and Immunity, Joint Research Center for Human Retrovirus infection, Kumamoto University, Kumamoto 8600811, Japan
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Kotaro Shirakawa
12Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 6068507, Japan
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Akifumi Takaori-Kondo
12Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 6068507, Japan
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Teresa Brevini
2Department of Medicine, University of Cambridge, Cambridge, UK
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Donna L. Mallery
8MRC – Laboratory of Molecular Biology, Cambridge, UK
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Oscar J. Charles
13Division of Infection and Immunity, UCL, London
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John E Bowen
7Department of Biochemistry, University of Washington, Seattle, 98195 USA
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Anshu Joshi
7Department of Biochemistry, University of Washington, Seattle, 98195 USA
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Alexandra C. Walls
7Department of Biochemistry, University of Washington, Seattle, 98195 USA
23Howard Hughes Medical Institute, Seattle, WA 98195, USA
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Laurelle Jackson
14Africa Health Research Institute, Durban, South Africa
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Sandile Cele
14Africa Health Research Institute, Durban, South Africa
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Darren Martin
15University of Cape Town, Cape Town 7701, South Africa
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Kenneth G.C. Smith
1Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK
2Department of Medicine, University of Cambridge, Cambridge, UK
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John Bradley
2Department of Medicine, University of Cambridge, Cambridge, UK
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John A. G. Briggs
16Max Planck Institute of Biochemistry, 82152 Martinsried, Germany
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Jinwook Choi
17Wellcome-MRC Cambridge Stem Cell Institute, Cambridge, UK
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Elo Madissoon
18Welcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
19European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Trust Genome Campus, Hinxton CB10 1SD, UK
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Kerstin Meyer
18Welcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
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Petra Mlcochova
1Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK
2Department of Medicine, University of Cambridge, Cambridge, UK
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Lourdes Ceron-Gutierrez
20Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Cambridge, UK
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Rainer Doffinger
20Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Cambridge, UK
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Sarah Teichmann
18Welcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
21Cavendish Laboratory/Dept Physics, University of Cambridge, JJ Thomson Ave, Cambridge CB3 0HE, UK
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Matteo Pizzuto
22Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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Anna de Marco
22Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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Davide Corti
22Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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Alex Sigal
14Africa Health Research Institute, Durban, South Africa
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Leo James
8MRC – Laboratory of Molecular Biology, Cambridge, UK
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David Veesler
7Department of Biochemistry, University of Washington, Seattle, 98195 USA
23Howard Hughes Medical Institute, Seattle, WA 98195, USA
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Myra Hosmillo
24Department of Virology, University of Cambridge, UK
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Joo Hyeon Lee
17Wellcome-MRC Cambridge Stem Cell Institute, Cambridge, UK
25Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
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Fotios Sampaziotis
1Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK
2Department of Medicine, University of Cambridge, Cambridge, UK
17Wellcome-MRC Cambridge Stem Cell Institute, Cambridge, UK
20Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Cambridge, UK
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Ian G Goodfellow
26NHS Blood and Transplant, Cambridge, UK
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Nicholas J. Matheson
1Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK
2Department of Medicine, University of Cambridge, Cambridge, UK
20Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Cambridge, UK
26NHS Blood and Transplant, Cambridge, UK
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Lipi Thukral
6CSIR Institute of Genomics and Integrative Biology, Delhi, India
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Kei Sato
4Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, 1088639, Japan
27CREST, Japan Science and Technology Agency, Saitama 3220012, Japan
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  • For correspondence: rkg20@cam.ac.uk keisato@g.ecc.u-tokyo.ac.jp
Ravindra K. Gupta
1Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK
2Department of Medicine, University of Cambridge, Cambridge, UK
14Africa Health Research Institute, Durban, South Africa
26NHS Blood and Transplant, Cambridge, UK
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  • ORCID record for Ravindra K. Gupta
  • For correspondence: rkg20@cam.ac.uk keisato@g.ecc.u-tokyo.ac.jp
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Abstract

The SARS-CoV-2 Omicron BA.1 variant emerged in late 2021 and is characterised by multiple spike mutations across all spike domains. Here we show that Omicron BA.1 has higher affinity for ACE2 compared to Delta, and confers very significant evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralising antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralisation. Importantly, antiviral drugs remdesevir and molnupiravir retain efficacy against Omicron BA.1. We found that in human nasal epithelial 3D cultures replication was similar for both Omicron and Delta. However, in lower airway organoids, Calu-3 lung cells and gut adenocarcinoma cell lines live Omicron virus demonstrated significantly lower replication in comparison to Delta. We noted that despite presence of mutations predicted to favour spike S1/S2 cleavage, the spike protein is less efficiently cleaved in live Omicron virions compared to Delta virions. We mapped the replication differences between the variants to entry efficiency using spike pseudotyped virus (PV) entry assays. The defect for Omicron PV in specific cell types correlated with higher cellular RNA expression of TMPRSS2, and accordingly knock down of TMPRSS2 impacted Delta entry to a greater extent as compared to Omicron. Furthermore, drug inhibitors targeting specific entry pathways demonstrated that the Omicron spike inefficiently utilises the cellular protease TMPRSS2 that mediates cell entry via plasma membrane fusion. Instead, we demonstrate that Omicron spike has greater dependency on cell entry via the endocytic pathway requiring the activity of endosomal cathepsins to cleave spike. Consistent with suboptimal S1/S2 cleavage and inability to utilise TMPRSS2, syncytium formation by the Omicron spike was dramatically impaired compared to the Delta spike. Overall, Omicron appears to have gained significant evasion from neutralising antibodies whilst maintaining sensitivity to antiviral drugs targeting the polymerase. Omicron has shifted cellular tropism away from TMPRSS2 expressing cells that are enriched in cells found in the lower respiratory and GI tracts, with implications for altered pathogenesis.

Competing Interest Statement

RKG has received honoraria from GSK, Janssen and ViiV for educational activities

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 4.0 International license.
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Posted January 13, 2022.
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SARS-CoV-2 Omicron spike mediated immune escape and tropism shift
Bo Meng, Isabella A.T.M Ferreira, Adam Abdullahi, Niluka Goonawardane, Akatsuki Saito, Izumi Kimura, Daichi Yamasoba, Pehuén Perera Gerba, Saman Fatihi, Surabhi Rathore, Samantha K Zepeda, Guido Papa, Steven A. Kemp, Terumasa Ikeda, Mako Toyoda, Toong Seng Tan, Jin Kuramochi, Shigeki Mitsunaga, Takamasa Ueno, Kotaro Shirakawa, Akifumi Takaori-Kondo, Teresa Brevini, Donna L. Mallery, Oscar J. Charles, CITIID-NIHR BioResource COVID-19 Collaboration, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Ecuador-COVID19 Consortium, John E Bowen, Anshu Joshi, Alexandra C. Walls, Laurelle Jackson, Sandile Cele, Darren Martin, Kenneth G.C. Smith, John Bradley, John A. G. Briggs, Jinwook Choi, Elo Madissoon, Kerstin Meyer, Petra Mlcochova, Lourdes Ceron-Gutierrez, Rainer Doffinger, Sarah Teichmann, Matteo Pizzuto, Anna de Marco, Davide Corti, Alex Sigal, Leo James, David Veesler, Myra Hosmillo, Joo Hyeon Lee, Fotios Sampaziotis, Ian G Goodfellow, Nicholas J. Matheson, Lipi Thukral, Kei Sato, Ravindra K. Gupta
bioRxiv 2021.12.17.473248; doi: https://doi.org/10.1101/2021.12.17.473248
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SARS-CoV-2 Omicron spike mediated immune escape and tropism shift
Bo Meng, Isabella A.T.M Ferreira, Adam Abdullahi, Niluka Goonawardane, Akatsuki Saito, Izumi Kimura, Daichi Yamasoba, Pehuén Perera Gerba, Saman Fatihi, Surabhi Rathore, Samantha K Zepeda, Guido Papa, Steven A. Kemp, Terumasa Ikeda, Mako Toyoda, Toong Seng Tan, Jin Kuramochi, Shigeki Mitsunaga, Takamasa Ueno, Kotaro Shirakawa, Akifumi Takaori-Kondo, Teresa Brevini, Donna L. Mallery, Oscar J. Charles, CITIID-NIHR BioResource COVID-19 Collaboration, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Ecuador-COVID19 Consortium, John E Bowen, Anshu Joshi, Alexandra C. Walls, Laurelle Jackson, Sandile Cele, Darren Martin, Kenneth G.C. Smith, John Bradley, John A. G. Briggs, Jinwook Choi, Elo Madissoon, Kerstin Meyer, Petra Mlcochova, Lourdes Ceron-Gutierrez, Rainer Doffinger, Sarah Teichmann, Matteo Pizzuto, Anna de Marco, Davide Corti, Alex Sigal, Leo James, David Veesler, Myra Hosmillo, Joo Hyeon Lee, Fotios Sampaziotis, Ian G Goodfellow, Nicholas J. Matheson, Lipi Thukral, Kei Sato, Ravindra K. Gupta
bioRxiv 2021.12.17.473248; doi: https://doi.org/10.1101/2021.12.17.473248

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