SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Brian J. Willett; Joe Grove; Oscar A. MacLean; Craig Wilkie; Giuditta De Lorenzo; Wilhelm Furnon; Diego Cantoni; Sam Scott; Nicola Logan; Shirin Ashraf; Maria Manali; Agnieszka Szemiel; Vanessa Cowton; Elen Vink; William T. Harvey; Chris Davis; Patawee Asamaphan; Katherine Smollett; Lily Tong; Richard J. Orton; Joseph Hughes; Poppy Holland; Vanessa Silva; David J. Pascall; Kathryn Puxty; Ana da Silva Filipe; Gonzalo Yebra; Sharif Shaaban; Matthew T.G. Holden; Rute Maria Pinto; Rory Gunson; Kate Templeton; Pablo R. Murcia; Arvind H. Patel; Paul Klenerman; Susanna Dunachie; Eleanor Barnes; Anthony Brown; Sandra Adele; Barbara Kronsteiner; Sam M. Murray; Priyanka Abraham; Alexandra Deeks; M. Azim Ansari; Thushan de Silva; Lance Turtle; Shona Moore; James Austin; Sally Forrest; Jonathan Ball

doi:10.1038/s41564-022-01143-7

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Brian J. Willett, Joe Grove, Oscar A. MacLean, Craig Wilkie, Giuditta De Lorenzo, Wilhelm Furnon, Diego Cantoni, Sam Scott, Nicola Logan, Shirin Ashraf, Maria Manali, Agnieszka Szemiel, Vanessa Cowton, Elen Vink, William T. Harvey, Chris Davis, Patawee Asamaphan, Katherine Smollett, Lily Tong, Richard J. OrtonJoseph Hughes, Poppy Holland, Vanessa Silva, David J. Pascall, Kathryn Puxty, Ana da Silva Filipe, Gonzalo Yebra, Sharif Shaaban, Matthew T.G. Holden, Rute Maria Pinto, Rory Gunson, Kate Templeton, Pablo R. Murcia, Arvind H. Patel, Paul Klenerman, Susanna Dunachie, Eleanor Barnes, Anthony Brown, Sandra Adele, Barbara Kronsteiner, Sam M. Murray, Priyanka Abraham, Alexandra Deeks, M. Azim Ansari, Thushan de Silva, Lance Turtle, Shona Moore, James Austin, Sally Forrest, Jonathan Ball

Research output: Contribution to journal › Article › peer-review

461 Citations (Scopus)

Abstract

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant.

Original language	English
Pages (from-to)	1161-1179
Number of pages	19
Journal	Nature Microbiology
Volume	7
Issue number	8
DOIs	https://doi.org/10.1038/s41564-022-01143-7
Publication status	Published - 1 Aug 2022
Externally published	Yes

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461 Citations
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Publisher Correction: SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway
Willett, B. J., Grove, J., MacLean, O. A., Wilkie, C., De Lorenzo, G., Furnon, W., Cantoni, D., Scott, S., Logan, N., Ashraf, S., Manali, M., Szemiel, A., Cowton, V., Vink, E., Harvey, W. T., Davis, C., Asamaphan, P., Smollett, K., Tong, L. & Orton, R. J. & 30 others, Hughes, J., Holland, P., Silva, V., Pascall, D. J., Puxty, K., da Silva Filipe, A., Yebra, G., Shaaban, S., Holden, M. T. G., Pinto, R. M., Gunson, R., Templeton, K., Murcia, P. R., Patel, A. H., Klenerman, P., Dunachie, S., Barnes, E., Brown, A., Adele, S., Kronsteiner, B., Murray, S. M., Abraham, P., Deeks, A., Ansari, M. A., de Silva, T., Turtle, L., Moore, S., Austin, J., Forrest, S. & Ball, J., 1 Oct 2022, 1 p.
Research output: Other contribution

Open Access
14 Citations (Scopus)

Cite this

Willett, B. J., Grove, J., MacLean, O. A., Wilkie, C., De Lorenzo, G., Furnon, W., Cantoni, D., Scott, S., Logan, N., Ashraf, S., Manali, M., Szemiel, A., Cowton, V., Vink, E., Harvey, W. T., Davis, C., Asamaphan, P., Smollett, K., Tong, L., ... Ball, J. (2022). SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway. Nature Microbiology, 7(8), 1161-1179. https://doi.org/10.1038/s41564-022-01143-7

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title = "SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway",

abstract = "Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant.",

author = "Willett, \{Brian J.\} and Joe Grove and MacLean, \{Oscar A.\} and Craig Wilkie and \{De Lorenzo\}, Giuditta and Wilhelm Furnon and Diego Cantoni and Sam Scott and Nicola Logan and Shirin Ashraf and Maria Manali and Agnieszka Szemiel and Vanessa Cowton and Elen Vink and Harvey, \{William T.\} and Chris Davis and Patawee Asamaphan and Katherine Smollett and Lily Tong and Orton, \{Richard J.\} and Joseph Hughes and Poppy Holland and Vanessa Silva and Pascall, \{David J.\} and Kathryn Puxty and \{da Silva Filipe\}, Ana and Gonzalo Yebra and Sharif Shaaban and Holden, \{Matthew T.G.\} and Pinto, \{Rute Maria\} and Rory Gunson and Kate Templeton and Murcia, \{Pablo R.\} and Patel, \{Arvind H.\} and Paul Klenerman and Susanna Dunachie and Eleanor Barnes and Anthony Brown and Sandra Adele and Barbara Kronsteiner and Murray, \{Sam M.\} and Priyanka Abraham and Alexandra Deeks and Ansari, \{M. Azim\} and \{de Silva\}, Thushan and Lance Turtle and Shona Moore and James Austin and Sally Forrest and Jonathan Ball",

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Willett, BJ, Grove, J, MacLean, OA, Wilkie, C, De Lorenzo, G, Furnon, W, Cantoni, D, Scott, S, Logan, N, Ashraf, S, Manali, M, Szemiel, A, Cowton, V, Vink, E, Harvey, WT, Davis, C, Asamaphan, P, Smollett, K, Tong, L, Orton, RJ, Hughes, J, Holland, P, Silva, V, Pascall, DJ, Puxty, K, da Silva Filipe, A, Yebra, G, Shaaban, S, Holden, MTG, Pinto, RM, Gunson, R, Templeton, K, Murcia, PR, Patel, AH, Klenerman, P, Dunachie, S, Barnes, E, Brown, A, Adele, S, Kronsteiner, B, Murray, SM, Abraham, P, Deeks, A, Ansari, MA, de Silva, T, Turtle, L, Moore, S, Austin, J, Forrest, S & Ball, J 2022, 'SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway', Nature Microbiology, vol. 7, no. 8, pp. 1161-1179. https://doi.org/10.1038/s41564-022-01143-7

TY - JOUR

T1 - SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

AU - Willett, Brian J.

AU - Grove, Joe

AU - MacLean, Oscar A.

AU - Wilkie, Craig

AU - De Lorenzo, Giuditta

AU - Furnon, Wilhelm

AU - Cantoni, Diego

AU - Scott, Sam

AU - Logan, Nicola

AU - Ashraf, Shirin

AU - Manali, Maria

AU - Szemiel, Agnieszka

AU - Cowton, Vanessa

AU - Vink, Elen

AU - Harvey, William T.

AU - Davis, Chris

AU - Asamaphan, Patawee

AU - Smollett, Katherine

AU - Tong, Lily

AU - Orton, Richard J.

AU - Hughes, Joseph

AU - Holland, Poppy

AU - Silva, Vanessa

AU - Pascall, David J.

AU - Puxty, Kathryn

AU - da Silva Filipe, Ana

AU - Yebra, Gonzalo

AU - Shaaban, Sharif

AU - Holden, Matthew T.G.

AU - Pinto, Rute Maria

AU - Gunson, Rory

AU - Templeton, Kate

AU - Murcia, Pablo R.

AU - Patel, Arvind H.

AU - Klenerman, Paul

AU - Dunachie, Susanna

AU - Barnes, Eleanor

AU - Brown, Anthony

AU - Adele, Sandra

AU - Kronsteiner, Barbara

AU - Murray, Sam M.

AU - Abraham, Priyanka

AU - Deeks, Alexandra

AU - Ansari, M. Azim

AU - de Silva, Thushan

AU - Turtle, Lance

AU - Moore, Shona

AU - Austin, James

AU - Forrest, Sally

AU - Ball, Jonathan

PY - 2022/8/1

Y1 - 2022/8/1

N2 - Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant.

AB - Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant.

U2 - 10.1038/s41564-022-01143-7

DO - 10.1038/s41564-022-01143-7

M3 - Article

SN - 2058-5276

VL - 7

SP - 1161

EP - 1179

JO - Nature Microbiology

JF - Nature Microbiology

IS - 8

ER -

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Abstract

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Publisher Correction: SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

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