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 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; PITCH Consortium; The COVID-19 Genomics UK (COG-UK) Consortium; John Haughney; David L. Robertson; Massimo Palmarini; Surajit Ray; Emma C. Thomson

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 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, PITCH Consortium, The COVID-19 Genomics UK (COG-UK) Consortium, John Haughney, David L. Robertson, Massimo Palmarini, Surajit Ray, Emma C. Thomson^*

^*Corresponding author for this work

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

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	32
Journal	Nature Microbiology
Volume	7
Issue number	8
Early online date	7 Jul 2022
DOIs	https://doi.org/10.1038/s41564-022-01143-7
Publication status	Published - Aug 2022

Keywords

COVID-19

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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., ... Thomson, E. C. (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

@article{e994248674db46fdb666b256e04270c4,

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.",

keywords = "COVID-19",

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 Richard Orton 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 {PITCH Consortium} and {The COVID-19 Genomics UK (COG-UK) Consortium} and John Haughney and Robertson, {David L.} and Massimo Palmarini and Surajit Ray and Thomson, {Emma C.}",

note = "Funding was provided by Health Data Research UK (HDR UK) for the Evaluation of Variants Affecting Deployed COVID-19 Vaccine (EVADE) study (E.C.T., S.R., O.A.M., C.W. and B.J.W.; grant code: 2021.0155). This research is part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant ref MC_PC_20058). This work was also supported by The Alan Turing Institute via {\textquoteleft}Towards Turing 2.0{\textquoteright} EPSRC Grant Funding. COG-UK is supported by funding from the Medical Research Council (MRC, part of UK Research & Innovation (UKRI)), the National Institute of Health Research (NIHR; grant code: MC_PC_19027) and Genome Research Limited, operating as the Wellcome Sanger Institute (R.M.P., D.L.R. and E.C.T.). Medical Research Council (MRC) provided funding for both the COVID-19 DeplOyed VaccinE (DOVE) study (grant code: MCUU1201412) and COG-UK (E.C.T.). A.d.S.F., J.H., R.O., J.G., E.C.T., N.L. and D.L.R. were funded by the Medical Research Council (MRC; grant code: MC_UU_12014/12). W.T.H. was supported by the MRC (grant codes MR/R024758/1 and MR/W005611/1). The G2P-UK National Virology Consortium was funded by UK Research and Innovation (UKRI) award MR/W005611/1 (M.P., E.C.T., A.H.P. and D.L.R.). D.L.R. was funded by Wellcome Trust (grant code: 220977/Z/20/Z). N.L. and B.J.W. were funded by the Biotechnology and Biological Sciences Research Council (grant codes: BBSRC, BB/R004250/1 and BB/R019843/1). J.G. was funded by a Wellcome Trust and Royal Society Sir Henry Dale Fellowship (grant code: 107653/Z/15/A). D.J.P. was funded by UKRI through the JUNIPER consortium (grant number MR/V038613/1). The PITCH Consortium is funded by the United Kingdom Department of Health and Social Care.",

year = "2022",

month = aug,

doi = "10.1038/s41564-022-01143-7",

language = "English",

volume = "7",

pages = "1161–1179",

journal = "Nature Microbiology",

issn = "2058-5276",

publisher = "Nature publishing group",

number = "8",

}

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, R, 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, PITCH Consortium, The COVID-19 Genomics UK (COG-UK) Consortium, Haughney, J, Robertson, DL, Palmarini, M, Ray, S & Thomson, EC 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

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 - PITCH Consortium

AU - The COVID-19 Genomics UK (COG-UK) Consortium

AU - Haughney, John

AU - Robertson, David L.

AU - Palmarini, Massimo

AU - Ray, Surajit

AU - Thomson, Emma C.

N1 - Funding was provided by Health Data Research UK (HDR UK) for the Evaluation of Variants Affecting Deployed COVID-19 Vaccine (EVADE) study (E.C.T., S.R., O.A.M., C.W. and B.J.W.; grant code: 2021.0155). This research is part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant ref MC_PC_20058). This work was also supported by The Alan Turing Institute via ‘Towards Turing 2.0’ EPSRC Grant Funding. COG-UK is supported by funding from the Medical Research Council (MRC, part of UK Research & Innovation (UKRI)), the National Institute of Health Research (NIHR; grant code: MC_PC_19027) and Genome Research Limited, operating as the Wellcome Sanger Institute (R.M.P., D.L.R. and E.C.T.). Medical Research Council (MRC) provided funding for both the COVID-19 DeplOyed VaccinE (DOVE) study (grant code: MCUU1201412) and COG-UK (E.C.T.). A.d.S.F., J.H., R.O., J.G., E.C.T., N.L. and D.L.R. were funded by the Medical Research Council (MRC; grant code: MC_UU_12014/12). W.T.H. was supported by the MRC (grant codes MR/R024758/1 and MR/W005611/1). The G2P-UK National Virology Consortium was funded by UK Research and Innovation (UKRI) award MR/W005611/1 (M.P., E.C.T., A.H.P. and D.L.R.). D.L.R. was funded by Wellcome Trust (grant code: 220977/Z/20/Z). N.L. and B.J.W. were funded by the Biotechnology and Biological Sciences Research Council (grant codes: BBSRC, BB/R004250/1 and BB/R019843/1). J.G. was funded by a Wellcome Trust and Royal Society Sir Henry Dale Fellowship (grant code: 107653/Z/15/A). D.J.P. was funded by UKRI through the JUNIPER consortium (grant number MR/V038613/1). The PITCH Consortium is funded by the United Kingdom Department of Health and Social Care.

PY - 2022/8

Y1 - 2022/8

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.

KW - COVID-19

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

Keywords

UN SDGs

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