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

PITCH Consortium; The COVID-19 Genomics UK (COG-UK) Consortium

doi:10.1038/s41564-022-01143-7

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

PITCH Consortium
, The COVID-19 Genomics UK (COG-UK) Consortium

MRC-University of Glasgow Centre for Virus Research
University of Glasgow
NHS Greater Glasgow and Clyde
MRC Biostatistics Unit
Public Health Scotland
School of Medicine
NHS Lothian
University of Oxford
University of Oxford
John Radcliffe Hospital
Mahidol University
University of Sheffield
Sheffield Teaching Hospitals NHS Foundation Trust
University of Liverpool
Liverpool University Hospitals NHS Foundation Trust
University of Birmingham
University Hospital Trust
Newcastle University
Newcastle upon Tyne NHS Hospitals Foundation Trust
Barking, Havering and Redbridge University Hospitals NHS Trust
Barts Health NHS Trust
Forster Green Hospital
Betsi Cadwaladr University Health Board
Blackpool Teaching Hospitals NHS Foundation Trust
Bournemouth University
University of Cambridge
Cambridge University Hospitals NHS Foundation Trust
Cardiff and Vale University Health Board
Cardiff University
Guys and St Thomas' NHS Foundation Trust
Wellcome Trust Genome Campus
University of Portsmouth
Queen's Medical Centre
University Hospitals of Leicester NHS Trust
County Durham and Darlington NHS Foundation Trust
University of Nottingham
Department of Medicine
Kettering General Hospital
North West London Pathology
East Kent Hospitals University NHS Foundation Trust
Ipswich Hospital NHS Trust
East Sussex Healthcare NHS Trust
Gateshead Health NHS Foundation Trust
UCL Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust
UCL Great Ormond Street Institute of Child Health
Hampshire Hospitals NHS Foundation Trust
Health Services Laboratories
East Birmingham Hospital
Ellison Building
Hull University Teaching Hospitals NHS Trust
Imperial College Healthcare NHS Trust
Imperial College London
St. George’s University Hospitals NHS Foundation Trust
St. George’s University of London
University of Glasgow, G11 6NT
Isle of Wight NHS Trust
King's College Hospital NHS Foundation Trust
King's College London
Liverpool Clinical Laboratories
Maidstone and Tunbridge Wells NHS Trust
University Hospital of South Manchester
Buckinghamshire Healthcare NHS Trust
Royal Oldham Hospital
Norfolk and Norwich University Hospitals NHS Foundation Trust
Norfolk County Council
North Cumbria Integrated Care NHS Foundation Trust
North Middlesex University Hospital NHS Trust
North Tees and Hartlepool NHS Foundation Trust
Northumbria Healthcare NHS Foundation Trust
Northern Lincolnshire & amp; Goole NHS Foundation Trust
Portsmouth Hospitals University NHS Trust
Public Health Agency
Public Health England
Public Health Wales
Quadram Institute Bioscience
Queen Elizabeth Hospital Birmingham
Queen's University of Belfast
Royal Brompton and Harefield Hospital Trust and Imperial College
Royal Devon and Exeter National Health Service Foundation Trust
Royal Free NHS Trust
South Tees Hospitals NHS Foundation Trust
Southwest Pathology Services
Swansea University
The Queen Elizabeth Hospital King’s Lynn NHS Foundation Trust
The Royal Marsden NHS Foundation Trust
The Royal Wolverhampton NHS Trust
University College London
University College of London Hospitals
University Hospital Southampton NHS Foundation Trust
Poole Hospital NHS Foundation Trust
Brighton and Sussex University Hospitals
University of Brighton
University of East Anglia
University of Edinburgh
University of Exeter
University of Southampton
Watford General Hospital
Whittington Health NHS Trust
London School of Hygiene and Tropical Medicine

Research output: Contribution to a Journal (Peer & Non Peer) › Article › peer-review

525 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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SDG 3 Good Health and Well-being

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10.1038/s41564-022-01143-7

Cite this

@article{22ba5c15ffaf47208b58f0974cf80a20,

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 = "\{PITCH Consortium\} and \{The COVID-19 Genomics UK (COG-UK) Consortium\} and 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 Alex Richter and Christopher Duncan and Rebecca Payne and Amy Ash and Cherian Koshy and Beatrix Kele and Teresa Cutino-Moguel and Fairley, \{Derek J.\} and McKenna, \{James P.\} and Tanya Curran and Helen Adams and Christophe Fraser and David Bonsall and Helen Fryer and Katrina Lythgoe and Laura Thomson and Tanya Golubchik and Abigail Murray and Dawn Singleton and Beckwith, \{Shaun M.\} and Anna Mantzouratou and Magdalena Barrow and Buchan, \{Sarah L.\} and Nicola Reynolds and Ben Warne and Joshua Maksimovic and Karla Spellman and Kathryn McCluggage and Michaela John and Robert Beer and Safiah Afifi and Sian Morgan and Andrew Mack and Angela Marchbank and Anna Price and Arthur Morriss and Catherine Bresner and Christine Kitchen and Ian Merrick and Joel Southgate and Martyn Guest and Owen Jones and Robert Munn and Connor, \{Thomas R.\} and Thomas Whalley and Trudy Workman and William Fuller and Amita Patel and Bindi Patel and Gaia Nebbia and Jonathan Edgeworth and Dorman, \{Matthew J.\}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = aug,

day = "1",

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

language = "English",

volume = "7",

pages = "1161--1179",

journal = "Nature Microbiology",

issn = "2058-5276",

publisher = "Nature Research",

number = "8",

}

TY - JOUR

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

AU - PITCH Consortium

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

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 - Richter, Alex

AU - Duncan, Christopher

AU - Payne, Rebecca

AU - Ash, Amy

AU - Koshy, Cherian

AU - Kele, Beatrix

AU - Cutino-Moguel, Teresa

AU - Fairley, Derek J.

AU - McKenna, James P.

AU - Curran, Tanya

AU - Adams, Helen

AU - Fraser, Christophe

AU - Bonsall, David

AU - Fryer, Helen

AU - Lythgoe, Katrina

AU - Thomson, Laura

AU - Golubchik, Tanya

AU - Murray, Abigail

AU - Singleton, Dawn

AU - Beckwith, Shaun M.

AU - Mantzouratou, Anna

AU - Barrow, Magdalena

AU - Buchan, Sarah L.

AU - Reynolds, Nicola

AU - Warne, Ben

AU - Maksimovic, Joshua

AU - Spellman, Karla

AU - McCluggage, Kathryn

AU - John, Michaela

AU - Beer, Robert

AU - Afifi, Safiah

AU - Morgan, Sian

AU - Mack, Andrew

AU - Marchbank, Angela

AU - Price, Anna

AU - Morriss, Arthur

AU - Bresner, Catherine

AU - Kitchen, Christine

AU - Merrick, Ian

AU - Southgate, Joel

AU - Guest, Martyn

AU - Jones, Owen

AU - Munn, Robert

AU - Connor, Thomas R.

AU - Whalley, Thomas

AU - Workman, Trudy

AU - Fuller, William

AU - Patel, Amita

AU - Patel, Bindi

AU - Nebbia, Gaia

AU - Edgeworth, Jonathan

AU - Dorman, Matthew J.

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.

UR - https://www.scopus.com/pages/publications/85133843705

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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