Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role in the Alpha variant B.1.1.7

The COVID-19 Genomics UK (COG-UK) Consortium; Bo Meng; Steven A. Kemp; Guido  Papa; Rawlings Datir; Isabella A.T.M.  Ferreira; Sara Marelli; William T.  Harvey; Spyros Lytras; Ahmed  Mohamed; Giulia Gallo; Nazia Thakur; Dami A. Collier; Petra Mlcochova; Lidia M. Duncan; Alessandro M. Carabelli; Julia C. Kenyon; Andrew M. Lever; Anna De Marco; Christian Saliba; Katja Culap; Elisabetta Cameroni; Nicholas J.  Matheson; Luca Piccoli; Davide Corti; Leo C.  James; David L.  Robertson; Dalan  Bailey; Ravindra K. Gupta

doi:10.1016/j.celrep.2021.109292

Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role in the Alpha variant B.1.1.7

The COVID-19 Genomics UK (COG-UK) Consortium, Bo Meng, Steven A. Kemp, Guido Papa, Rawlings Datir, Isabella A.T.M. Ferreira, Sara Marelli, William T. Harvey, Spyros Lytras, Ahmed Mohamed, Giulia Gallo, Nazia Thakur, Dami A. Collier, Petra Mlcochova, Lidia M. Duncan, Alessandro M. Carabelli, Julia C. Kenyon, Andrew M. Lever, Anna De Marco, Christian SalibaKatja Culap, Elisabetta Cameroni, Nicholas J. Matheson, Luca Piccoli, Davide Corti, Leo C. James, David L. Robertson, Dalan Bailey, Ravindra K. Gupta

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

64 Citations (Scopus)

236 Downloads (Pure)

Abstract

We report severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike ΔH69/V70 in multiple independent lineages, often occurring after acquisition of receptor binding motif replacements such as N439K and Y453F, known to increase binding affinity to the ACE2 receptor and confer antibody escape. In vitro, we show that, although ΔH69/V70 itself is not an antibody evasion mechanism, it increases infectivity associated with enhanced incorporation of cleaved spike into virions. ΔH69/V70 is able to partially rescue infectivity of spike proteins that have acquired N439K and Y453F escape mutations by increased spike incorporation. In addition, replacement of the H69 and V70 residues in the Alpha variant B.1.1.7 spike (where ΔH69/V70 occurs naturally) impairs spike incorporation and entry efficiency of the B.1.1.7 spike pseudotyped virus. Alpha variant B.1.1.7 spike mediates faster kinetics of cell-cell fusion than wild-type Wuhan-1 D614G, dependent on ΔH69/V70. Therefore, as ΔH69/V70 compensates for immune escape mutations that impair infectivity, continued surveillance for deletions with functional effects is warranted.

Original language	English
Article number	109292
Number of pages	24
Journal	Cell Reports
Volume	35
Issue number	13
Early online date	8 Jun 2021
DOIs	https://doi.org/10.1016/j.celrep.2021.109292
Publication status	Published - 29 Jun 2021

Bibliographical note

Funding Information:
R.K.G. is supported by a Wellcome Trust Senior Fellowship in Clinical Science (WT108082AIA). I.A.T.M.F. is funded by the Sub-Saharan African Network for TB/HIV Research Excellence fellowship (SANTHE, a DELTAS Africa Initiative; DEL-15?006). 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), and Genome Research Limited, operating as the Wellcome Sanger Institute. This study was supported by the Cambridge NIHRB Biomedical Research Centre. S.A.K. is supported by the Bill and Melinda Gates Foundation via PANGEA grant OPP1175094. D.L.R. is funded by the MRC (MC UU 1201412). W.H. is funded by the MRC (MR/R024758/1). We thank James Voss for the kind gift of HeLa cells stably expressing ACE2, Paul Lehner for Calu-3 cells, and Simon Cook for H1299 cells. N.J.M. is funded by the MRC (CSF ref. MR/P008801/1), NHSBT (grant ref. WPA15-02), and the Addenbrooke's Charitable Trust, Cambridge University Hospitals (grant ref. 900239). We thank Wendy Barclay and Thomas Peacock for helpful discussions and the Geno2pheno UK Consortium. S.L. is funded by Medical Research Council MC_UU_12014/12. This study was also partly funded by the Rosetrees Trust. A.M.L. is funded by the Cambridge NIHRB Biomedical Research Centre. R.K.G. B.M. R.D. I.A.T.M.F. D.L.R. L.C.J. D.B. L.P. A.D.M. N.J.M. and D.A.C. designed the study and experiments. W.T.H. and A.M.C. designed and performed structural analyses. S.A.K. B.M. S.M. L.M.D. A.D.M. C.S. E.C. and K.C. performed experiments. L.P. A.D.M. D.A.C. B.M. R.K.G. D.L.R. D.B. R.D. I.A.T.M.F. and S.A.K. interpreted data. L.P. D.A.C. R.D. I.A.T.M.F. R.K.G. B.M. S.A.K. and D.L.R. performed data analysis and manuscript preparation. A.D.M. C.S. K.C. E.C. L.P. and D.A.C. are employees of Vir Biotechnology and may hold shares in Vir Biotechnology. R.K.G. has received consulting fees from UMOVIS lab, Gilead Sciences, and ViiV Healthcare and a research grant from InvisiSmart Technologies.

Publisher Copyright:
© 2021 The Author(s)

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Keywords

Alpha variant
antibody escape
B.1.1.7
COVID-19
deletion
infectivity
neutralizing antibodies
resistance
SARS-CoV-2
spike mutation
Recurrence
Pandemics
SARS-CoV-2/genetics
Humans
COVID-19/immunology
Phylogeny
Spike Glycoprotein, Coronavirus/genetics
Antibodies, Viral/immunology
HEK293 Cells
Antibodies, Neutralizing/immunology
Vero Cells
Cell Line
Chlorocebus aethiops
Animals
Immune Evasion
Protein Binding
Mutation

ASJC Scopus subject areas

General Biochemistry,Genetics and Molecular Biology

Access to Document

10.1016/j.celrep.2021.109292Licence: Creative Commons: Attribution (CC BY)

MengB2021Recurrent Final published version, 4.43 MBLicence: Creative Commons: Attribution (CC BY)

Cite this

The COVID-19 Genomics UK (COG-UK) Consortium, Meng, B., Kemp, S. A., Papa, G., Datir, R., Ferreira, I. A. T. M., Marelli, S., Harvey, W. T., Lytras, S., Mohamed, A., Gallo, G., Thakur, N., Collier, D. A., Mlcochova, P., Duncan, L. M., Carabelli, A. M., Kenyon, J. C., Lever, A. M., De Marco, A., ... Gupta, R. K. (2021). Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role in the Alpha variant B.1.1.7. Cell Reports, 35(13), Article 109292. https://doi.org/10.1016/j.celrep.2021.109292

@article{4b0401f449884836959f40acba1c6ae9,

title = "Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role in the Alpha variant B.1.1.7",

abstract = "We report severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike ΔH69/V70 in multiple independent lineages, often occurring after acquisition of receptor binding motif replacements such as N439K and Y453F, known to increase binding affinity to the ACE2 receptor and confer antibody escape. In vitro, we show that, although ΔH69/V70 itself is not an antibody evasion mechanism, it increases infectivity associated with enhanced incorporation of cleaved spike into virions. ΔH69/V70 is able to partially rescue infectivity of spike proteins that have acquired N439K and Y453F escape mutations by increased spike incorporation. In addition, replacement of the H69 and V70 residues in the Alpha variant B.1.1.7 spike (where ΔH69/V70 occurs naturally) impairs spike incorporation and entry efficiency of the B.1.1.7 spike pseudotyped virus. Alpha variant B.1.1.7 spike mediates faster kinetics of cell-cell fusion than wild-type Wuhan-1 D614G, dependent on ΔH69/V70. Therefore, as ΔH69/V70 compensates for immune escape mutations that impair infectivity, continued surveillance for deletions with functional effects is warranted.",

keywords = "Alpha variant, antibody escape, B.1.1.7, COVID-19, deletion, infectivity, neutralizing antibodies, resistance, SARS-CoV-2, spike mutation, Recurrence, Pandemics, SARS-CoV-2/genetics, Humans, COVID-19/immunology, Phylogeny, Spike Glycoprotein, Coronavirus/genetics, Antibodies, Viral/immunology, HEK293 Cells, Antibodies, Neutralizing/immunology, Vero Cells, Cell Line, Chlorocebus aethiops, Animals, Immune Evasion, Protein Binding, Mutation",

author = "{The COVID-19 Genomics UK (COG-UK) Consortium} and Bo Meng and Kemp, {Steven A.} and Guido Papa and Rawlings Datir and Ferreira, {Isabella A.T.M.} and Sara Marelli and Harvey, {William T.} and Spyros Lytras and Ahmed Mohamed and Giulia Gallo and Nazia Thakur and Collier, {Dami A.} and Petra Mlcochova and Duncan, {Lidia M.} and Carabelli, {Alessandro M.} and Kenyon, {Julia C.} and Lever, {Andrew M.} and {De Marco}, Anna and Christian Saliba and Katja Culap and Elisabetta Cameroni and Matheson, {Nicholas J.} and Luca Piccoli and Davide Corti and James, {Leo C.} and Robertson, {David L.} and Dalan Bailey and Gupta, {Ravindra K.} and Loman, {Nicholas J.} and Sam Nicholls and Chauhan, {Anoop J.} and Anna Price and Alan McNally and Andrew Bosworth and Joshua Quick and Joanne Stockton and Alex Richter and Andrew Beggs and Angus Best and Jeremy Mirza and Emma Moles-Garcia and Taylor, {Graham P.}",

note = "Funding Information: R.K.G. is supported by a Wellcome Trust Senior Fellowship in Clinical Science (WT108082AIA). I.A.T.M.F. is funded by the Sub-Saharan African Network for TB/HIV Research Excellence fellowship (SANTHE, a DELTAS Africa Initiative; DEL-15?006). 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), and Genome Research Limited, operating as the Wellcome Sanger Institute. This study was supported by the Cambridge NIHRB Biomedical Research Centre. S.A.K. is supported by the Bill and Melinda Gates Foundation via PANGEA grant OPP1175094. D.L.R. is funded by the MRC (MC UU 1201412). W.H. is funded by the MRC (MR/R024758/1). We thank James Voss for the kind gift of HeLa cells stably expressing ACE2, Paul Lehner for Calu-3 cells, and Simon Cook for H1299 cells. N.J.M. is funded by the MRC (CSF ref. MR/P008801/1), NHSBT (grant ref. WPA15-02), and the Addenbrooke's Charitable Trust, Cambridge University Hospitals (grant ref. 900239). We thank Wendy Barclay and Thomas Peacock for helpful discussions and the Geno2pheno UK Consortium. S.L. is funded by Medical Research Council MC_UU_12014/12. This study was also partly funded by the Rosetrees Trust. A.M.L. is funded by the Cambridge NIHRB Biomedical Research Centre. R.K.G. B.M. R.D. I.A.T.M.F. D.L.R. L.C.J. D.B. L.P. A.D.M. N.J.M. and D.A.C. designed the study and experiments. W.T.H. and A.M.C. designed and performed structural analyses. S.A.K. B.M. S.M. L.M.D. A.D.M. C.S. E.C. and K.C. performed experiments. L.P. A.D.M. D.A.C. B.M. R.K.G. D.L.R. D.B. R.D. I.A.T.M.F. and S.A.K. interpreted data. L.P. D.A.C. R.D. I.A.T.M.F. R.K.G. B.M. S.A.K. and D.L.R. performed data analysis and manuscript preparation. A.D.M. C.S. K.C. E.C. L.P. and D.A.C. are employees of Vir Biotechnology and may hold shares in Vir Biotechnology. R.K.G. has received consulting fees from UMOVIS lab, Gilead Sciences, and ViiV Healthcare and a research grant from InvisiSmart Technologies. Publisher Copyright: {\textcopyright} 2021 The Author(s) Copyright {\textcopyright} 2021 The Author(s). Published by Elsevier Inc. All rights reserved.",

year = "2021",

month = jun,

day = "29",

doi = "10.1016/j.celrep.2021.109292",

language = "English",

volume = "35",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Elsevier",

number = "13",

}

The COVID-19 Genomics UK (COG-UK) Consortium, Meng, B, Kemp, SA, Papa, G, Datir, R, Ferreira, IATM, Marelli, S, Harvey, WT, Lytras, S, Mohamed, A, Gallo, G, Thakur, N, Collier, DA, Mlcochova, P, Duncan, LM, Carabelli, AM, Kenyon, JC, Lever, AM, De Marco, A, Saliba, C, Culap, K, Cameroni, E, Matheson, NJ, Piccoli, L, Corti, D, James, LC, Robertson, DL, Bailey, D & Gupta, RK 2021, 'Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role in the Alpha variant B.1.1.7', Cell Reports, vol. 35, no. 13, 109292. https://doi.org/10.1016/j.celrep.2021.109292

TY - JOUR

T1 - Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role in the Alpha variant B.1.1.7

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

AU - Meng, Bo

AU - Kemp, Steven A.

AU - Papa, Guido

AU - Datir, Rawlings

AU - Ferreira, Isabella A.T.M.

AU - Marelli, Sara

AU - Harvey, William T.

AU - Lytras, Spyros

AU - Mohamed, Ahmed

AU - Gallo, Giulia

AU - Thakur, Nazia

AU - Collier, Dami A.

AU - Mlcochova, Petra

AU - Duncan, Lidia M.

AU - Carabelli, Alessandro M.

AU - Kenyon, Julia C.

AU - Lever, Andrew M.

AU - De Marco, Anna

AU - Saliba, Christian

AU - Culap, Katja

AU - Cameroni, Elisabetta

AU - Matheson, Nicholas J.

AU - Piccoli, Luca

AU - Corti, Davide

AU - James, Leo C.

AU - Robertson, David L.

AU - Bailey, Dalan

AU - Gupta, Ravindra K.

AU - Loman, Nicholas J.

AU - Nicholls, Sam

AU - Chauhan, Anoop J.

AU - Price, Anna

AU - McNally, Alan

AU - Bosworth, Andrew

AU - Quick, Joshua

AU - Stockton, Joanne

AU - Richter, Alex

AU - Beggs, Andrew

AU - Best, Angus

AU - Mirza, Jeremy

AU - Moles-Garcia, Emma

AU - Taylor, Graham P.

N1 - Funding Information: R.K.G. is supported by a Wellcome Trust Senior Fellowship in Clinical Science (WT108082AIA). I.A.T.M.F. is funded by the Sub-Saharan African Network for TB/HIV Research Excellence fellowship (SANTHE, a DELTAS Africa Initiative; DEL-15?006). 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), and Genome Research Limited, operating as the Wellcome Sanger Institute. This study was supported by the Cambridge NIHRB Biomedical Research Centre. S.A.K. is supported by the Bill and Melinda Gates Foundation via PANGEA grant OPP1175094. D.L.R. is funded by the MRC (MC UU 1201412). W.H. is funded by the MRC (MR/R024758/1). We thank James Voss for the kind gift of HeLa cells stably expressing ACE2, Paul Lehner for Calu-3 cells, and Simon Cook for H1299 cells. N.J.M. is funded by the MRC (CSF ref. MR/P008801/1), NHSBT (grant ref. WPA15-02), and the Addenbrooke's Charitable Trust, Cambridge University Hospitals (grant ref. 900239). We thank Wendy Barclay and Thomas Peacock for helpful discussions and the Geno2pheno UK Consortium. S.L. is funded by Medical Research Council MC_UU_12014/12. This study was also partly funded by the Rosetrees Trust. A.M.L. is funded by the Cambridge NIHRB Biomedical Research Centre. R.K.G. B.M. R.D. I.A.T.M.F. D.L.R. L.C.J. D.B. L.P. A.D.M. N.J.M. and D.A.C. designed the study and experiments. W.T.H. and A.M.C. designed and performed structural analyses. S.A.K. B.M. S.M. L.M.D. A.D.M. C.S. E.C. and K.C. performed experiments. L.P. A.D.M. D.A.C. B.M. R.K.G. D.L.R. D.B. R.D. I.A.T.M.F. and S.A.K. interpreted data. L.P. D.A.C. R.D. I.A.T.M.F. R.K.G. B.M. S.A.K. and D.L.R. performed data analysis and manuscript preparation. A.D.M. C.S. K.C. E.C. L.P. and D.A.C. are employees of Vir Biotechnology and may hold shares in Vir Biotechnology. R.K.G. has received consulting fees from UMOVIS lab, Gilead Sciences, and ViiV Healthcare and a research grant from InvisiSmart Technologies. Publisher Copyright: © 2021 The Author(s) Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2021/6/29

Y1 - 2021/6/29

N2 - We report severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike ΔH69/V70 in multiple independent lineages, often occurring after acquisition of receptor binding motif replacements such as N439K and Y453F, known to increase binding affinity to the ACE2 receptor and confer antibody escape. In vitro, we show that, although ΔH69/V70 itself is not an antibody evasion mechanism, it increases infectivity associated with enhanced incorporation of cleaved spike into virions. ΔH69/V70 is able to partially rescue infectivity of spike proteins that have acquired N439K and Y453F escape mutations by increased spike incorporation. In addition, replacement of the H69 and V70 residues in the Alpha variant B.1.1.7 spike (where ΔH69/V70 occurs naturally) impairs spike incorporation and entry efficiency of the B.1.1.7 spike pseudotyped virus. Alpha variant B.1.1.7 spike mediates faster kinetics of cell-cell fusion than wild-type Wuhan-1 D614G, dependent on ΔH69/V70. Therefore, as ΔH69/V70 compensates for immune escape mutations that impair infectivity, continued surveillance for deletions with functional effects is warranted.

AB - We report severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike ΔH69/V70 in multiple independent lineages, often occurring after acquisition of receptor binding motif replacements such as N439K and Y453F, known to increase binding affinity to the ACE2 receptor and confer antibody escape. In vitro, we show that, although ΔH69/V70 itself is not an antibody evasion mechanism, it increases infectivity associated with enhanced incorporation of cleaved spike into virions. ΔH69/V70 is able to partially rescue infectivity of spike proteins that have acquired N439K and Y453F escape mutations by increased spike incorporation. In addition, replacement of the H69 and V70 residues in the Alpha variant B.1.1.7 spike (where ΔH69/V70 occurs naturally) impairs spike incorporation and entry efficiency of the B.1.1.7 spike pseudotyped virus. Alpha variant B.1.1.7 spike mediates faster kinetics of cell-cell fusion than wild-type Wuhan-1 D614G, dependent on ΔH69/V70. Therefore, as ΔH69/V70 compensates for immune escape mutations that impair infectivity, continued surveillance for deletions with functional effects is warranted.

KW - Alpha variant

KW - antibody escape

KW - B.1.1.7

KW - COVID-19

KW - deletion

KW - infectivity

KW - neutralizing antibodies

KW - resistance

KW - SARS-CoV-2

KW - spike mutation

KW - Recurrence

KW - Pandemics

KW - SARS-CoV-2/genetics

KW - Humans

KW - COVID-19/immunology

KW - Phylogeny

KW - Spike Glycoprotein, Coronavirus/genetics

KW - Antibodies, Viral/immunology

KW - HEK293 Cells

KW - Antibodies, Neutralizing/immunology

KW - Vero Cells

KW - Cell Line

KW - Chlorocebus aethiops

KW - Animals

KW - Immune Evasion

KW - Protein Binding

KW - Mutation

UR - http://www.scopus.com/inward/record.url?scp=85108560704&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2021.109292

DO - 10.1016/j.celrep.2021.109292

M3 - Article

C2 - 34166617

AN - SCOPUS:85108560704

SN - 2211-1247

VL - 35

JO - Cell Reports

JF - Cell Reports

IS - 13

M1 - 109292

ER -

Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role in the Alpha variant B.1.1.7

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

Fingerprint

Cite this