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Recurrent emergence and transmission of a SARS-CoV-2 spike deletion H69/V70
Open accessPreprint — published as 10.1016/j.celrep.2021.109292
Abstract
SARS-CoV-2 amino acid replacements in the receptor binding domain (RBD) occur relatively frequently and some have a consequence for immune recognition. Here we report recurrent emergence and significant onward transmission of a six-nucleotide out of frame deletion in the S gene, which results in loss of two amino acids: H69 and V70. We report that in human infections ΔH69/V70 often co-occurs with the receptor binding motif amino acid replacements N501Y, N439K and Y453F, and in the latter two cases has followed the RBD mutation. One of the ΔH69/V70+ N501Y lineages, now known as B.1.1.7, has undergone rapid expansion and includes eight S gene mutations: RBD (N501Y and A570D), S1 (ΔH69/V70 and Δ144) and S2 (P681H, T716I, S982A and D1118H). In vitro , we show that ΔH69/V70 does not reduce serum neutralisation across multiple convalescent sera. However, ΔH69/V70 increases infectivity and is associated with increased incorporation of cleaved spike into virions. ΔH69/V70 is able to compensate for small infectivity defects induced by RBD mutations N501Y, N439K and Y453F. In addition, replacement of H69 and V70 residues in the B.1.1.7 spike reduces its infectivity and spike mediated cell-cell fusion. Based on our data ΔH69/V70 likely acts as a permissive mutation that allows acquisition of otherwise deleterious immune escape mutations. Enhanced surveillance for the ΔH69/V70 deletion with and without RBD mutations should be considered as a global priority not only as a marker for the B.1.1.7 variant, but potentially also for other emerging variants of concern. Vaccines designed to target the deleted spike protein could mitigate against its emergence as increased selective forces from immunity and vaccines increase globally. Highlights: ΔH69/V70 is present in at least 28 SARS-CoV-2 lineages ΔH69/V70 does not confer escape from convalescent sera ΔH69/V70 increases spike infectivity and compensates for RBD mutations ΔH69/V70 is associated with greater spike cleavage B.1.1.7 requires ΔH69/V70 for optimal spike cleavage and infectivity
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“Although distinct, the variants share common characteristics, including known escape mutations that were previously identified under antibody pressure selection in vitro 2,3,[13][14][15][16][17] .”
From Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies (2021) · cites this paper as [2]
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“The B.1.1.7 variant emerged in the United Kingdom, the B.1.351variant (also termed 501Y.V2) in South Africa and the P.1 and P.2 lineages in Brazil 2,3,5,9-12 .”
From Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies (2021) · cites this paper as [2]
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Metadata
- Authors
- Kemp, S. A., Meng, B., Ferriera, I. A., Datir, R., Harvey, W. T., Papa, G., Lytras, S., Collier, D. A., Mohamed, A., Gallo, G., Thakur, N., The COVID-19 Genomics UK (COG-UK) Consortium, Carabelli, A. M., Kenyon, J. C., Lever, A. M., De Marco, A., Saliba, C., Culap, K., Cameroni, E., Piccoli, L., Corti, D., James, L. C., Bailey, D., Robertson, D. L., & Gupta, R. K.
- Affiliations
- University of Cambridge (GB)
- University of Glasgow (GB)
- MRC Laboratory of Molecular Biology (GB)
- MRC University of Glasgow Centre for Virus Research (GB)
- The Pirbright Institute (GB)
- National University of Singapore (SG)
- Vir Biotechnology (Switzerland) (CH)
- Corresponding author
- Gupta, Ravindra K.
- ORCID
- Kemp, Steven A
- Meng, Bo
- Datir, Rawlings
- Harvey, William T
- Papa, Guido
- Lytras, Spyros
- Collier, Dami A
- Gallo, Giulia
- Thakur, Nazia
- Carabelli, Alessandro M
- Kenyon, Julia C
- Lever, Andrew M
- Saliba, Christian
- Culap, Katja
- Cameroni, Elisabetta
- Piccoli, Luca
- Corti, Davide
- James, Leo C
- Bailey, Dalan
- Robertson, David L
- Gupta, Ravindra K.
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2020-12-14
- OpenAlex
- W3112108776
- Cited by
- 252
- References
- 68
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 6 · 2023: 13 · 2022: 47 · 2021: 181 · 2020: 3
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- SSRN Electronic Journal (acceptedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Bill and Melinda Gates Foundation (OPP 1175094)
- NHS Blood and Transplant (WPA15‐02)
- Wellcome Trust (WT108082AIA, DEL-15-006)
- UK Research and Innovation (MC_PC_19027)
- National Institute for Health and Care Research
- University of Cambridge
- Rosetrees Trust
- Cambridge University Hospitals
- Medical Research Council (MC_UU_12014, MC UU 12014/12, MR/P008801/1, MR/R024758/1, 1201412)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Physical Sciences › Mathematics › Modeling and Simulation › COVID-19 epidemiological studies
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
- Keywords
- SARS-CoV-2, receptor-binding domain mutations, N501Y, immune evasion, neutralizing antibodies, viral infectivity, cell-cell fusion, variants of concern, S gene mutations, vaccine design, Omicron BA.1, BA.2
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