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

Willett, B. J. et al. (2022) SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway. Nature Microbiology, 7(8), pp. 1161-1179. (doi: 10.1038/s41564-022-01143-7) (PMID:35798890) (PMCID:PMC9352574)

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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.

Item Type:Articles
Additional Information: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.
Glasgow Author(s) Enlighten ID:Grove, Dr Joe and Robertson, Professor David and Willett, Professor Brian and Asamaphan, Dr Patawee and Palmarini, Professor Massimo and Scott, Mr Sam and Tong, Dr Lily and Davis, Dr Chris and Harvey, Dr William and Orton, Dr Richard and Vink, Elen and Szemiel, Dr Agnieszka and Cowton, Dr Vanessa and Gunson, Dr Rory and Da Silva Filipe, Dr Ana and Hughes, Dr Joseph and Wilkie, Dr Craig and Pinto, Dr Rute and Cantoni, Dr Diego and De Lorenzo, Dr Giuditta and Furnon, Dr Wilhelm and Thomson, Professor Emma and Haughney, Dr John and Puxty, Dr Kathryn and MacLean, Dr Oscar and Logan, Miss Nicola and Pascall, Dr David and Ray, Professor Surajit and Smollett, Dr Katherine and Patel, Professor Arvind and Ashraf, Dr Shirin and Murcia, Professor Pablo
Authors: 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., 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., PITCH Consortium, , The COVID-19 Genomics UK (COG-UK) Consortium, , Haughney, J., Robertson, D. L., Palmarini, M., Ray, S., and Thomson, E. C.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > School of Infection & Immunity
College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
College of Science and Engineering > School of Mathematics and Statistics > Statistics
Journal Name:Nature Microbiology
Publisher:Nature Research
ISSN (Online):2058-5276
Published Online:07 July 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Nature Microbiology 7(8): 1161-1179
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172630014Cross-Cutting Programme – Viral Genomics and Bioinformatics (Programme 9)David RobertsonMedical Research Council (MRC)MC_UU_12014/12III - Centre for Virus Research
302632Using a comparative One Health approach to investigate the structural basis of antigenic variation among human and avian influenza virusesJill PellMedical Research Council (MRC)MR/R024758/1Institute of Biodiversity, Animal Health and Comparative Medicine
301313Atypical bovine morbillivirus infections in the Serengeti ecosystemBrian WillettBiotechnology and Biological Sciences Research Council (BBSRC)BB/R004250/1III - Centre for Virus Research
302172A One Health approach to pan-valent morbillivirus vaccinesBrian WillettBiotechnology and Biological Sciences Research Council (BBSRC)BB/R019843/1III - Centre for Virus Research
316100Studying hepatitis C virus to determine how viruses harness structural disorder to control entry and antibody resistance.Joseph GroveWellcome Trust (WELLCOTR)107653/A/15/ZIII - Centre for Virus Research