SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway
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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.
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 & Thomson , E C 2022 , ' SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway ' , Nature Microbiology , vol. First Online . https://doi.org/10.1038/s41564-022-01143-7
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DescriptionFunding 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.
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