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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.

SUBMITTER: Willett BJ

PROVIDER: S-EPMC9352574 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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

Willett Brian J BJ Grove Joe J MacLean Oscar A OA Wilkie Craig C De Lorenzo Giuditta G Furnon Wilhelm W Cantoni Diego D Scott Sam S Logan Nicola N Ashraf Shirin S Manali Maria M Szemiel Agnieszka A Cowton Vanessa V Vink Elen E Harvey William T WT Davis Chris C Asamaphan Patawee P Smollett Katherine K Tong Lily L Orton Richard R Hughes Joseph J Holland Poppy P Silva Vanessa V Pascall David J DJ Puxty Kathryn K da Silva Filipe Ana A Yebra Gonzalo G Shaaban Sharif S Holden Matthew T G MTG Pinto Rute Maria RM Gunson Rory R Templeton Kate K Murcia Pablo R PR Patel Arvind H AH Klenerman Paul P Dunachie Susanna S Haughney John J Robertson David L DL Palmarini Massimo M Ray Surajit S Thomson Emma C EC

Nature microbiology 20220707 8

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 individu ...[more]

PMID: 35798890

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Project description:The SARS-CoV-2 Omicron BA.1 variant emerged in late 2021 and is characterised by multiple spike mutations across all spike domains. Here we show that Omicron BA.1 has higher affinity for ACE2 compared to Delta, and confers very significant evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralising antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralisation. Importantly, antiviral drugs remdesevir and molnupiravir retain efficacy against Omicron BA.1. We found that in human nasal epithelial 3D cultures replication was similar for both Omicron and Delta. However, in lower airway organoids, Calu-3 lung cells and gut adenocarcinoma cell lines live Omicron virus demonstrated significantly lower replication in comparison to Delta. We noted that despite presence of mutations predicted to favour spike S1/S2 cleavage, the spike protein is less efficiently cleaved in live Omicron virions compared to Delta virions. We mapped the replication differences between the variants to entry efficiency using spike pseudotyped virus (PV) entry assays. The defect for Omicron PV in specific cell types correlated with higher cellular RNA expression of TMPRSS2, and accordingly knock down of TMPRSS2 impacted Delta entry to a greater extent as compared to Omicron. Furthermore, drug inhibitors targeting specific entry pathways demonstrated that the Omicron spike inefficiently utilises the cellular protease TMPRSS2 that mediates cell entry via plasma membrane fusion. Instead, we demonstrate that Omicron spike has greater dependency on cell entry via the endocytic pathway requiring the activity of endosomal cathepsins to cleave spike. Consistent with suboptimal S1/S2 cleavage and inability to utilise TMPRSS2, syncytium formation by the Omicron spike was dramatically impaired compared to the Delta spike. Overall, Omicron appears to have gained significant evasion from neutralising antibodies whilst maintaining sensitivity to antiviral drugs targeting the polymerase. Omicron has shifted cellular tropism away from TMPRSS2 expressing cells that are enriched in cells found in the lower respiratory and GI tracts, with implications for altered pathogenesis.

Dataset Information

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

Publications

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

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