RT Journal Article
SR Electronic
T1 SARS-CoV-2 Omicron spike mediated immune escape and tropism shift
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.12.17.473248
DO 10.1101/2021.12.17.473248
A1 Bo Meng
A1 Isabella A.T.M Ferreira
A1 Adam Abdullahi
A1 Niluka Goonawardane
A1 Akatsuki Saito
A1 Izumi Kimura
A1 Daichi Yamasoba
A1 Pehuén Perera Gerba
A1 Saman Fatihi
A1 Surabhi Rathore
A1 Samantha K Zepeda
A1 Guido Papa
A1 Steven A. Kemp
A1 Terumasa Ikeda
A1 Mako Toyoda
A1 Toong Seng Tan
A1 Jin Kuramochi
A1 Shigeki Mitsunaga
A1 Takamasa Ueno
A1 Kotaro Shirakawa
A1 Akifumi Takaori-Kondo
A1 Teresa Brevini
A1 Donna L. Mallery
A1 Oscar J. Charles
A1 CITIID-NIHR BioResource COVID-19 Collaboration
A1 The Genotype to Phenotype Japan (G2P-Japan) Consortium
A1 Ecuador-COVID19 Consortium
A1 John E Bowen
A1 Anshu Joshi
A1 Alexandra C. Walls
A1 Laurelle Jackson
A1 Sandile Cele
A1 Darren Martin
A1 Kenneth G.C. Smith
A1 John Bradley
A1 John A. G. Briggs
A1 Jinwook Choi
A1 Elo Madissoon
A1 Kerstin Meyer
A1 Petra Mlcochova
A1 Lourdes Ceron-Gutierrez
A1 Rainer Doffinger
A1 Sarah Teichmann
A1 Matteo Pizzuto
A1 Anna de Marco
A1 Davide Corti
A1 Alex Sigal
A1 Leo James
A1 David Veesler
A1 Myra Hosmillo
A1 Joo Hyeon Lee
A1 Fotios Sampaziotis
A1 Ian G Goodfellow
A1 Nicholas J. Matheson
A1 Lipi Thukral
A1 Kei Sato
A1 Ravindra K. Gupta
YR 2022
UL http://biorxiv.org/content/early/2022/01/13/2021.12.17.473248.abstract
AB 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.Competing Interest StatementRKG has received honoraria from GSK, Janssen and ViiV for educational activities