Journal
NATURE
Volume 603, Issue 7902, Pages 706-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-022-04474-x
Keywords
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Categories
Funding
- Wellcome Trust Senior Fellowship in Clinical Science [WT108082AIA]
- Cambridge NIHRB Biomedical Research Centre
- SANTHE award [DEL-15-006]
- Africa Research Excellence Fund Research Development Fellowship [AREF-318-ABDUL-F-C0882]
- MRC (TSF) [MR/T032413/1]
- NHSBT [WPA15-02]
- Addenbrooke's Charitable Trust [900239]
- G2P-UK National Virology consortium - MRC/UKRI [MR/W005611/1]
- The Rosetrees Trust
- Geno2pheno UK consortium
- EPSRC [EP/V002910/1]
- AMED Research Program on Emerging and Re-emerging Infectious Diseases [20fk0108270, 20fk0108413, 20fk0108163, 20fk0108146, 20fk0108451]
- JST SICORP [JPMJSC20U1, JPMJSC21U5]
- JST CREST [JPMJCR20H4]
- AMED Research Program on HIV/AIDS [21fk0410033, 21fk0410039]
- AMED Japan Program for Infectious Diseases Research and Infrastructure [20wm0325009, 21wm0325009]
- JST A-STEP [JPMJTM20SL]
- JST SICORP (e-ASIA) [JPMJSC20U1]
- JSPS KAKENHI [19K06382, 18H02662, 21H02737]
- JSPS Fund for the Promotion of Joint International Research (Fostering Joint International Research) [18KK0447]
- JSPS [JPJSCCA20190008, DC1 19J20488]
- JSPS Leading Initiative for Excellent Young Researchers (LEADER)
- Takeda Science Foundation
- Tokyo Biochemical Research Foundation
- Mitsubishi Foundation
- Shin-Nihon Foundation of Advanced Medical Research
- Grant for Joint Research Projects of the Research Institute for Microbial Diseases, Osaka University
- intramural grant from Kumamoto University COVID-19 Research Projects (AMABIE)
- Intercontinental Research and Educational Platform Aiming for Eradication of HIV/AIDS
- Joint Usage/Research Center program of Institute for Frontier Life and Medical Sciences, Kyoto University
- National Institute of Allergy and Infectious Diseases [DP1AI158186, HHSN272201700059C]
- Pew Biomedical Scholars Award
- Investigators in the Pathogenesis of Infectious Disease Awards from the Burroughs Wellcome Fund
- Fast Grants
- Bill and Melinda Gates Foundation [OPP1156262]
- EASL Juan Rodes fellowship
- UKRI Future Leaders fellowship
- Bill and Melinda Gates award [INV-018944]
- National Institutes of Health [R01 AI138546]
- Grants-in-Aid for Scientific Research [18KK0447, 21H02737, 19K06382] Funding Source: KAKEN
Ask authors/readers for more resources
The Omicron variant of SARS-CoV-2 has a higher affinity for ACE2 and can evade neutralizing antibodies more effectively compared to the Delta variant. A third dose of mRNA vaccine can provide enhanced protection. Omicron has lower replication in lung and gut cells and less efficiently cleaves its spike protein compared to Delta.
The SARS-CoV-2 Omicron BA.1 variant emerged in 2021(1) and has multiple mutations in its spike protein(2). Here we show that the spike protein of Omicron has a higher affinity for ACE2 compared with Delta, and a marked change in its antigenicity increases Omicron's evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralizing antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralization. Importantly, the antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However, in lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared with Delta. The differences in replication were mapped to the entry efficiency of the virus on the basis of spike-pseudotyped virus assays. The defect in entry of Omicron pseudotyped virus to specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2, and deletion of TMPRSS2 affected Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways(3) demonstrated that the Omicron spike inefficiently uses the cellular protease TMPRSS2, which promotes cell entry through plasma membrane fusion, with greater dependency on cell entry through the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to use TMPRSS2, syncytium formation by the Omicron spike was substantially impaired compared with the Delta spike. The less efficient spike cleavage of Omicron at S1/S2 is associated with a shift in cellular tropism away from TMPRSS2-expressing cells, with implications for altered pathogenesis.
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