Abstract
The SARS-CoV-2 Omicron BA.1 variant emerged in 20211 and has multiple mutations in its spike protein2. 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 pathways3 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.
Highlights
To understand the impact of these substitutions on receptor engagement, we determined the kinetics and affinity of monomeric human ACE2 binding to immobilized Omicron, Wuhan-Hu-1 and Delta receptor binding domain (RBD) using biolayer interferometry (BLI)
AT In order to further explore our pseudotyped virus (PV) entry and infection findings, we studied the expression of R ACE2 and TMPRSS2 across our target cells by qPCR on RNA extracts from cell lysates (Figure 3b)
We found greater TMPRSS2 mRNA in cells where Omicron PV entry was LE impaired relative to Delta: for example Calu-3 and Organoids were higher in TMPRSS2 compared to H1299, Hela-ACE2, and 293T-A2ΔT2
Summary
AOlmteircerdonTMimPpRaScSts2tursoapgiesmbyaSnAdRfuS-sCoogVe-n2VicIitEy W Received:21December2021 E Accepted: 26 January 2022 R Accelerated Article Preview online xx xx xxxx. Bo Meng[1,2,44], Adam Abdullahi[1,2,44], Isabella A.T.M. Ferreira[1,2,44], Niluka Goonawardane 1,2,44 Akatsuki Saito[3,44], Izumi Kimura[4,44], Daichi Yamasoba[4,44], Pehuén Pereyra Gerber[1,2], Saman Fatihi[5], Surabhi Rathore[5], Samantha K Zepeda[6], Guido Papa[7], Steven A. The Omicron variant has 15 amino acid mutations in the RBD (Supplementary Figure 1 and 2). To understand the impact of these substitutions on receptor engagement, we determined the kinetics and affinity of monomeric human ACE2 binding to immobilized Omicron, Wuhan-Hu-1 and Delta RBDs using biolayer interferometry (BLI).
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