8 Cell/Nature/Science Gao Fu, He Dayi, Yuan Guoyong and other teams revealed the potential mechanism of Omicron's antibody escape and rapid spread

On March 3, 2022, Columbia University's He team published a research paper titled "Antibody evasion properties of SARS-CoV-2 Omicron sublineages" online in Nature, which showed that With the exception of the recently authorized LY-CoV1404 (bebtelovimab), no authorized monoclonal antibody therapy can adequately cover all sublineages of the Omicron variant (click to read).

On February 28, 2022, Cong Yao, Wang Yanxing, and Huang Zhong of the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, jointly published a joint communication entitled "Molecular basis of receptor binding and antibody neutralization of" online in Nature Omicron", the findings shed new light on Omicron's receptor involvement and antibody neutralization/evasion, and may also inform the design of widely effective SARS-CoV-2
vaccines.

On February 8, 2022, Science published online the title "Structures of the Omicron Spike trimer with ACE2 and an anti-Omicron antibody" by the Xu Huaqiang/Yin Wanchao team of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, and the team of Jimin Trust Deng Shijun The latest results, the study analyzes the spike protein of the toxic Omicron variant, and the high-resolution cryo-EM structure that binds its receptor ACE2 and the broad-spectrum anti-new crown antibody JMB2002, respectively, elucidates the molecular mechanism of rapid transmission and immune escape of the Omicron variant, and reveals the new mechanism of action of the therapeutic antibody JMB2002, providing new ideas for the design and development of broad-spectrum anti-new crown antibodies (click to read
。

On January 21, 2022, the research team of Zhu Xuan/Chen Fuhe/Yuan Guoyong of the University of Hong Kong and the research team of the Key Laboratory of Tropical Translational Medicine of the Ministry of Education of Hainan Medical College jointly published the title "Attenuated replication and pathogenicity of SARS-CoV-2" online in Nature B.
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529 Omicron", which showed that replication of the Omicron variant was significantly attenuated in Calu3
and Caco2 cells.
Further mechanistic studies have shown that the Omicron variant is inefficient in the use of transmembrane serine protease 2 (TMPRSS2) compared to WT and previous variants, which may explain its reduced replication in Calu3 and Caco2 cells
.
Compared to the WT and Delta variants, Omicron replication in the upper and lower respiratory tract of infected K18-hACE2 mice was significantly reduced, which led to significant improvements
in lung pathology.
Compared with SARS-CoV-2 WT, Alpha, Beta, and Delta variants, infection with the Omicron variant resulted in minimal
weight loss and mortality.
Overall, the study shows that the Omicron variant has reduced viral replication and pathogenicity in mice compared to WT and previous variants (click to read).

On January 5, 2022, Wang Peiyi of Southern University of Science and Technology, Gao Fu and Qi Jianxun of the Institute of Microbiology, Chinese Academy of Sciences jointly published a report entitled "Receptor binding and complex structures of human ACE2 to spike RBD from Omicron and Delta SARS-CoV-2" online in Cell This study explores the binding properties between the human receptor ACE2 (hACE2) and VOC RBD, and resolves the crystal and cryo-EM structures
of the Omicron RBD-hACE2 complex and the Delta RBD-hACE2 complex.
The study found that, unlike Alpha, Beta, and Gamma, Omicron RBD has a similar binding affinity to hACE2 compared to prototype RBD, which may be due to immune evasion and compensation
for transmissibility of multiple mutations.
The complex structure of Omicron-hACE2 and Delta-hACE2 reveals the structural basis of how RBD-specific mutations bind to hACE2 (click to read).

Several recent Omicron subvariants of the pathogen SARS-CoV-2 have shown such strong antibody resistance that the vaccine's protective effect against infection has diminished, and most current monoclonal therapies have lost their efficacy, manifested by an increasing number of breakthrough infections
during the convalescent period and/or in vaccinated individuals.

Fortunately, treatment options remain.

In the United States, three antivirals have received emergency use authorization for the treatment of COVID-19: remdesivir, molnupiravir, and nirmatrelvir (also known as PF-07321332, used in combination with ritonavir and marketed as PAXLOVID™).

。 The first two target RNA-dependent RNA polymerases (RdRp) and the latter target 3CLprotease (3CLpro; Also known as main protease (Mpro) and nonstructural protein 5 (NSP5).

Both enzymes are essential during the viral life cycle and are relatively conserved
in coronaviruses.

Remdesivir is intravenous and has been reported to reduce relative risk by 87%, while monopivir and nirmatrelvir are oral and have clinical efficacy of 31% and 89%
in reducing hospitalization and mortality, respectively.
As the use of these antivirals increases, there are concerns that resistance may emerge, especially if used
as monotherapy.
For remdesivir, in vitro and in vivo studies have revealed mutations associated with drug resistance, and resistance to monoprevir or nirmatrelvir is currently being actively
studied.

This study reports that SARS-CoV-2 can acquire resistance to nirmatrelvir in vitro through multiple pathways
.
The researchers studied the in vitro passage of SARS-CoV-2 in nirmatrelvir using two separate methods, one of which was large-scale
.
In fact, both produce highly resistant viruses, and their sequences show a large number of 3CL protease mutations
.

In further replicates, the researchers selected 53 separate viral lineages and observed mutations
on 23 different enzyme residues.
However, several common nirmatrelvir-resistant mutation pathways are preferred, with most viruses from T21I, P252L, or T304I being precursor mutations
.

Construction and analysis of 13 recombinant SARS-CoV-2 clones showed that these mutations mediate only low levels of resistance, while higher resistance requires the accumulation
of additional mutations.
In addition, the E166V mutation provides the strongest resistance (about 100-fold), but this mutation results in a loss of fitness for viral replication, recovered
by compensatory changes such as L50F and T21I.

Verification of identified mutations in isogenic recombinant SARS-CoV-2 (Figure from Nature)

Overall, the results of this study suggest that resistance to nirmatrelvir by SARS-CoV-2 in vitro is easily developed through multiple pathways, and the specific mutations identified in this study will provide a strong theoretical basis
for future research on the mechanism of SARS-CoV-2 resistance and the design of a new generation of protease inhibitors.

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