The team of Xu Huaqiang/Yin Wanchao of the Chinese Academy of Sciences and Jimin Trustworthy analyzed the mechanism of infection enhancement and immune escape of Omicron BA.1 and BA.2, and explored the potential evolutionary path of Omicron

Since November 2021 in iNature, the newly emerged Omicron variant, with enhanced infectivity, quickly replaced a variety of "worrisome variant (VOC)" dominated by Delta and became the main popular variant; at the same time, it carries a large number of mutations and has The strong immune escape ability has brought huge challenges to the global epidemic prevention and control
.

Popular new coronavirus Omicron variants include BA.
1 and BA.
2
.

However, BA.
2 spreads faster than the BA.
1 variant, causing more confirmed cases than BA.
1 by the end of February 2022
.

However, the underlying molecular mechanism for the rapid spread of Omicron BA.
2 is not well understood
.

On April 13, 2022, the team of Xu Huaqiang/Yin Wanchao from Shanghai Institute of Materia Medica, Chinese Academy of Sciences, together with Jimin Trusted Research Team, published a non-peer-reviewed article titled "Structural and biochemical mechanism for increased infectivity and immunity on the preprint platform bioRxiv.
evasion of Omicron BA.
1 and BA.
2 variants and their mouse origins” research paper, receptor binding studies show that the potency of the BA.
2 spike trimer on human ACE2 is comparable to wild-type and Omicron BA.
1 strain spikes The burst trimer binds 11 and 2 times the potency of ACE2
.

The structure of the BA.
2 spike trimer indicates that all three receptor-binding domains (RBDs) in the spike trimer are in an open conformation, ready to bind with high affinity to human ACE2, for increased infectivity of BA.
2 laid the foundation
.

 JMB2002 is a therapeutic antibody that potently inhibits Omicron BA.
1 and also shows potent neutralizing activity against Omicron BA.
2
.

In addition, both BA.
1 and BA.
2 spike trimers were able to efficiently bind mouse ACE2
.

In contrast, wild-type spike trimers bound well to cat ACE2, but not to mouse ACE2
.

The structures of BA.
1 and BA.
2 spike trimers bound to mouse ACE2 reveal the basis for their high-affinity interaction
.

Taken together, these results suggest that Omicron BA.
1 and BA.
2 variants arise from a possible evolutionary pathway of the human-mouse-human cycle, which may have important implications for establishing effective strategies against viral infection
.

Since November 2021, the newly emerged Omicron variant, with enhanced infectivity, quickly replaced a variety of "worrisome variant (VOC)" dominated by Delta and became the main popular variant; at the same time, it carried a large number of mutations, with The strong immune escape ability has brought huge challenges to the global epidemic prevention and control
.

Statistics show that the number of confirmed cases and deaths around the world are still rising.
The cumulative number of confirmed cases has exceeded 500 million.
At present, there are still more than 1 million new cases every day, and almost all of them are infected by Omicron variant strains
.

Popular new coronavirus Omicron variants include BA.
1 and BA.
2
.

Compared with a variety of "concerned variants (VOC)" that have appeared before, the Omicron variant has more mutations, especially the spike protein on the surface of the capsule that is involved in viral infection, making nearly 90% of the Neutralizing antibodies are ineffective or have reduced potency
.

In the early stage of urgent research, the research team quickly analyzed the spike protein of the BA.
1 mutant strain and the high-resolution cryo-electron microscope structure that binds to the human receptor ACE2, and explained the enhanced infectivity of the BA.
1 mutant strain from the atomic level combined with functional experiments.
, and the molecular mechanism of immune escape; and conquered the structure of the spike protein of the BA.
1 mutant strain and the specific therapeutic antibody JMB2002, expounding the molecular mechanism of the antibody JMB2002 with broad-spectrum anti-COVID-19
.

The related work was published online in Science on February 8, 2022 under the title "Structures of the Omicron Spike trimer with ACE2 and an anti-Omicron antibody"
.

However, BA.
2 spreads faster than the BA.
1 variant, causing more confirmed cases than BA.
1 by the end of February 2022 (Fig.
1A)
.

It is particularly noteworthy that in many areas hardest hit by the new crown epidemic in Asia, including South Korea, Hong Kong, China and Shanghai, China, almost all confirmed cases are caused by BA.
2
.

Statistics show that there have been more than 20,000 positive infections per day in Shanghai recently, and the cumulative number of positive infections has exceeded 300,000.
The pressure of epidemic prevention and control far exceeds that of the Wuhan epidemic at the beginning of the new crown outbreak in early 2020
.

As the two most famous megacities in China, Hong Kong and Shanghai, because of the spread of BA.
2, have had a huge impact on people's lives and work, and also brought huge losses to economic construction
.

The research team focused on the spike protein of the Omicron variant strain, and carried out systematic functional assays and mechanism studies
.

The binding force test showed that the ability of BA.
2 to bind to the receptor ACE2 was about 2 times higher than that of the BA.
1 mutant spike protein; at the same time, thermodynamic experiments showed that BA.
2 was more stable than the BA.
1 mutant spike protein.
The receptor binding domain (RBD) of BA.
2, and a more flexible variant of the spike protein trimer; from the resolved structure of the BA.
2 spike protein bound to its receptor ACE2, the spike protein trimer is also seen Adjacent RBD-specific interactions in vivo formed RBD dimers similar to those in the BA.
1 mutant spike protein structure (Fig.
1B-1C); in addition, from the resolved BA.
2 spike protein binding to its receptor ACE2 structure, it can be seen that BA.
2 is more likely to be in the conformation of the RBD-opened spike protein than the BA.
1 mutant strain that can bind to the receptor ACE2.
This information explains that the Omicron mutant strain BA.
2 is more infectious than BA.
1.
Sexual enhancement issues
.

Combining the structures of the spike proteins of BA.
2 and BA.
1 mutant strains that bind the receptor human ACE2, the study found that only a few (less than 10%) mutations on the spike protein were located inside the protein, and other mutations were located in the spike The surface of the protein (Fig.
1B) includes antigenic epitopes bound by various classes of neutralizing antibodies, which structurally explains the molecular mechanism by which both Omicron variants BA.
2 and BA.
1 can resist most neutralizing antibodies
.

In terms of the number of mutations, the spike proteins of BA.
2 and BA.
1 mutants have 31 and 37 point mutations, respectively, while BA.
2 and BA.
1 mutants also have 22 point mutation differences
.

From the overall view of the 1273 amino acid sequence of the spike protein, the mutation rate of the Omicron variant strains is within 3%, and most of the surface of the spike protein is still close to the original strain.
and antibodies, can still protect Omicron-infected patients to a certain extent, which also structurally explains the immune protection mechanism against Omicron mutants caused by the first-generation vaccines, and also promotes the promotion of the third dose of the new crown vaccine as soon as possible.
theoretical basis is provided
.

Figure 1 A, the change in the proportion of 2019-nCoV infection of the three mutant strains since 2022; B, the display of the mutation sites of Omicron BA.
2 relative to the original type; C, the binding effect of the spike protein trimer of the Omicron BA.
2 mutant strain Side view of the structure of the three ACE2s in the body; D, top view of the structure of the Omicron BA.
2 mutant spike protein trimer-binding antibody JMB2002; E, illustration of the antibody JMB2002 blocking the binding of human ACE2 protein to the spike protein
.

At the same time, the research data shows that the neutralizing antibody JMB2002 with a new mechanism of action developed by the team of Jimin Trust Deng Sujun can also bind to the spike protein of the BA.
2 mutant strain, inhibit the replication of the BA.
2 mutant strain virus, and maintain the same Inhibits comparable activity of BA.
1 mutants
.

The research team further conquered the structure of the BA.
2 mutant spike protein and the specific therapeutic antibody JMB2002 (Figure 1D)
.

Through structural comparison, it can be seen that JMB2002 binds the same epitope of BA.
2 and BA.
1 mutant spike protein, and also inhibits the BA.
2 mutant strain by preventing the spike protein from binding to its receptor ACE2 ( Figure 1E)
.

These data further corroborate that the JMB2002 antibody has great potential for broad-spectrum anti-COVID-19
.

Figure 2 A, mouse-derived ACE2 protein can bind to Omicron BA.
2 and BA.
1 spike proteins; B, human, mouse, cat, rat, dog ACE2 proteins bind to primitive, Omicron BA.
2, BA.
1 Differences in the binding ability of the spike protein of the virus strains; C, The structure of the spike protein trimers of Omicron BA.
2 and BA.
1 mutant strains binding to two mouse ACE2 receptors respectively; D, Different new coronavirus strains have different effects on human, mouse, Selective infection in cats
.

In order to better prevent and control the new crown epidemic caused by Omicron, the research team further explored the potential evolutionary path of Omicron
.

By purifying the receptor ACE2 proteins of more than 20 different species, the binding capacity of Omicron and the original strain spike protein was determined and compared.
The data showed that, unlike human ACE2, the Omicron spike protein enhanced the binding ability of a variety of animal-derived ACE2 , including the ability of horses, pigs and sheep to bind Omicron spike protein, which is significantly lower than that of the original strain; while the ability of cat-derived ACE2 to bind Omicron and the original strain spike protein is similar; unexpectedly, it was found that the ACE2 that cannot bind the original strain spike protein Mouse ACE2, however, has the ability to bind Omicron spike protein similar to human ACE2 (Figure 2A-2B)
.

The research team quickly analyzed the high-resolution cryo-EM structures of the spike proteins of BA.
2 and BA.
1 mutant strains binding to mouse ACE2, respectively, and found that three point mutations Q493R, Q498R and N501Y mediate the interaction of binding to mouse ACE2.
plays a key role in (Figure 2C-2D)
.

These data suggest that Omicron mutants may have the ability to spread in wild-type mice, and elucidated the relevant molecular mechanisms
.

Subsequently, the research team proposed that the Omicron mutant strain may be a potential circulation through which the new coronavirus evolves in mice and then infects humans, which has a certain guiding role in the prevention and control of the new crown epidemic
.

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