The latest research progress of the Corona Virus Disease 2019 mutant strain "Omicron"

Chun Gao, Fu-Juan Feng, Jing-Jing Jiang, Xiao-Wen Yao, Xiao-Hui Yu, Jiu-Cong Zhang

1. School of Clinical Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, China

2. Department of Gastroenterology, The 940 Hospital of Joint Logistic Support Force of PLA, Lanzhou 730050, China

ABSTRACT Coronavirus disease 2019 (COVID-19) that broke out at the end of December 2019 has been raging for 3 years, bringing unpredictable harm to the physical and mental health of all mankind and global economic development. The new type of coronavirus pneumonia is a new type of respiratory infectious disease with a high incidence and fatality rate caused by SARSCoV-2. Up to now, hundreds of millions of people have been infected with new coronary pneumonia worldwide, and millions of people have died. Due to the specificity of the new coronavirus itself and its high mutation rate, a series of different new coronavirus variants have appeared, which has caused the new crown pneumonia epidemic to repeat. Recently, the World Health Organization (WHO) announced a new variant "omicron" (omicron, B.1.1.529), and declared that the mutant strain may be highly infectious, antibody tolerant and highly resistant to vaccines. This article briefly reviews the latest research progress of the "omicron" variants.

Keywords:Corona Virus Disease 2019 SARS-CoV-2 Variants Omicron Progress?Corresponding author: ZHANG Jiu-cong, M.D., Postdoctoral Fellow, Associate Chief Physician, Associate Professor, Postgraduate Tutor.E-mail: zhangjiucong@163.com.

Corona Virus Disease 2019 (COVID-19) is an emerging infectious disease of the respiratory system caused by SARS-CoV-2. Its main clinical manifestations are fever and cough, as well as some less typical extrapulmonary manifestations [1-2]. The global outbreak of COVID-19 that began in late 2019 poses a great threat to public health. With the emergence of vaccines against the new coronavirus pneumonia and the active and effective preventive measures of human beings, the immune barrier of human beings has been widely formed, so that the new coronavirus pneumonia has been effectively controlled in different countries and regions. However, with the pandemic of the new coronary pneumonia, the virus continues to evolve and mutate while it continues to spread, forming multiple mutant strains, which makes SARS-CoV-2 appear repeatedly and has a trend of continuous evolution and development. Despite extensive research efforts on mutants, how, when and where new mutants emerge remains a rather uncertain question. The omicron variant (B.1.1529) was first discovered in South Africa in November 2021. According to the World Health Organization's weekly epidemiological update, the omicron variant (B.1.1.529) has spread to 57 countries and regions around the world. As of January 23,2022, the number of confirmed cases of new coronary pneumonia in the world has exceeded 350 million, and the cumulative death toll has reached 5.59 million. In addition to millions of deaths from COVID-19, the COVID-19 pandemic has had a huge impact on human physical and mental health. Therefore, studying the omicron variant responsible for the surge in COVID-19 cases in South Africa and other parts of the world is critical to public health and the prevention and control of the outbreak.

1. Novel coronavirus etiology and pathogenic mechanism

Coronaviruses (CoVs) belong to the family Coronaviridae and are enveloped viruses with a single-stranded positive-stranded RNA genome about 26-32 bases in size. This is the largest genome among the known RNA viruses. There are protrusions on the membrane that protrude around, like a corolla and named [3]. According to phylogeny, coronaviruses can be subdivided into four genera, α,β, γ, and δ. SARS-CoV-2, which caused the new coronary pneumonia pandemic, is a new member of β-CoV [4], and the other two types are It is SARS-CoV, MERS-CoV, they are highly similar,especially SARS-CoV [5]. COVID-19, caused by the coronavirus, is a zoonotic disease. Studies have found that in addition to humans,mammals such as birds and chickens, dogs, and mice can also be affected [6].

All coronaviruses share similar organization and expression genes.One end of the encoded open reading frame is 16 non-structural proteins, followed by spike surface protein (S protein), nucleocapsid protein (N protein), There are four important structural proteins such as matrix protein (M protein) and small envelope protein (E protein). The type and virulence of coronaviruses and the ability to infect across hosts mainly depend on the S protein [7-8]. The S protein consists of two subunits, S1 and S2. The S1 subunit binds to cell surface receptors, and the S2 subunit mediates membrane fusion and helps the virus enter the cell [9]. The N protein accompanies and protects the viral RNA genome, and a spike composed of three S glycoproteins promotes receptor binding and membrane fusion[10], thereby participating in viral replication. M proteins play a central role in viral assembly, interacting with transmembrane and endodomains [11], and interacting with RNAs that carry genome packaging signals [12], thereby turning cell membranes into viral and host factor aggregation Together, they form workshops that make new virus particles. The above studies have confirmed that the M protein is closely related to the virus replication process. During virus infection, a large amount of E protein is accumulated in cells[13], and Ortego [14] et al found that deletion of E protein in different coronaviruses may lead to a decrease in virus maturation and release,indicating that this protein is involved in the viral cycle It played an important role.

2. The reason for the mutation of the new coronavirus

Due to the particularity of RNA structure, susceptibility to mutation is an inherent property of most RNA viruses, and SARS-CoV-2 is no exception. Coronavirus is the largest RNA virus. Compared with the double-stranded structure of DNA, the single-stranded structure of RNA is more unstable and therefore more prone to mutation [15]. [16]found that the average replacement rate of SARS-CoV-2 was about 0-1 × 10-4 per locus per year. Based on analysis of sequencing data archived in public repositories, the SARS-CoV-2 genome mutation rate was found to be estimated at 0.8 × 10-3 to 2.38 ×10-3 nucleotide substitutions per locus per year, non-synonymous and The synonymous substitution rate was estimated to be 1.16×10-3～3.30×10-3 and 1.67×10-3～4.67×10-3 nucleotide substitutions per locus per year, respectively, which is similar to other RNA viruses[17] -18]. The larger RNA genome in SARS-CoV-2 allows for additional modification of the genome through mutation, increasing the likelihood of intraspecific variation, interspecific "host jumping"and the emergence of SARS-CoV-2 under appropriate conditions[19-20] . Studies have found that when the receptor-binding domain(RBD) is involved, RBD mediates virus entry into host cells and is an important target for vaccine serum monoclonal antibodies. All four reported mutations in alpha (B.1.1.7), beta (B.1.351), gamma(P.1) and delta (B.1.617.2) in the RBD, with the N501Y mutation located on the RBD is common to all variants except the delta variant, which results in an increased affinity of the S protein for the ACE2 receptor, thereby enhancing viral attachment and subsequent entry into host cells.

3. Omicron variant

3.1 "Variation of Concern" (VOC)

The World Health Organization has been monitoring and evaluating variants of the new coronavirus globally since January 2020, and has classified them as variants of concern (VOC), variants of concern(VOI), and variants requiring further monitoring strains. Higher levels of VOCs than VOIs, VOCs have been shown to be associated with increased transmissibility, increased virulence, or altered clinical disease manifestations, public health and social measures,or decreased effectiveness of existing diagnostics, vaccines, and treatments [21-22]. The CDC is currently monitoring four variants.The first is called the alpha (B.1.1.7) variant, which was originally discovered in the UK [23]. The second is a beta (B.1.351) variant first discovered in South Africa. The third is the gamma (P.1) variant found in Brazilian tourists. The delta variant was first identified in India in December 2020 [24]. The well-known delta variant is a VOC.Recently, the WHO has also listed omicron as a "variant of concern"(VOC). This variant carries a very high number of mutations in the S protein, about 32, compared with only five S protein mutations in the highly damaging delta variant, which constitutes a very high potential global risk. The classification of new coronavirus variants is constantly updated, which makes its control more challenging.

3.2 Discovery and epidemiology of Omicron variants

A new variant strain B.1.1.529 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was found in Botswana and South Africa in early November 2021, and in a quarantined hotel in Hong Kong, my country on November 26, 2021 Two cases of infected patients who had no contact with each other were found in this study, and were named the omicron variant by the World Health Organization, which was listed as a "required concern" (VOC)variant [25-26]. Haogao et al. [27] sequenced the complete SARSCoV-2 genomes of two patients from Hong Kong, China and found that the genomes of the two cases were not very different, and found that the virus sequence from one of the patients was similar to that in South Africa and Botswana. Several initially reported cases of omicron were highly similar in viral sequence, which established the presence of the omicron variant.

Since the discovery of the mutant strain, the epidemic has recurred in many countries. As of December 8, 2021, 57 countries have reported confirmed cases of the omicron mutant strain [28], and some experts said that the omicron mutant strain Actual spread may extend beyond areas where cases have been reported. The variant strain not only appeared in South Africa, but also spread to varying degrees in some countries in Asia, Europe, South America and Oceania [29].As of December 8, 2021, South Korea has reported 12 new cases of infection with the omicron variant of the new coronavirus, with a total of 24 confirmed cases[30], and Japan has added 60 cases,and announced the suspension of the entry of foreigners from all countries and regions. Many European countries such as Britain,France, Germany, and the Netherlands have found “traces” of omicron variants [31]. As of the morning of December 4, local time,16 states in the United States have reported at least 35 confirmed cases of omicron. Most of the cases have a history of living in South Africa, and some cases have been vaccinated before [32]. The Dutch government stated on November 28, 2021 that the 13 confirmed cases of omicron infection in the country were all from two flights arriving in the Netherlands from South Africa on the 26th [33].Among the confirmed patients with omicron variant strains, there are not only unvaccinated patients, but also patients who have been vaccinated with two doses of vaccine. For example, the two patients diagnosed in Hong Kong, China, it can be found that the mutation of omicron variant strains may be greatly enhanced. The ability of this variant to evade current vaccines.

3.3 Infectivity of Omicron variant strains

The infectivity of SARS-CoV-2 mainly depends on the binding affinity of ACE2 and RBD complexes, and furin also plays a role as a unique protease cleavage site for SARS-CoV-2 [34]. omicron has 3 mutations at the furin protease cleavage site and 15 mutations at the RBD, indicating a marked change in its infectivity. Due to natural selection, the virus has increased BFE changes through mutation,thereby enhancing the binding affinity of the ACE2-RBD complex,or evaded antibody protection through mutation, enhancing its evolutionary advantage in RBD [35]. Since the virus has optimized its infectivity in human cells, one should not expect any single mutation to significantly increase viral infectivity. An efficient infection route is that the virus has multiple RBD mutations to accumulate and enhance its infectivity, which may be a related mechanism of omicron infectivity [36].

The N440K, T478K and N501Y mutations in the S protein of 2019-nCoV enhanced BFEs by 0.62, 1.00 and 0.55 kcal/mol, respectively.Of these, T478K is one of two RBD mutations in the delta variant,while the N501Y mutation is present in many popular variants,including alpha, beta, and gamma. All mutations, especially several mutations distant from the ACE2 and RBD binding sites, caused little or no changes in BFEs. Overall, the cumulative BFE change was 2.60 kcal/mol, indicating a 13-fold increase in viral infectivity[37]. In contrast, the omicron variant was far more contagious than the previously prevalent delta variant.

3.4 Vaccine tolerance of Omicron variants

Vaccination has proven to be the most effective means of preventing and controlling COVID-19. There are four types of vaccines we currently use, namely viral vaccines, viral vector vaccines, DNA/RNA vaccines and protein vaccines [38]. The currently used COVID-19 vaccines basically target the S protein [39]. Some experts believe that vaccination may lead to changes in the S protein, which may greatly enhance the ability of the mutant to evade current vaccines,but the existence of individual differences and different types of vaccines may lead to the occurrence of different immune responses in the same person, so it is very important to It is difficult to accurately characterize the full effect of the S protein mutation of the omicron variant on the vaccines currently in use. Jiahui et al. [40-41] found that RBD mutations in omicron variants can significantly alter the binding mode of known antibodies. Positive changes enhanced the binding between the antibody and the RBD complex,while negative changes weakened this binding, and the study further confirmed that negative BFE changes were more variable than positive BFE. This illustrates the potential impact of RBD mutations in omicron variants on vaccines.

It is not very easy to tell whether a mutation will disrupt an antibody and RBD complex, because the omicron variant involves multiple RBD mutations, which may produce multiple "escapes" for each antibody and RBD complex of different mutations. Jiahui et al. [37]found that the antibody destruction rate of the omicron variant was 0.58 and the Delta was 0.28 by comparing the delta variant with the omicron variant. It is because of the rapid spread of omicron variants that Pfizer CEO Albert Burra even mentioned that people may need a fourth dose of the vaccine earlier than expected [42]. At present, the number of infected cases of this variant is on the rise, but there are still few related reports. Therefore, it is impossible to systematically and effectively judge the actual breakthrough rate of the omicron variant-induced vaccine for the total population of the world. But we can foresee that mutated viruses may be more destructive to vaccines in the coming years due to increased vaccination rates, which puts higher demands on scientists to work on more powerful vaccines.

3.5 Antibody Tolerance of Omicron Variants

It is critical to assess whether mutations in omicron variants pose an irreversible threat to U.S. Food and Drug Administration (FDA)-approved monoclonal antibodies and several other monoclonal antibodies in clinical development. Jiahui et al. [41] predicted similar threats from other mutant strains through artificial intelligence,namely alpha, beta, gamma, delta mutant strains, and found that they were in good agreement with experimental data. The researchers analyzed and summarized a variety of monoclonal antibodies,namely Eli Lilly's monoclonal antibody (LY-CoV016) and Regeneron's (REGN10933, REGN10987 and REGN10933/10987)monoclonal antibodies, and tried to summarize the effect of omicron variants on monoclonal antibodies. Whether the antibody is tolerant or resistant.

3.5.1 Bamlanivimab and Etesevimab

Clinically, Bamlanivimab (LY-CoV555) is used in combination with Etesevimab (LY-CoV555). The study found that although these two mAbs were performed on the basis of the original S protein Optimized, but sensitive to mutations, K417N and N501Y may significantly impair this antibody-RBD complex and may also reduce the efficacy of banivirumab and atelvizumab. E484A induces a negative BFEs change of -2.79 kcal/mol in the banivirumab and RBD complex [37], since the mutation of most omicron variants enhances the binding of S protein and ACE2, we can assume that the change in BFEs May lead to a significant reduction in the efficacy of banivirumab, making it less competitive with ACE2. Although these two monoclonal antibodies may have a slight synergistic effect in clinical use, they are prone to fail to exert a good immune effect on the mutations brought by the omicron variant. If the omicron variant becomes the predominant variant in the world, banivirumab and atelsulimumab may not meet the needs of the market.

3.5.2 casirivimab and imdevimab

Regeneron's casirivimab (REGN10933) and imdevimab(REGN10987) monoclonal antibodies are the latest FDA-approved combination antibodies against COVID-19. Unlike Bamlanivimab and Etesevimab monoclonal antibodies, the company's two monoclonal antibodies do not overlap each other and bind noncompetitively to different parts of the RBD of the coronavirus S protein, preventing the virus from entering cells by blocking the binding interface between RBD and ACE2, And effectively avoid virus resistance caused by mutation [43]. Jiahui et al. [37] found that the magnitude of BEFs changes in the complexes induced by omicron mutation was significantly reduced. If the omicron variant continues to be less virulent in the future, it will have a very slight negative effect on casirivimab and imdevimab.

4. Summary and Outlook

The B.1.1.529 variant is fast becoming the main dangerous variant of the COVID-19 pandemic. In South Africa, the areas where omicron variant cases appear are all under-vaccinated people, but the number of infected people in various regions is still increasing. The proportion of the population in South Africa who have completed the whole process of vaccination is only 24%, and the natural infection rate is about 4.9%, which is not enough to construct vaccines and Immune barrier to natural infection. As more people become infected, more strains of the virus emerge from the omicron variant. Due to the severity of this new omicron variant,we should advocate that in populations with high rates of COVID-19 transmission, even individuals who have received two doses of the vaccine should actively receive booster shots, while wearing masks and maintaining a safe distance. Much is known about other variants of the SARS-CoV-2 virus, but little is known about the omicron variant of this virus. As the number of patients infected with the omicron variant increases, we will learn more about this variant,and it is hoped that the newly discovered knowledge will help guide treatment and prevention through vaccination strategies and other public policies. But one of the ways to continue to fight the virus is to continue to practice social distancing, wear masks, practice proper hygiene, and be adequately vaccinated. At present, research on the mutation mechanism of the omicron variant of the new coronavirus and effective antiviral treatment measures are being carried out in an orderly manner. Even if the new coronavirus evolves to make our vaccines ineffective, we still firmly believe that scientists from various countries can Vaccines are adjusted to have anti-virus capabilities; we also believe that with the help of people from all over the world, mankind will eventually defeat the new crown virus.Conflict of Interest Statement

All authors declare no conflict of interest.

Author Contribution

Gao Chun: writing and revising the paper; Yu Xiaohui and Jiang Jingjing: responsible for reviewing and revising the paper; Feng Fujuan and Yao Xiaowen: responsible for data sorting; Zhang Jiucong: responsible for thesis design and topic selection, and data sorting and analysis.