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The Omicron Variant of the Sars-Cov-2 Virus As the Dominant Agent of a New Risk of Disease amid the COVID-19 Pandemic

Over the two years that have passed since the WHO announced on March 11, 2020, a pandemic of the new coronavirus disease COVID-19, more than 460 million cases of the disease have been detected in the world, of which more than five million have been fatal. During the natural evolution of the COVID-19 pathogen, dominant variants emerge that account for most new infections. The WHO constantly monitors coronavirus mutations that potentially pose an epidemiological danger. Currently, the WHO divides modified variants of the SARS-CoV-2 virus into variants of concern (VOC) and variants of interest (VOI). The WHO-designated group of variants of concern includes potentially the most dangerous lines, which are characterized by a complex of new properties. This group also includes the Omicron variant, which has become the dominant agent of the new wave of the COVID-19 pandemic. The aim of this work is to analyze the characteristics of the SARS-CoV-2 Omicron strain, the dominant agent of the new wave of the COVID-19 pandemic. The proposed mechanism of origin of the Omicron variant, its geographical distribution, the features of the disease caused by it, and the distinguishing features from diseases caused by the Delta variant and the original Wuhan strain of the SARS-CoV-2 virus, mutations of the Omicron variant compared to the parent strain of the SARS-CoV-2 virus, the genetic variability of the Omicron variant, and the epidemiological characteristics of the disease it causes are considered. Particular attention is paid to evaluation of the preventive and therapeutic effectiveness of the existing medical means of protection against COVID-19 in relation to the Omicron strain.

A characteristic feature of the COVID-19 pandemic is the emergence of dominant variants during the natural evolution of the pathogen, which are asso-ciated with most of the new cases of infection. Currently, the WHO divides the modified variants of the SARS-CoV-2 virus into two groups: variants of concern, which includes the most epidemically dangerous variants and variants of interest, which includes potentially dangerous lines characterized by a complex of new properties.
The group of variants of concern until the end of November 2021 included the lines Alpha (first identified in the UK), Beta (first identified in South Africa), Gamma (first identified in Brazil), and Delta (first identified in India) of the SARS-CoV-2 virus. Of these #  lineages, only the Delta variant was the dominant variant of the SARS-CoV-2 virus worldwide. 1 On November 22, 2021, SARS-CoV-2 variant B.1.1.529 was detected for the first time in South Africa and Botswana based on samples collected on November 11-16 [1,2]. Subsequently, it was possible to establish the place and date of collection of the first sample, in which variant B.1.1.529 was identified: South Africa, November 8, 2021 [3,4]. Retrospective studies have shown that more than 70% of clinical samples collected in the Gauteng Province (South Africa) from November 14 to 23 contained variant B.1.1.529.
On , the WHO designated variant B.1.1.529 as "of concern" and named it Omicron. The reason for classifying variant B.1.1.529 as "of concern" was the unusually large number of mutations, including in the structural S protein, which is the main target for medical protective means (MPM) with a different mechanism of action. The possible consequences of mutations at that time (end of November 2021) were not yet determined [5,6]. According to the GISAID project, variant B.1.1.529 was assigned the identifier clade GR/484A [7], and the Nextstrain project was assigned the identifier clade 21K [8]. By early 2022, variant B.1.1.529 had already been identified in 135 countries [9,10]. The incidence reached a record level for the entire time of the COVID-19 pandemic, more than 15 million new cases of the disease were detected in the week from January 5 to 12. 2 The purpose of this work is to analyze the characteristics of the Omicron variant of the SARS-CoV-2 virus, the dominant agent of the fifth wave of the COVID-19 pandemic. The following will be considered: the proposed mechanism for the origin of the Omicron variant; its geographical distribution; features of the disease it causes and distinguishing features from diseases caused by the Delta variant and the original Wuhan strain of the SARS-CoV-2 virus; mutations of the Omicron variant compared to the parent strain of the SARS-CoV-2 virus; the genetic variability of the Omicron variant; and epidemiological characteristics of the disease caused by the Omicron variant. Particular attention is paid to evaluation of the preventive and therapeutic efficacy of the existing incinerators against COVID-19 in relation to the disease caused by the Omicron variant.
When considering the proposed mechanism for the origin of the Omicron variant, we will proceed from the principle of monophyleticity, according to which this variant arose at one time, in one place, from a well-defined predecessor, which was one of the earlier SARS-CoV-2 virus variants. Since by the estimated time of occurrence of the Omicron variant, the domi-1 SARS-CoV-2 Variant Classifications and Definitions. cdc.gov.
Centers for Disease Control and Prevention, June 18, 2021. 2 https://gogov.ru/covid-v-stats/world nant agent of the COVID-19 pandemic was the Delta variant everywhere, 3 most mutations in this strain (compared to the original Wuhan strain of the SARS-CoV-2 virus) were also preserved in the Omicron variant. It is the Delta variant that, with a high degree of probability, is the original parental strain for Omicron.
The question of the mechanism of origin of the Omicron variant should be considered in the context of the emergence of other strains of the SARS-CoV-2 virus classified by the WHO as "of concern." To explain the origin of the Omicron variant, four main hypotheses are currently being considered.
(1) The Omicron variant (like the Alpha variant) arose as a result of multiple passages of the COVID-19 pathogen in an immunocompromised host, such as an HIV-infected individual. 4 (2) Omicron is the product of a genetic interaction of the Delta variant with another causative agent of acute respiratory viral disease. This hypothesis relies on the fact that some fragments of the Omicron genetic sequence, not found in any of the earlier versions of the SARS-CoV-2 virus, have been identified in many other viruses that cause acute respiratory diseases. 1,5 (3) Omicron arose as a result of passage through an intermediate host, which could be rodents infected with a coronavirus infection from humans. The new variant, which subsequently infected people, is the result of adaptive mutations [11]. This assumption is substantiated by the fact that the N501Y mutation contained in the S protein of the Omicron variant causes an increased infectivity of the SARS-CoV-2 virus for mouse models [12].
(4) The Omicron variant could have arisen due to the mass treatment of COVID-19 patients with convalescent plasma in South Africa. Screening of spontaneously arisen antigenically modified variants of the SARS-CoV-2 virus, potentially capable of overcoming specific immunity, is quite likely. 6 From our point of view, the first of the hypotheses considered seems to be the most competent. The large number of mutations in the sequence of the Omicron variant is a consequence of numerous mutations in the body of an HIV-infected person receiving medical care sufficient for survival [13]. In this regard, the very place where the Omicron variant appeared, South Africa, where HIV-infected people make up more than 20% of the population, seems like no coincidence [14].
Let us draw parallels with the Alpha variant (B.1.1.7) of the SARS-CoV-2 virus, which allegedly arose as a result of passages in the body of a COVID-19 patient with an immunodeficiency state, in the treatment of which VNA-based drugs (virus-neutralizing antibodies) and chemotherapy drugs related to the class of abnormal nucleosides were used. This variant was also characterized by increased transmissibility (approximately 70%) compared to strains belonging to other clades of the COVID-19 pathogen. At the same time, the Alpha variant showed no increase in the severity of the disease compared to other strains identified by that time (November 2020) belonging to the D614G cluster [15,16]. Moreover, some mutations outside the S protein (for example, deletion of the Q27 stop in ORF 8) are associated with a milder course of the disease [17].
The initial parent strain for the Omicron variant is the Delta variant (the most virulent SARS-CoV-2 virus line for humans), the appearance of which can presumably be associated with spontaneous mutations of the SARS-CoV-2 virus during transmission among homeless people in India (in the absence of treatment or preventive and planned medical care). The emerging mutant of the virus was characterized by increased infectivity, changes in the symptoms of the disease, and an increase in its lethality (compared to the prototype Wuhan strain) [18]. Among the known variants of the SARS-CoV-2 virus, the Omicron has no equal in terms of its range expansion rate.
The first site of detection of the Omicron variant outside the original epidemic focus was Hong Kong (November 24, 2021). On November 25, a confirmed case of the disease caused by the Omicron variant was identified in Israel. The patient was a traveler returning from Malawi [19]. On November 26, the first case of the disease caused by the Omicron variant was detected in Belgium [20], and on November 27, in the UK, Germany, and Italy [21]. On November 28, 13 cases were confirmed in the Netherlands at once among air passengers who arrived from South Africa on November 26 7 [22], and later five more cases were found among this group of passengers [23].
The number of confirmed cases of COVID-19 caused by Omicron reflects both the actual incidence rate and the intensity of using not only molecular biological (various PCR variants) but also molecular genetic (genome sequencing) methods in diagnostics [24]. Most of the test systems used to diagnose COVID-19 allow identification of the pathogen not at the strain level but at the species level. Therefore, for example, data for the United States, where only 95217 cases of the disease caused by the Omicron variant were officially confirmed (against the incidence rate measured in hundreds of thousands of new cases per day), appear clearly underestimated. 7 Actuele informatie over COVID-19/RIVM. Symptoms of COVID-19 caused by Omicron, as well as those caused by other variants of the SARS-CoV-2 virus, vary from mild symptoms to severe disease [25,26]. The most common symptoms are headache, loss of smell (anosmia) and taste (ageusia), nasal congestion, runny nose, cough, muscle pain, sore throat, fever, diarrhea, and labored breathing [26]. These symptoms are divided into three general clusters: the cluster of respiratory symptoms, the cluster of myalgia and arthralgia, and the cluster of symptoms of the digestive system [27][28][29]. In general, it can be stated that the symptoms of the disease caused by Omicron do not differ significantly from those for other variants of the SARS-CoV-2 virus [30]. Studies conducted at the US Centers for Disease Control and Prevention (CDC) for the period from December 1 to 7, 2021 [31], and later in England (December 25, 2021) [32] showed that the most frequently reported symptoms were cough, fatigue, and nasal congestion or runny nose, sneezing, and sore throat. These symptoms do not allow differentiation from any of the other variants of the COVID-19 pathogen or other pathogens of respiratory viral diseases. The only possible distinguishing feature of the disease caused by the Omicron variant is increased night sweating, although it is possible that this symptom is associated with the use of antipyretics [33].
The average duration of the incubation period for COVID-19 is from four to five days, varying from two to seven days [34]. The disease caused by Omicron is characterized by a shorter incubation period (2-5 days) [35]; moreover, it has been established that a person who has contact with an Omicron-infected person is capable of transmitting the virus within a day. The reason for this is the significantly higher rate of reproduction on the mucous membranes of the upper respiratory tract than other variants of the COVID-19 pathogen. 8 Let us consider the mutations of the Omicron variant in comparison with the original Wuhan variant of the SARS-CoV-2 virus, for which it is customary to indicate differences that arose in the course of genetic evolution (Table 1). Of particular importance are mutations in the structural S protein, which change its antigenic structure and affinity for the ACE2 receptor [38].
Phylogenetic studies make it possible to establish the recent origin of the Omicron variant. Using the molecular clock method, it was established that the divergence of the Delta and Omicron variants occurred in late September-early October 2021 [39].    [42].
One of the leaders in the number of confirmed cases of the disease caused by Omicron is Denmark. The likely reason for this is the use in this country of quantitative PCR diagnostics, designed to detect changes in the S-protein gene of the SARS-CoV-2 virus, leading to mutations del 69-70, E484K, L452R, and N501Y [43]. Using this test system, it is possible to determine the Delta variant containing the L452R mutation but not the N501Y mutation [44,45] The data currently available show that the infectivity of the Omicron is significantly higher than that of other variants of the SARS-CoV-2 virus. The appearance of Omicron in any region is accompanied by a sharp surge in incidence. As an example, consider the data on COVID-19 incidence in the United States and the UK for the period from November 1, 2021, to January 15, 2022 (including the likely dates of the appearance and start of the spread of Omicron), taken with a 15-day interval ( Table 2). As follows from the data presented, in the United States and Great Britain, countries where most of the population was vaccinated, a sharp surge in COVID-19 incidence was observed during the specified period, the most likely cause of which was the spread of the Omicron variant. In some regions of the UK, the incidence doubling time was less than two days [46].
In Russia, where Omicron has become the leading agent of the fifth wave of the COVID-19 epidemic, with a declared herd immunity rate exceeding 60%, 9 9 https://стопкоронавирус.рф/information the number of confirmed cases doubled in a week (January 9 to 16, 2022). According to data currently available, the Omicron variant is inferior to the Delta variant in terms of the severity of the disease caused (the risk of hospitalization is reduced by about 41%) [47]. However, the significantly higher infectivity of Omicron is likely to prevent a reduction in the burden on the health care system due to the sharp increase in the number of cases. The main burden on the healthcare system in the event of an outbreak of a dangerous infectious disease is associated with the hospitalization of patients who need it. When used to calculate the necessary amount of hospitalizations per day, use the following formula: (1) where N hosp is the necessary amount of hospitalizations per day, N i is the total cases of the disease per day, and d hosp is the share of disease cases that require hospitalization.
It follows that with a 40% reduction in the risk of hospitalization for Omicron infection (compared to the Delta variant), the maximum increase in the number of new cases that do not yet require an increase in hospitalization should not exceed 67%. This calculation indirectly confirms the assessment of the European Center for Disease Prevention and Control of December 15, 2021, according to which the spread of the Omicron variant is likely to lead to an increase in the number of hospitalizations and deaths due to the exponential increase in cases caused by increased transmissibility [48].
It should be expected that the consequences of the spread of the Omicron variant in a particular region will depend on a number of factors, the main ones of which should be considered the actual level of herd immunity and the average age of the population. Since the start of the Omicron outbreak in South Africa, it has been speculated that this variant is a naturally = hosp hosp , i N Nd occurring attenuated variant of the SARS-CoV-2 virus, the further spread of which will end the COVID-19 pandemic. Indeed, for the same region, the epidemiological indicators of the next wave of the pandemic depended on the dominant strain, which illustrates the comparison of the mortality rate for the first-to-fourth waves of the COVID-19 epidemic in Russia (Table 3). The information currently available suggests that, with a sharp increase in the incidence rate, the mortality rate during the fifth wave of the COVID-19 epidemic in Russia will be lower than during the third and fourth waves. The development in a number of countries, against the background of already carried out mass vaccination, of outbreaks, the dominant agent of which is Omicron, raises the question of the effectiveness of existing vaccines in relation to this variant [49]. For the most widely used vaccines in the world for immunization (BNT162b2 Pfizer/BioNTech, mRNA1273 Moderna, Johnson&Johnson, Gam-COVID-Vac (Sputnik V), AZD1222 AstraZeneca, Sinopharm, CoronaVac Sinovac, and Novavax), their protective efficacy in phase 3 of clinical trials was determined under conditions where the dominant agent was the original strain of the SARS-CoV-2 virus. Even when the Delta variant appeared, it was noted that the effectiveness of the BNT162b2, mRNA1273, and AZD1222 vaccines was somewhat lower in relation to this variant compared to the Alpha variant [50,51].
The pharmaceutical companies AstraZeneca, BioNTech, Moderna, and Johnson&Johnson conducted a study of the effectiveness of their vaccines in relation to the Omicron variant in experiments in vitro and in vivo. According to vaccine developers, the period of their modernization to increase their effectiveness against the Omicron strain after testing will take approximately 100 days [52]. The pharmaceutical company Novavax, which developed a subunit protein vaccine, announced the development of an upgraded version of the Omicron vaccine. The planned completion time for studies is 5-6 weeks [53,54]. The developer of the Gam-COVID-Vac vaccine (Sputnik V), the Gamaleya National Center for Epidemiology and Microbiology of the Ministry of Health of the Russian Federation, said that a modified version of the vaccine would be ready for mass production by mid-January 2022 [55]. The pharmaceutical company Sinovac, which produces the inactivated vaccine, said it would upgrade its product to the Omicron variant and make it available in three months [56].
The reduced effectiveness of existing vaccines in relation to the Omicron variant and the need for their modernization are evidenced by the data presented in Table 4.
Based on the data presented, it can be concluded that for both the BNT162b2 Pfizer/BioNTech vaccine and the mRNA1273 Moderna vaccine, there was a significant decrease in both the protective efficacy and the duration of vaccination in relation to the Omicron variant compared to the Delta variant. Three to five months after immunization, the vaccinated showed an increased susceptibility to infection. This largely explains the fact that, in the United States in late 2021-early 2022, an average of more than 650000 new cases of the disease were registered daily, despite the fact that the proportion of those vaccinated by that time had already exceeded 74%. 10 The predictive performance of some other MPM classes in relation to the disease caused by the Omicron variant of the SARS-CoV-2 virus is presented in Table 5.
As follows from the data presented, the protective efficacy of various types of medical protective means primarily determines the structural region of the virion that is the target for these agents. An example is 10 https://gogov.ru/covid-19/world the decrease in virus-neutralizing activity for monoclonal antibodies the targets of which are epitopes located on the S protein (the most altered region of the Omicron variant compared to the original strain of the SARS-CoV-2 virus).

* * *
The Omicron variant (B.1.617), which appeared during the natural evolution of the SARS-CoV-2 virus, has become the leading agent of a new wave of the COVID-19 pandemic. This strain has been classified by the WHO as a variant of concern. The reason for this decision was the unusually large number of mutations, including in the structural S protein.
It is most likely that Omicron arose as a result of multiple passages of the COVID-19 pathogen in an immunocompromised host, such as an HIV-infected host. The reason for its appearance could be the massive use  1.529). Differentiation of these sublines can be done by sequencing the S-protein gene. The infectivity of the Omicron strain is significantly higher than that of other variants of the SARS-CoV-2 virus. In terms of the severity of the disease caused, this variant is inferior to the Delta variant: the risk of hospitalization is reduced by about 41%.
The existing vaccines against COVID-19 show reduced efficacy against the Omicron strain. However, the immune response induced by them protects, if not from infection, then from the development of a severe form of the disease requiring hospitalization. The most effective means of combating the spread of Omicron is the fastest modification of the existing vaccines and the implementation of mass immunization in a short time, including previously vaccinated and recovered patients. Table 5. Predictive efficacy of specific and nonspecific MPM of various classes in relation to the disease caused by the Omicron variant of the SARS-CoV-2 virus *Source: https://www.who.int/news/item/07-12-2021-who-recommends-against-the-use-of-convalescent-plasma-to-treat-covid-19.

MPM class
Drugs for which the preventive and therapeutic efficacy against COVID-19 caused by the original version of the SARS-CoV-2 virus has been established Preventive and protective efficacy against disease caused by the Omicron variant VNA-based drugs Convalescent plasma [58] Since convalescent plasma has not been found to improve survival or reduce the need for mechanical ventilation, WHO does not recommend its use* Monoclonal antibodies (McAb) VIR-7831 (sotrovimab) and VIR-7832 [59] McAb VIR-7831 and McAb VIR-7832 neutralized the Omicron variant with a 2-to 3-fold decrease in efficacy [60]. For many other McAbs and their mixtures, a decrease in specific activity by 1-2 orders of magnitude or more was found in relation to the Omicron variant compared to the prototype strain of the SARS-CoV-2 virus [61] Small