key: cord-0920417-x94pw7zi authors: Tian, Dandan; Sun, Yanhong; Xu, Huihong; Ye, Qing title: The emergence and epidemic characteristics of the highly mutated SARS‐CoV‐2 Omicron variant date: 2022-02-11 journal: J Med Virol DOI: 10.1002/jmv.27643 sha: d40559c17d2419b75475bba44f502fca70b4e1bb doc_id: 920417 cord_uid: x94pw7zi Recently, the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) Omicron variant (B.1.1.529) was first identified in Botswana in November 2021. It was first reported to the World Health Organization (WHO) on November 24. On November 26, 2021, according to the advice of scientists who are part of the WHO's Technical Advisory Group on SARS‐CoV‐2 Virus Evolution (TAG‐VE), the WHO defined the strain as a variant of concern (VOC) and named it Omicron. Compared to the other four VOCs (Alpha, Beta, Gamma, and Delta), the Omicron variant was the most highly mutated strain, with 50 mutations accumulated throughout the genome. The Omicron variant contains at least 32 mutations in the spike protein, which was twice as many as the Delta variant. Studies have shown that carrying many mutations can increase infectivity and immune escape of the Omicron variant compared with the early wild‐type strain and the other four VOCs. The Omicron variant is becoming the dominant strain in many countries worldwide and brings new challenges to preventing and controlling coronavirus disease 2019 (COVID‐19). The current review article aims to analyze and summarize information data about the biological characteristics of amino acid mutations, the epidemic characteristics, immune escape, and vaccine reactivity of the Omicron variant, hoping to provide a scientific reference for monitoring, prevention, and vaccine development strategies for the Omicron variant. B.1.1.529 was first detected in specimens collected on November 11, 2021 , in Botswana and on November 14, 2021, in South Africa. It was first reported to the WHO on November 24. On November 26, the WHO defined it as the fifth variant of concern (VOC) and named it Omicron. 15 The Omicron variant is the most mutated strain among many SARS-CoV-2 variants (including VOCs and VOIs) during the COVID-19 pandemic. The amino acid mutations of the Omicron variant are widely distributed on four structural proteins, including Spike (S), Envelope (E), Membrane (M), Nucleocapsid (N) proteins, and nonstructural proteins (NSPs) (NSP3, NSP4, NSP5, NSP6, NSP12, NSP1). 16 The SARS-CoV-2 spike protein consists of S1 and S2 subunits and furin protease cleavage sites. The S1 subunit consists of an N-terminal domain (NTD) and receptor-binding domain (RBD). The receptor-binding motif (RBM) directly contacts the receptor (angiotensin-converting enzyme-2, ACE2) on the surface of human cells, which mediates the invasion of the virus into cells and determines the transmissibility of the virus. 1, 7, 17 In addition, the spike protein is the dominant neutralization target of convalescent plasma, vaccines, and monoclonal antibodies (mAbs). 18, 19 Adaptive mutation of the SARS-CoV-2 genome can change the infectivity, immune evasion, and phenotypic characteristics of the virus. 13, 14, 20 The emergence of the Omicron variant has caused serious concern about the increased infectivity, immune escape ability, and reinfection risk. 21 Therefore, many countries have made travel restrictions to prevent the rapid spread of the Omicron variant. (T19I, L24S, ins25PPA, D142D, V213G, G339D, S371 L, S373P, S375F, T376A, D405N, R408S, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, N969K) (https:// www.nicd.ac.za/diseases-a-z-index/disease-index-covid-19/sars-cov -2-genomic-surveillance-update/). Compared to the Omicron (21K, BA.1), the Omicron (21 L, BA.2) spike protein lacks Δ69-70, which is associated with S gene target failure (SGTF) and is not detected by SGTF. The number of mutations of the Omicron variant spike protein is twice that of the Delta variant, which has spread in many countries worldwide. 14 Notably, approximately 15 of these mutations are located in RBD, a primary target of neutralizing antibodies (NAbs), 22 and are more common than other VOCs (Delta: L452R, T478K; Beta: K417N, E484K, N501Y; three Gama K417T, E484K, N501Y; Alpha: N501Y in RBD). [12] [13] [14] Omicron variant has critical mutations in the spike protein that were previously reported in other VOCs (Alpha, Beta, Gamma, and Delta) and VOIs (Kappa, Zeta, Lambda, and Mu), 23 higher than that of the early wild-type strain 8 and that Delta seems to be approximately 60% more transmissible than Alpha. 28 In addition, the Omicron variant carrying "Q498R-N501Y" double mutations may further improve the binding affinity of RBD to the hACE2 receptor. 29 It is worth noting that there are triple mutations "H655Y + N679K + P681H" near the furin cleavage site of the Omicron variant spike protein. Previous studies found that "H655Y + N679K + P681H" might accelerate S1/S2 cleavage through furin protease and enhance the fusion of the virus and host cell membrane, leading to enhanced replication ability and infectivity of the virus. 30, 31 Molecular evidence provides a good explanation for how mutations in the spike protein (such as K417N, N440K, G446S, S4777N, T478K, and N501Y) 32-35 cause a reduction in the neutralizing activity of mAbs, convalescent plasma, and serum-induced by vaccines. 36 Molecular dynamic simulations have pointed out that "K417N-E484K-N501Y" triple mutations induce spike protein conformational changes greater than those induced by N501Y or E484K alone. 36 Triple mutations allowed SARS-CoV-2 variants carrying "K417N-E484K-N501Y" mutations to more effectively escape neutralization activity, leading to the Beta variant that caused the second wave of outbreaks in South Africa to be more immune escape than other VOCs (Alpha, Gamma, and Delta). It is worth noting that the Omicron variant also has a similar triple mutation, "K417N + E484A + N501Y," which may produce immune escape. 37 In addition, a team of virologist Paul Bienias of Rockefeller University, New York, found that the pseudovirus carrying 20 mutations PMS20 (all reported mutations) was resistant to the neutralization of the convalescent plasma and serum-induced by mRNA vaccine. 38 Compared to the Delta variant, Omicron has received much attention for just 2 weeks after its appearance. An in silico analysis showed that the infectivity of Omicron might be more than 10-fold higher than that of the original virus and approximately twice as high as that of Delta. 38 According to reported data, researchers estimated that the Rt of Omicron is 1.4-to 3.1-fold higher than that of Delta. (https://www.ecdc.europa.eu/en/news-events/epidemiologicalupdate-omicron-variant-concern-voc-data-19-December-2021). SARS-CoV-2 not only invades the respiratory system but also causes other organ injuries in severe cases, such as kidney injury, 47 liver injury, 48 myocardial injury, 49 coagulation dysfunction, 50 and gastrointestinal symptoms. 51, 52 Compared with the early original strains, many clinical studies have suggested that Alpha, Beta, and Delta variants increase the risk of hospitalization, ICU admission, and death. 8, 9, 11, 12 Previously reported cases from South Africa 46 and 43 cases of Omicron in the United States 53,54 found that the symptoms of confirmed cases were asymptomatic or had mild symptoms, and no deaths were reported (among the 43 confirmed cases in the United States, symptoms were 89% cough, 65% fatigue, 59% stuffy or runny nose, 14% fever, 8% nausea, 4% diarrhea, and 3% loss of taste or smell). Subsequently, UKHSA announced that ten individuals infected with Omicron were hospitalized, and one died. 55 As of December 20, 2021, seven deaths in those infected with Omicron have been reported. However, the impact of Omicron on the rate of hospitalization and mortality needs more cases and longer observation times to be determined. The serum neutralization assay found that the escape was in- The data supporting this study's findings are available from the corresponding author upon reasonable request. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding A pneumonia outbreak associated with a new coronavirus of probable bat origin The pathogenesis and treatment of the 'Cytokine Storm' in COVID-19 Epidemiological analysis of COVID-19 and practical experience from China Assessment of global asymptomatic SARS-CoV-2 infection and management practices from China Epidemiology, genetic recombination, and pathogenesis of coronaviruses Emerging SARS-CoV-2 mutation hot spots include a novel RNA-dependent-RNA polymerase variant Early transmissibility assessment of the N501Y mutant strains of SARS-CoV-2 in the United Kingdom South Africa responds to new SARS-CoV-2 variant Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus SARS-CoV-2 variants of concern are emerging in India The global epidemic of SARS-CoV-2 variants and their mutational immune escape The global epidemic of the SARS-CoV-2 Delta variant, key spike mutations and immune escape SARS-CoV-2 variants, spike mutations and immune escape Classification of Omicron (B.1.1.529): SARS-CoV-2 variant of concern Probable transmission of SARS-CoV-2 Omicron variant in quarantine hotel SARS-CoV-2 effects on the renin-angiotensin-aldosterone system, therapeutic implications Structure of the SARS-CoV-2 spike receptorbinding domain bound to the ACE2 receptor SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor Evaluating the effects of SARS-CoV-2 spike mutation D614G on transmissibility and pathogenicity Detection of SARS-CoV-2 Omicron (B.1.1.529) variant has created panic among the people across the world: what should we do right now? A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2 University S coronavirus antiviral & resistance database Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding The basis of a more contagious 501Y.V1 variant of SARS-CoV-2 SARS-CoV-2 D614G variant exhibits efficient replication ex vivo and transmission in vivo Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role in the Alpha variant B.1.1.7. Cell Rep SARS-CoV-2 variant prediction and antiviral drug design are enabled by RBD in vitro evolution Delta coronavirus variant: scientists brace for impact Analysis of SARS-COV2 spike protein variants among Iraqi isolates Monitoring the SARS-CoV-2 pandemic: screening algorithm with single nucleotide polymorphism detection for the rapid identification of established and emerging variants Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies SARS-CoV-2 evolution during treatment of chronic infection mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants SARS-CoV-2 501Y.V2 variants lack higher infectivity but do have immune escape Analysis of SARS-CoV-2 variant mutations reveals neutralization escape mechanisms and the ability to use ACE2 receptors from additional species Signatures in SARS-CoV-2 spike protein conferring escape to neutralizing antibodies High genetic barrier to SARS-CoV-2 polyclonal neutralizing antibody escape B.1.1.529 escape the majority of SARS-CoV-2 neutralizing antibodies of diverse epitopes Evaluation on the use of Nanopore sequencing for direct characterization of coronaviruses from respiratory specimens, and a study on emerging missense mutations in partial RdRP gene of SARS-CoV-2 Genomic characterization of SARS-CoV-2 isolates from patients in Turkey reveals the presence of novel mutations in spike and nsp12 proteins Evolutionary analysis of SARS-CoV-2: how mutation of Non-Structural Protein 6 (NSP6) could affect viral autophagy Mutations in SARS-CoV-2 viral RNA identified in Eastern India: possible implications for the ongoing outbreak in India and impact on viral structure and host susceptibility New COVID-19 variant is a concern as cases show a sharp increase in Gauteng Covid-19: Omicron may be more transmissible than other variants and partly resistant to existing vaccines, scientists fear Covid-19: South Africa's surge in cases deepens alarm over Omicron variant Kidney involvement in COVID-19 and its treatments Hepatic complications of COVID-19 and its treatment Crosstalk between coronavirus disease 2019 and cardiovascular disease and its treatment Characteristics of coagulation alteration in patients with COVID-19 The mechanism and treatment of gastrointestinal symptoms in patients with COVID-19 Cellular immune response to COVID-19 and potential immune modulators 529)-technical-brief-and-priority-actions-for-member-states 54. Omicron variant: what you need to know COVID-19 variants identified in the UK. 2021 Increased risk of SARS-CoV-2 reinfection associated with emergence of the Omicron variant in South Africa. medRxiv Analysis of COVID-19 vaccines: types, thoughts, and application The variants of SARS-CoV-2 and the challenges of vaccines The global epidemic of SARS-CoV-2 variants and their mutational immune escape Omicron (B.1.1.529): infectivity, vaccine breakthrough, and antibody resistance Omicron variant (B.1.1.529) of SARS-CoV-2, a global urgent public health alert ARS-CoV-2 Omicron has extensive but incomplete escape of Pfizer BNT162b2 elicited neutralization and requires ACE2 for infection Pfizer and BioNTech provide update on Omicron variant The significant immune escape of pseudotyped SARS-CoV-2 variant Omicron Reduced neutralization of SARS-CoV-2 Omicron variant by vaccine sera and monoclonal antibodies Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift Effectiveness of COVID-19 vaccines against the Omicron (B.1.1.529) variant of concern Booster of mRNA-1273 strengthens SARS-CoV-2 Omicron neutralization. medRxiv Omicron variant showed lower neutralizing sensitivity than other SARS-CoV-2 variants to immune sera elicited by vaccines after boost The emergence and epidemic characteristics of the highly mutated SARS-CoV-2 Omicron variant