The SARS-CoV-2 Omicron variant (B.1.1.529) has been the most recent variant of concern (VOC) established by the World Health Organization (WHO). Because of its greater infectivity and immune evasion, this variant quickly became the dominant type of circulating SARS-CoV-2 worldwide. Our literature review thoroughly explains the current state of Omicron emergence, particularly by comparing different omicron subvariants, including BA.2, BA.1, and BA.3. Such elaboration would be based on structural variations, mutations, clinical manifestation, transmissibility, pathogenicity, and vaccination effectiveness. The most notable difference between the three subvariants is the insufficiency of deletion (Δ69-70) in the spike protein, which results in a lower detection rate of the spike (S) gene target known as (S) gene target failure (SGTF). Furthermore, BA.2 had a stronger affinity to the human Angiotensin-converting Enzyme (hACE2) receptor than other Omicron sub-lineages. Regarding the number of mutations, BA.1.1 has the most (40), followed by BA.1, BA.3, and BA.3 with 39, 34, and 31 mutations, respectively. In addition, BA.2 and BA.3 have greater transmissibility than other sub-lineages (BA.1 and BA.1.1). These characteristics are primarily responsible for Omicron's vast geographical spread and high contagiousness rates, particularly BA.2 sub-lineages. In addition, BA.2 and BA.3 have greater transmissibility than other sub-lineages (BA.1 and BA.1.1). These char- acteristics are primarily responsible for Omicron’s vast geographical spread and high contagiousness rates, particularly BA.2 sub-lineages. Keywords: SARS-CoV-2, COVID-19, BA.2 sub-lineages, immune evasion, Omicron variant, spike protein, transmissibility. SUMMARY 481 The emergence of SARS-CoV-2 Omicron subvariants n INTRODUCTION C oronavirus disease (COVID-19) has become a worldwide pandemic since it was declared by the World Health Organization (WHO) on March, 2020. of America (USA) and the United Kingdom (UK) are the most affected countries, with 1,827,027 and 1,316,923 cases, respectively, followed by Germa- ny (446,143), Denmark (304,947), France (283,549), Japan (251,145), and Canada (189,819) [8]. As of October 19, 2022, the number of recent omicron variant cases globally is shown in Figure 1. The evolution over time indicates that Omicron be- came the predominant and exclusive VOC circu- lating globally during 2022 (Figure 2). BA.2, another omicron sub-variant, has been the most recent and common variant of SARS-CoV-2 globally [9]. BA.2 counted around 86% of all ana- lyzed sequences globally and more than 50% of new cases in the USA in March 2022. Further, it has appeared in China, the UK, and Germany [9, 11]. Finally, BA.3, a subvariant containing 1276 amino acids, was detected in Gauteng Province, South Africa. It was found that BA.3 has 34 mu- tations, including R216, which is a unique muta- tion. Further, compared to BA.1, BA.3 showed a higher capability to transmit among people [12]. There have been numerous mu- tations described for these variants, including (1) alpha (spike mutations: Δ69-70, Δ144, N501Y, A570D, D614G, P681H, T716I, S928A, D1118H), (2) beta (L18F, D80A, D215G, Δ242–244, K417N, E484K, N501Y, D614G, A701V), (3) gamma (L18F, T20N, P26S, D138Y, R190S, K417T, E484K, N501Y, D614G, H655Y, T1027I, V1176F), and (4) delta (T19R, G142D, Δ156–157, R158G, L452R, T478K, D614G, P681R, D950N) [18, 19]. Nowadays, the Omicron variant is the only VOC classified by the WHO. Four commonly identified sub-lineages of Omicron are the most common type globally, including 486 R.A. Farahat, A. Abdelaal, T.P . Umar, et al. higher transmissibility. This great affinity may be due to many mutations, including Q493R, S371L, S375F, Q498R, T478K, Asn501Tyr, K417, D614G, L452R, and N501Y [48, 49]. Compared to the SARS-CoV-2 Delta variant, Omi- cron leads to fewer severe clinical outcomes [50- 53]. Omicron replication occurs in the upper res- piratory airway leading to little lung harm with a mild form of the disease [54]. Clinical manifesta- tions induced by Omicron include flu symptoms such as fever, fatigue, headache, throat pain, and sore throat with no loss of taste. They also showed that, among patients having Omicron infection, the rate of vaccinated patients was lower than in the Delta cohort, with proportions of 2.3% and 4.4% for both lineages, respectively. In total, the hospitalization rate among patients infected with Delta was threefold higher than that of the Omicron group [72]. Co-Infection and Recombination of Omicron and Delta Co-infections with different variants enhance the risk of viral recombination and the production of new variants that could potentially be VOC. On the same wavelength created a bow- wave of distress and apprehension among gen- eral masses. It is considered the brutal pandemic and human tragedy that swept across the borders. The virus causing COVID-19 has the potential to change consistently. Since the beginning of the outbreak, several notable variants have been seen. Co-infection associated with various SARS-CoV-2 variants, especially Omicron subvariants, be- comes conceivable when numerous variants cir - culate in the same region simultaneously, which could open the way for new variants to emerge by viral homologous recombination [93]. Unfortu- nately, it seems that nations unable to contain the spillover of COVID-19 and new contagious vari- ants, including Omicron, continue to emerge [94]. Therefore, we need a global public health system to attack spillover from wild animals, and WHO should consider the concept of OneHealth more than ever. Policy and decision-makers should have learned the lesson, and now, they should recognize the cost of not preventing diseases. Passive and active surveillance of diseases is of paramount impor - tance, especially for newly emerging infectious diseases. Campaigns and awareness are crucial for healthcare workers and populations at the individual level.

Recent threat of multiple highly infectious Omicron subvariants globally has posed enormous healthcare challenge and has infused a state of fright among the general public. Among them, the most recent one XBB 1.16 subvariant is viewed as a more potential danger due to its high contagiousness and rapid spread. This hybrid lineage is highly transmissible with high infectivity. However, its dominance in coming days is uncertain. Its rapid spread does not necessarily mean that it may dominate. It is known that Omicron variant has high transmission rate and the subvariants are capable of overcoming immunity from prior infections and vaccinations. Mutations are the means of evading immunity. Both XBB 1.15 and XBB 1.16 have descended from the recombinant ancestor XBB variant. That XBB.1.6 is more deadly than its other Omicron counterparts is too early to deduce. XBB.1.5 has a rare mutation F486P located in its RBD that capacitates the virus to attach to cells giving an edge over other previous strains. XBB.1.5 is a XBB sublineage with additional mutated S486P spike at RBD that might boost the ability of a subvariant to evade body immunity (https://www.ecdc.europa.eu/en/news-events /update-sars-cov-2-variants-ecdc-assessment-xbb15-sub-lineage). As two nucleotides substitution in the same codon to alter phenylalanine to proline was required, the mutation possibly was rarely encountered during the COVID-19 pandemic as it peaked. Possibly due to its growth advantage and immune escape traits, the WHO has announced XBB.1.16 as a variant of interest (VOI) [1]. As per initial reports, XBB.1.16 has greater effective reproductive number as compared to XBB.1 and XBB.1.5 that leads to quicker transmission. XBB.1.16 has two S substitutions, E180V (NTD) and T478R (RBD). Both mutations contribute significantly towards its infectivity [2]. Many Indian provinces are experiencing a rise in COVID-19 cases, possibly be due to the new variant XBB.1.16 (nicknamed as Arcturus) which replaces the status released display-pdf yes is-olf no is-manuscript no is-preprint no is-journal-matter no is-scanned no is-retracted no Received 2023 Apr 21; Revised 2023 May 6; Accepted 2023 May 9; Collection date 2023 Jun. Dear Editor Recent threat of multiple highly infectious Omicron subvariants globally has posed enormous healthcare challenge and has infused a state of fright among the general public. Among them, the most recent one XBB 1.16 subvariant is viewed as a more potential danger due to its high contagiousness and rapid spread. This hybrid lineage is highly transmissible with high infectivity. However, its dominance in coming days is uncertain. Its rapid spread does not necessarily mean that it may dominate. It is known that Omicron variant has high transmission rate and the subvariants are capable of overcoming immunity from prior infections and vaccinations. Mutations are the means of evading immunity. Both XBB 1.15 and XBB 1.16 have descended from the recombinant ancestor XBB variant. That XBB.1.6 is more deadly than its other Omicron counterparts is too early to deduce. XBB.1.5 has a rare mutation F486P located in its RBD that capacitates the virus to attach to cells giving an edge over other previous strains. XBB.1.5 is a XBB sublineage with additional mutated S486P spike at RBD that might boost the ability of a subvariant to evade body immunity ( https://www.ecdc.europa.eu/en/news-events/update-sars-cov-2-variants-ecdc-assessment-xbb15-sub-lineage ). As two nucleotides substitution in the same codon to alter phenylalanine to proline was required, the mutation possibly was rarely encountered during the COVID-19 pandemic as it peaked. Possibly due to its growth advantage and immune escape traits, the WHO has announced XBB.1.16 as a variant of interest (VOI) [ 1 ]. As per initial reports, XBB.1.16 has greater effective reproductive number as compared to XBB.1 and XBB.1.5 that leads to quicker transmission. XBB.1.16 has two S substitutions, E180V (NTD) and T478R (RBD). Both mutations contribute significantly towards its infectivity [ 2 ]. Many Indian provinces are experiencing a rise in COVID-19 cases, possibly be due to the new variant XBB.1.16 (nicknamed as Arcturus) which replaces the earlier dominant variants fast. As per GISAID (Global Initiative on Sharing All Influenza Data), the INSACOG (Indian SARS-CoV-2 Genomics Consortium) discovered at least 344 sequences in Indian XBB.1.16 strain and has submitted 49% of the total XBB.1.16 submitted sequences. XBB.1.16 exhibits mutations in the non-spike region (ORF9b mutations) that possibly facilitates its efficient immunity evasion. This sub-variant has been detected in many countries including the US, Australia and the UK. Huge surge of cases are observed particularly in the South-East and Eastern Mediterranean regions. Almost similar to the Omicron variant, the usual symptoms that this novel subvariant exhibits are high fever, severe headache, sore throat, cough, body pain, cold and abdominal discomfiture with no loss of smell or taste. However, it may cause itchy conjunctivitis. Most reported cases had mild to moderate symptoms, and home isolation and treatment were enough for disease management. A sharp rise in COVID-19 cases among the children below the age of 12 years has been noticed. Although it is too early to deduce conclusion on this, there is a need to be vigilant. The ‘new normal’ scenario in the ongoing highly-transmissible pandemic despises that mass gatherings could potentially pose serious health issues facilitating disease transmission and spread. The risks of winter flu, hepatitis A and B, diarrhoea and measles as transmissible diseases, as also multidrug resistant (MDR) bacteria, are high in dense floating population [ 4 ], especially amid the rising cases of XBB.1.6 in India after BF.7 and XBB.1.5. Thus, the 2023 Indian Premier League (IPL) could become a possible superspreader through the fans, spectators and sports enthusiasts.