Omicron
The SARS-CoV-2 virus contains the S protein, which comprises the S1 subunit, the S2 subunit, and a cleavage site known as Furin protease. The S1 subunit includes the RBD and the N-terminal domain. The angiotensin-converting enzyme II (ACE2) receptor interacts with the receptor-binding motif (RBM) present on the membrane of human cells, which helps the virus evade the immune system and increases its transmissibility.21 To date, diverse variants of SARS-CoV-2 have been identified, circulating globally with different protein sequences, including Alpha (lineage B.1.1.7), Beta (lineage B.1.351), Gamma (lineage B.1.1.28.1), Delta (lineage B.1.617.2), Omicron (lineage B.1.1.529), Deltacron (AY.4-BA.1), XD (Delta-Omicron), XE (BA.1-BA.2), and XF (Delta-Omicron).22 Genome sequencing revealed that the Omicron variant corresponded to the Nextstrain clade 21K, the Pango lineage B.1.1.529, and the Global Influenza Surveillance and Response System (GISAID) clade GR/484A.21 Structural analysis indicates a higher number of non-synonymous mutations in the S-protein, making the virus more transmissible and capable of immune escape. Among those variants, circulating worldwide, four S-proteins (A570D, D1118H, S982A, T71I) are found in the Alpha variant; six S-proteins (A701V, D215G, D80A, Δ241, Δ242, Δ243) in Beta, eight (D138Y, L18F, K417T, P26S, T1027I, R190S, T20N, V1176F), with T19R and (V70F*) in Gamma, ten [T95I, E156-, G142D, F157-, R158G, (W258L*), (A222V*), (K417N*), T478K, L452R, D614G, D950N, P681R] in Delta; and finally, as many as thirty four (A67V, del142-144, T95I, del69-70, del211, Y145D, L212I, S371L, G339D, ins214EPE, S375F, S373P, N440K, K417N, S477N, G446S, T478K, Q493R, E484A, G496S, N501Y, Q498R, H655Y, Y505H, D614G, P681H, T547K, N856K, N679K, Q954H, N764K, D796Y, L981F, N969K) in Omicron.23 As of now, more than 60 mutations (deletions, alterations, and insertions) have been found in the Omicron genotype, including 30 substitutions (Y145D, A67V, T95I, S371L, L212I, G339D, S373P, K417N, S375F, G446S, N440K, T478K, S477N, G496S, E484A, Q493R, Q498R, N501Y, Y505H, T547K, H655Y, D614G, N679K, D796Y, P681H, N764K, N856K, N969K, Q954H and L981F), three deletions (V70/H69, N211, and G142/V143/Y144), and one insertion (EPE214). Several mutations can also be found in the envelope (E) protein (T9I), the membrane (M) protein (D3G, A63T, and Q19E), and the nucleocapsid (N) protein (P13L, G204R, and R203K), which may increase the virus’s contagiousness.24 There are fifteen mutations in the RBD of Omicron. The RBS-A, RBS-B, RBS-C, S309, and CR302 antigenic sites have been characterized in the RBD, and one or more of the 15 Omicron spike RBD mutations can be found in all of them.24 The S-protein of the Omicron variant carries some common mutations identical to previous VOCs and VOIs, including (Δ69–70, N501Y, P681H, D614G), (K417N), (H655Y, K417N), and (T478K) found in Alpha, Beta, Gamma, and Delta, respectively. Because of this wide range of mutations, Omicron has approximately 10-fold higher transmissibility, infectivity, and virulence than the original virus and 1.4 to 3.1-fold higher compared to Delta.21 It is worth noting that the Omicron variant also contains three mutations (H655Y, N679K, and P681H) near the furin cleavage site, which makes the virus more transmissible than previous variants.24 Omicron also reveals three substitutions (T478K, Q493K, and Q498R) that help it bind to ACE2 receptors with much more affinity than its prototype SARS-CoV-2, increasing the binding affinity (ΔGWT = 64.65 kcal/mol < ΔGOmic = 83.79 kcal/mol) of the RBDOmic with ACE2.25 The Omicron variant accumulated a staggering number of mutations in the open reading frame 1ab (ORF1ab) as well as the S-protein. ORF1a possesses six substitutions (A2710T, K856R, L2084I, P3395H, T3255I, and I3758V), ORF1b has two substitutions (P314L and I1566V), and an additional mutation was identified in ORF9b (P10S). However, only two mutations (nsp4: T492I or ORF1a: T3255I and nsp12: P323L or ORF1b: P314L) with noteworthy prevalence (>40%) were perceived in Delta and Delta Plus variants.24,26
Sub-variants of Omicron
The Omicron variant (BA.1/B.1.1.529.1) and its three sub-lineages (B.1.1.529.1.1/BA.1.1, B.1.1.529.2/BA.2, and B.1.1.529.3/BA.3) were initially discovered in the same region. BA.1 [hCoV-19/Botswana/R40B59_BHP_3321001248/2021 (EPI_ISL_6640916) (November 11, 2021, in Botswana, Greater Gaborone, South-East, Gaborone)], BA.2 [hCoV-19/South Africa/CERI-KRISP-K032307/2021 (November 17, 2021, in South Africa, Gauteng, Tshwane)], and BA.3 [hCoV-19/South Africa/NICD-N22163/2021 (EPI_ISL_7605713) (November 18, 2021, in South Africa, North-West)]. Over time, Omicron has been found to be more contagious. According to the GISAID database, a total of 258,129 complete genome sequences had been recorded by January 11, 2022. Of these, BA.1 accounted for 99.13% (255,898/258,129), BA.2 accounted for 0.85% (2,198/258,129), and BA.3 was accounted for 0.013% (33/258,129).27 Two novel Omicron lineages, BA.4 and BA.5, were found in South Africa and have identical spike proteins. These lineages caused a resurgence in infections from the first week of April 2022 onwards.17
BA.1, BA.1.1, BA.2, and BA.3 lineages
Different sub-lineages of Omicron are referred to as BA.1, BA.1.1, BA.2, and BA.3. Each of these sub-lineages has 39, 40, and 31 mutations, respectively, with 21 shared mutations (G142D, G339D, S373P, S375F, K417N, N440K, S477N, T478K, E484A, Q493R, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, N969K, and Q954H) among all of them (Table 1).14,17,28–30
Table 1The comparison of mutation between different Omicron lineages14,17,28–30
Mutations | Variants
|
---|
BA.1 | BA.1.1 | BA.2 | BA.2.12.1 | BA.2.13 | BA.3 | BA.4/BA.5 |
---|
T19I | | | Δ | Δ | Δ | | Δ |
L24S | | | Δ | Δ | Δ | | Δ |
del25-27 | | | Δ | Δ | Δ | | Δ |
A67V | Δ | Δ | | | | Δ | |
del69-70 | Δ | Δ | | | | Δ | Δ |
T95I | Δ | Δ | | | | Δ | |
G142D | Δ | Δ | Δ | Δ | Δ | Δ | Δ |
del143-145 | Δ | Δ | | | | Δ | |
N211I | Δ | Δ | | | | Δ | |
del212 | Δ | Δ | | | | Δ | |
V213G | | | Δ | Δ | Δ | | Δ |
G339D | Δ | Δ | Δ | Δ | Δ | Δ | Δ |
R346K | | Δ | | | | | |
S371L | Δ | Δ | | | | | |
S371F | | | Δ | Δ | Δ | Δ | Δ |
S373P | Δ | Δ | Δ | Δ | Δ | Δ | Δ |
S375F | Δ | Δ | Δ | Δ | Δ | Δ | Δ |
T376A | | | Δ | Δ | Δ | | Δ |
D405N | | | Δ | Δ | Δ | Δ | Δ |
R408S | | | Δ | Δ | Δ | | Δ |
K417N | Δ | Δ | Δ | Δ | Δ | Δ | Δ |
N440K | Δ | Δ | Δ | Δ | Δ | Δ | Δ |
G446S | Δ | Δ | | | | Δ | |
L452M | | | | | Δ | | |
L452Q | | | | Δ | | | |
L452R | | | | | | | Δ |
S477N | Δ | Δ | Δ | Δ | Δ | Δ | Δ |
T478K | Δ | Δ | Δ | Δ | Δ | Δ | Δ |
E484A | Δ | Δ | Δ | Δ | Δ | Δ | Δ |
F486V | | | | | | | Δ |
Q493R | Δ | Δ | Δ | Δ | Δ | Δ | |
G496S | Δ | Δ | | | | | |
Q498R | Δ | Δ | Δ | Δ | Δ | Δ | Δ |
N501Y | Δ | Δ | Δ | Δ | Δ | Δ | Δ |
Y505H | Δ | Δ | Δ | Δ | Δ | Δ | Δ |
T547K | Δ | Δ | | | | | |
D614G | Δ | Δ | Δ | Δ | Δ | Δ | Δ |
H655Y | Δ | Δ | Δ | Δ | Δ | Δ | Δ |
N679K | Δ | Δ | Δ | Δ | Δ | Δ | Δ |
P681H | Δ | Δ | Δ | Δ | Δ | Δ | Δ |
S704L | | | | Δ | | | |
N764K | Δ | Δ | Δ | Δ | Δ | Δ | Δ |
D796Y | Δ | Δ | Δ | Δ | Δ | Δ | Δ |
N856K | Δ | Δ | | | | | |
Q954H | Δ | Δ | Δ | Δ | Δ | Δ | Δ |
N969K | Δ | Δ | Δ | Δ | Δ | Δ | Δ |
L981F | Δ | Δ | | | | | |
Along with 21 shared mutations, mutations at the RBM (Q493R, N501Y, Q498R, T478K, and Y505H) create a higher positive electrostatic surface potential, which could increase the interaction rate between the viral RBD and the electronegative human angiotensin-converting enzyme-II (hACE2). Other mutations, including N679K, H655Y, and P681H, also facilitate the prefusion state of the spike protein.13,27,31 BA.1 and BA.1.1 share 8 common mutations (A67V, ins 214EP, R216E, S371L, N856K, G496S, T547K, L981F), while BA.2 and BA.3 share two common mutations (S371F, D405N). Additionally, 10 common mutations (Y145del, N211I, L212V, V213R, G446S, H69del, V70del, T95I, V143del, Y144del) are found among BA.1.1, BA.1, and BA.3.13 Though BA.1 and BA.2 have 21 spike mutations in common, BA.1 and BA.2 share nine and six common amino acid mutations, respectively, with most VOCs. This suggests the possibility of the genesis of Omicron from these VOCs (Table 2).10,13,31–33
Table 2Comparison of Omicron BA.1 and BA.2 with VOCs10,13,31–33
| Common mutations | Mutations |
---|
Comparisons with BA.1 variant | | |
| 9 (VOCs) | Δ69–70, ΔY144, K417N, T478K, N505Y, D614G, H655Y, P681H |
| 6 (Alpha – B.1.1.7) | Δ69–70, ΔY144, N501Y, D614G, P681H |
| 3 (Beta – B.1.351) | K417N, N501Y, D614G |
| 3 (Gamma – B.1.1.28.1) | N501Y, D614G, H655Y |
| 2 (Delta – B.1.617.2) | T678K, D614G |
| 7 (Omicron – B.1.1.529) | Δ69–70, ΔY144, P681H, K417N, H655Y, T678K |
Comparison with BA.2 variant | | |
| 6 (VOCs) | K417N, T478K, N501Y, D614G, H655Y, P681H (NO DELETION in Δ69–70, ΔY144) |
| 3 (Alpha - B.1.1.7) | N501Y, D614G, P681H |
| 3 (Beta – B.1.351) | K417N, N501Y, D614G |
| 3 (Gamma – B.1.1.28.1) | N501Y, D614G, H655Y |
| 2 (delta – B.1.617.2) | T478K, D614G |
The BA.2 sub-lineage lacks a particular genetic structure that distinguishes it from the standard or original variety, to be known as “Stealth Omicron”.34 Among all Omicron sub-lineages, BA.3 and BA.2 have greater transmission potential than BA.1.1 and BA.1. This study predicted that mutations in BA.1.1 (K478), BA.2 (R400, R490, and R495), and BA.3 (R397 and H499) form hydrogen bonds and new salt bridges. Omicron and its sub-variants or lineage mutations at RBM residues such as Q498, Q493R, N501Y, Y505H, and T478K, significantly contribute to the binding affinity with human ACE2. Interactions involving Omicron variant mutations at residues 493, 496, 498, and 501 seem to restore ACE2 binding efficiency lost due to other mutations like K417N.13 BA.2 sub-lineages, including BA.2.12.1 (BA.2+L452Q+S704L) and BA.2.13 (BA.2+L452M), exhibit higher ACE2-binding affinities compared to BA.1 and exhibit higher transmissibility due to the L452 mutation compared to BA.2.28 Some researchers discovered that BA.2 was significantly more resistant to one class of antibodies that bind to the S-protein portion involved in host cell binding than BA.1, while BA.2 was more sensitive to another type of spike antibody.35
BA.4 and BA.5 lineages
The Network for Genomic Surveillance in South Africa identified the BA.4 and BA.5 subvariants of Omicron in January and February of 2022, respectively. By April, these lineages had become the most prevalent, causing the fifth wave of this infection.36 From April 2022 onwards, these two lineages quickly superseded BA.2, accounting for over 50% of identified cases. By the end of April 2022 in South Africa, BA.4 and BA.5 comprised 35% and 20% of cases, respectively.37 Mutually the variants share identical amino acid (25 spike mutations) mutations, including F486V, along with the spike trimers T4 fibritin trimerization domain, GSAS, and 6P mutations.28,34 BA.4 and BA.5 have additional S-mutations such as 69-70del, F486V, L452R, and the wild-type amino acid at Q493, compared to the BA.2 variant (Table 1). Additionally, BA.4 differs from BA.5 by having the N: P151S mutation as well as mutations at N: P151S and ORF7b: L11F as well as a triad amino acid deletion in NSP1: 141-143del outside of the S-protein. BA.5 also has the M: D3N mutation. On the other side, BA.5 has extra reversals at ORF6: D61 and nucleotide positions 27,259 and 26,858, relative to BA.2. Both BA.4 and BA.5 have an identical mutation in NSP8 (nuc: G12160A). Mutations in spike amino acids (L452R, F486V, and R493Q) facilitate the binding between hACE2 and antibodies.17,38 Although both the BA.4 and BA.5 variants exhibit higher transmissibility due to the L452 mutation compared to BA.2, they have lower receptor-binding capability due to the R493Q and F486V reversals, potentially slowing their dispersion.28 Compared to BA.2, which spread more than the initial Omicron strain BA.1, BA.4 and BA.5 are more infectious. Omicron variations cannot be detected by several spike gene-targeted PCR tests due to minor losses in this gene.39 According to studies, BA.5 and BA.4 lineages have arisen with variations like the F486V and L452R mutations in the S-protein receptor binding domain, relative to BA.1 (Omicron). The BA.5 and BA.4 S-proteins are similar to BA.2 (Omicron) except for the L452R and F486V, 69–70 additional deletion. In comparison to BA, both contain the amino acid changes R493Q, L452R, and F486V in the S-protein receptor binding domain. The F486V mutation in the S-proteins of the BA.4 and BA.5 lineages contributes to increased infection. Additionally, the BA.4 and BA.5 lineages can evade immunological reactions.37
Delmicron or Deltacron
On January 7, 2022, a group of scientists from Cyprus University in Nicosia, led by virologist Leondios Kostrikis, identified a new “Super Variant” that possesses constituents of both Delta (lineage AY.4) and Omicron (lineage BA.1). They nicknamed it “DELTACRON” and 25 sequences were submitted to the open-source database GISAID.40 This hybrid variant has the nearly complete spike gene (codons 156 to 179) of an Omicron variant (21K/BA.1) within the spine of the Delta (21J/AY.4) lineage.41 Genomic analysis of “DELTACRON” revealed that recombination events are rare and only occur in the S gene at the inter-lineage level, as this recombinant variant originated from divergent lineages of the same species, AY.4 and BA.1. The S-protein has 36 amino acid mutations: 27 found in BA.1, 5 in AY.4, and four shared by both BA.1 and AY.4 (Fig. 1).42,43 On November 11, 2021, the first “Deltacron”-like Omicron strain was isolated in South Africa, followed by Botswana on November 23.32 In immunocompromised individuals, simultaneous infections with Delta (considered the most deadly) and Omicron (considered the most mutated) may facilitate this recombination, although it is an exceedingly rare event.22 Shishi Luo, a senior scientist of bioinformatics at the genomics company Helix, explained that if both Delta and Omicron variants infect the same cell simultaneously, there is a possibility of forming this new recombinant variant, Deltacron or Delmicron. When Omicron was detected in America, 29,719 positive samples were collected and sequenced over four months from November 2021 to February 2022. Out of these samples, two distinct incidences of infection with a recombinant Delta-Omicron variant, along with 20 co-infections, were discovered. This suggests that if simultaneous infection occurs in a human, the virus may eventually engage in recombination, but it remains very rare.44 There are ongoing debates as scientific reports examine whether this recombinant strain is a sequencing error or sample contamination. Nevertheless, co-infections of Omicron and Delta variants have been observed in some populations. From December 6, 2021, to January 16, 2022, 14,214 sequences indicated co-circulating Delta and Omicron variants in the United States.29,32 On January 9, at the Medical University of South Carolina in Charleston, Krutika Kuppalli, a member of the WHO’s COVID-19 technical team, stated that no super variant like Deltacron had been formed by Omicron and Delta.40
XD, XE, and XF sub-variants
In January 2022, a new SARS-CoV-2 recombinant variant, an amalgamation of Omicron (lineage BA.1) and Delta (lineage AY.4), was detected in France and later named “Deltacron” by the WHO.22 According to reports published by the UKHSA on March 25, 2022, and by the WHO in its regular epidemiological updates, three new emerging recombinant variants with high transmission rates were identified: XE (BA.1 + BA.2), XF (Delta + Omicron), and XD (Omicron + Delta). The most recent variants, XF and XE, emerged after the XD variant, which was the first to arise.45,46
XD sub-variant
The XD recombinant lineage was first identified in December 2021 and established in France by the Institut Pasteur.20,46 Although this variant was initially confined to France, as of March 18, 2022, cluster analysis and random sampling revealed that the XD lineage had spread to several Belgian provinces, as well as the Netherlands, Denmark, and Germany.19 The XD variant includes genomic parts ORF1a and ORF1b from the Delta AY.4 genome and harbors the spike protein from the Omicron BA.1 genome. XD carries a greater fraction of its genomic parts (nucleotide positions 1 to 21,463 and 25,581 to the endpoint) from Delta AY.4, integrating a lesser portion (nucleotide positions 21,643 to 25,581) from Omicron BA.1 variant (Fig. 2). Additional XD components, such as E, ORF6, M, ORF7b, ORF7a, N, ORF8, and 3UTR, have Delta ancestry.20 Additionally, the XD recombinant variant carries a novel E172D mutation in the NSP2 genomic region.46
XE sub-variant
The XE sub-variant, a recombinant of the Omicron sister variants BA.1 and BA.2, was first discovered in the UK on January 19, 2022, by genome sequencing.22,45 Later, it has also been found in Thailand.47 As daily COVID-19 cases rise and many countries face the possibility of a fourth pandemic wave, this virus has caused serious concern among scientists and attracted global attention.48 The XE variant has BA.1 mutations for NSP1-6 and BA.2 mutations for the remainder of the genome, with the recombination site located within the non-structural protein (NSP6) of the SARS-CoV-2 genome (nucleotide location 11,537) (Fig. 2). Therefore, compared to BA.2, this recombinant variant has fewer genetic elements from BA.1.20,45 However, the XE variant has three unique mutations not found in all BA.1 or BA.2 sequences: synonymous mutations C3241T and C14599T, and the amino acid mutationV1069I in NSP3, NSP12, and NSP3, respectively, which cleaves the viral polyproteins during replication.45,49 According to Maria Van Kerkhove of the WHO, XE appears to be 10% more transmissible than its parent variant BA.2, which was previously the most contagious strain of SARS-CoV-2. Additionally, the UK has recently recorded growth rates for XE that are up to 20% higher than those for BA.2.50
XF sub-variant
According to a report by the European Centre for Disease Prevention and Control, the XF variant was first identified in the UK in January 2022.38 The XF variant comprises genomic components (NSP1 to NSP3) from the Delta variant and the subsequent portion (spike and structural proteins) from the Omicron BA.1 variant. Nucleotide positions 1 to 5,386 belong to Delta, while the remainder of nucleotides belong to Omicron BA.1 (Fig. 2). Unlike the XD variant, the XF variant contains more genetic elements from Omicron BA.1.20