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2021, The Year of the Various SARS-CoV-2 Variants of Concern – from Alpha to Omicron

A review of the various SARS-CoV-2 Omicron mutations

2021 was the year of multiple variants of concerns (VOCs) starting with the Alpha variant in the UK, which was first detected in November 2020, and spread quickly by mid-December 2020. Now a year later, we have the Omicron variant, which was also designated a variant of concern by the World Health Organization (WHO). Following the Alpha variant, the world was shaken by three other variants: the Beta variant (Tegally et al., 2021) detected in South Africa, followed by the Gamma variant (Faria et al., 2021) in South America,  and later the Delta variant (Wall et al., 2021) from India. The Alpha, Beta, and Gamma variants had initially been labeled VOCs, but have since been re-annotated to variant being monitored (VBM) by the CDC. A recent review A Review of SARS-CoV-2 Variants, that we published in July of 2021 details some of what was known up to the emergence and description of the Delta variant.

Omicron a Blessing in Disguise?

Within just a few weeks Omicron has gone from initial discovery to representing the major variant in new infections across the globe. To-date, very little has been published in peer-reviewed publications, but preprints of studies involving Omicron are being added to the emerging literature every day. A recent South African study highlighted that  90% of all Omicron infections are asymptomatic (up from 40% for previous variants), come with a substantially lower risk of hospitalization (80% lower compared to the Delta variant) (Wolter et al., 2021), and compared to the Delta variant, have 70% lower odds of severe disease. Similar data on the severity of Omicron are emerging from research by other groups (Christie, B., 2021). While Omicron seems to induce milder infections, there appears to be however some troubling data indicating that Omicron may partially or completely evade immunity acquired through previous infection (Dejnirattisai et al., 2021). Furthermore, recent data indicates that even 2-dose mRNA vaccine regimens leave individuals vulnerable to Omicron, though boosters are still very effective (Garcia-Beltran et al., 2021). Based on recent observations, it is reasonable to speculate that the COVID-19 pandemic could follow the paradigm of the 1918 flu pandemic and become less life threatening over the course of several years by mutating into variants that cause milder infections and disease states which in turn are easier to manage from a medical care point of view. While the current situation does show some parallels to the Spanish flu, there are still uncertainties whether we have a so-called “Parallel Pandemic” with multiple strains running their course.

The Variant Omicron

The variant Omicron (Pango B.1.1.529, Nextstrain clade 21K) is defined by 30 amino acid changes in the spike protein, three small deletions, and one small insertion compared to the original virus. The list of identified differences is as follows:

  • A67V, Δ69-70, T95I, G142D, Δ143-145, Δ211, L212I, ins214EPE, G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493K, G496S, Q498R, N501Y, Y505H, T547K, D614G, H655Y, N679K, P681H, N764K, D796Y, N856K, Q954H, N969K, and L981F
  • Omicron also carries a number of changes in the NSP3, NSP4 , NSP5 , NSP6, NSP12, NSP14, E, M and N proteins which may affect its activity.
  • There is increasing speculation that Omicron is more antigenically distinct from the original SARS-Cov-2 strain than any previous variant including Beta and Delta (Dejnirattisai et al., 2021, Garcia-Beltran et al., 2021).

Since the spike protein is the most studied, and there is much data on both naturally occurring and lab-created mutations we offer the following tables as a rough guide for what is known. Some of the mutations (e.g., N501Y) have been researched extensively and the findings of the impact of these mutations have been published, while for other mutations little to no information is currently available.

A Summary of the various Omicron mutations and their impact on biological functions

The various domains affected by the Omicron mutations are nicely depicted in the image shown in Figure 1 (Schütz et al., 2020), which shows a schematic of the 2019-nCoV S primary structure. Following are the tables (Tables 1 – 6) that summarize the different mutations in the various domains SARS-CoV-2 S protein sub-domains.

Figure 1: Schematic of SARS-CoV-2 spike protein primary and 3D-structures with the various domains colored which harbor the Omicron mutations. (Image credit: Schütz et al., 2020)

N-terminal domain (NTD) mutations

Table 1: NTD mutations and their impact on biological features.

Receptor binding domain (RBD) mutations

Table 2: RBD mutations and biological features.

Receptor binding motif (RBM) mutations

Table 3: RBM mutations and biological features.

Subdomain 1 and Subdomain 2 (SD1/SD2)

Table 4: SD1/SD2 mutations and biological features.

Polybasic cleavage site

Table 5: Polybasic cleavage site mutations and biological features.

C-terminal domain (S2 domain)

Table 6: C-terminal domain (S2) mutations and biological features

The Garcia-Beltran et al., paper (2021) nicely summarizes the differences between the SARS-CoV-2 wild-type, the Delta, and the Omicron variants (see Figure 2).

Figure 2: Emergence of SARS-CoV-2 Omicron among global variants of concern (Garcia-Beltran et al., 2021).


Christie, B., Covid-19: Early studies give hope omicron is milder than other variants (2021) BMJ, https://doi: 10.1136/bmj.n3144.

Dejnirattisai et al., Reduced neutralisation of SARS-CoV-2 omicron B.1.1.529 variant by post-immunisation serum. (2021) Lancet, https://doi: 10.1016/S0140-6736(21)02844-0.

Faria et al., Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil. (2021) Science, May 21;372(6544):815-821.

Garcia-Beltran et al., mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant. (2021) Cell, https://doi.org/10.1016/j.cell.2021.12.033.

Greaney et al., Comprehensive mapping of mutations in the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human plasma antibodies. (2021) Cell Host Microbe, Mar 10;29(3):463-476.

Gong et al., Contribution of single mutations to selected SARS-CoV-2 emerging variants spike antigenicity. (2021) Virology, Nov;563:134-145.

Liu, Z. et al., Identification of SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization. (2021) Cell Host Microbe, Mar 10;29(3):477-488.

McCallum et al., N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2. (2021) Cell, Apr 29;184(9):2332-2347.

McCallum et al., Molecular basis of immune evasion by the Delta and Kappa SARS-CoV-2 variants. (2021b) Science, Dec 24;374(6575):1621-1626.

Meng et al., Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role in the Alpha variant B.1.1.7. (2021) Cell Rep, 2021 Jun 29;35(13).

Saito et al., Enhanced fusogenicity and pathogenicity of SARS-CoV-2 Delta P681R mutation. (2021) Nature, Nov 25. doi: 10.1038/s41586-021-04266-9.

Schuetz et al., Peptide and peptide-based inhibitors of SARS-CoV-2 entry. (2020) Adv Drug Deliv Rev., 2020 Dec;167:47-65.

Schmidt et al., High genetic barrier to SARS-CoV-2 polyclonal neutralizing antibody escape. (2021) Nature, 2020 Dec;600(7889):512-516.

Starr et al., Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding. (2020) Cell, 2020 Sep 3;182(5):1295-1310.

Tegally et al., Detection of a SARS-CoV-2 variant of concern in South Africa. (2021) Nature, Apr;592(7854):438-443.

Wall et al., Neutralising antibody activity against SARS-CoV-2 VOCs B.1.617.2 and B.1.351 by BNT162b2 vaccination. (2021) Lancet, Jun 3;S0140-6736(21)01290-3.

Wang et al., Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. (2021) Nature, May;593(7857):130-135.

Wang et al., Increased resistance of SARS-CoV-2 variant P.1 to antibody neutralization. (2021b) Cell Host Microbe, May 12;29(5):747-751.

Wolter et al., Early assessment of the clinical severity of the SARS-CoV-2 Omicron variant in South Africa. (2021) medRxiv, https://doi.org/10.1101/2021.12.21.21268116.

Zhou et al., Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine-induced sera. (2021) Cell, Apr 29;184(9):2348-2361.

Nick Marshall


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