Possible impact of spike protein mutations on SARS-CoV-2 Omicron variant

Even as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to circulate around the world, multiple new mutations continue to emerge. These have led to the detection of new variants, including the Alpha, Beta, and Delta variants that have been shown to be more transmissible, more capable of immune evasion, or both, compared to the ancestral variants.

Study: S glycoprotein diversity of the Omicron Variant. Image Credit: CROCOTHERY/ShutterstockStudy: S glycoprotein diversity of the Omicron Variant. Image Credit: CROCOTHERY/Shutterstock

At the end of November 2021, the latest new variant, called the Omicron, was reported by South Africa as a result of genome sequencing surveillance. With over 30 new mutations and markedly higher transmissibility, scientists are wondering if this could drive devastating new surges of reinfection, overcoming the immunity elicited by earlier infections or by current vaccines.

A new preprint explores the spike glycoprotein mutations in the Omicron variant, with their putative effects on the biological characteristics of the virus.


The Omicron variant, B.1.1.529, was first designated a variant of concern (VOC) by the World Health Organization (WHO) based on the presence of numerous mutations, some of which are common to earlier VOCs. This meant that the Omicron variant was likely to be more infectious, cause more severe disease, escape neutralization by antibodies elicited by earlier variants or vaccines, and be more difficult to diagnose and/or treat.

The detection of the Omicron variant in South Africa occurred against a backdrop of rapidly rising cases, but further genomic sequencing studies are required to tell if this variant is driving the newest surge in infections. The earliest evidence of this variant is in a sample collected on November 9th, 2021.

The viral spike is the surface protein that mediates viral attachment to the host cell angiotensin-converting enzyme 2 (ACE2) receptor, thereby making viral entry into the host cell possible. It is therefore also the prime target of neutralizing antibodies to the virus.

The spike glycoprotein has two subunits, the S1 and S2, which mediate ACE2 attachment and membrane fusion, respectively, to accomplish viral entry into the target host cell. These two subunits require to be cleaved by a host furin enzyme and then show non-covalent interactions.

The RBD of the S1 subunit is involved in ACE2 receptor engagement, while the NTD recognizes several attachment factors. The S2 subunit contains the viral-host cell membrane fusion apparatus, which shows a large conformational change to cause fusion to occur. This allows the viral genome to enter the target cell via endocytosis, paving the way for productive infection.

The RBD is immunodominant, eliciting the majority of protective and binding antibodies to the virus. Since it also accomplishes virus-host cell receptor engagement, an RBD mutation is especially likely to affect the ability of antibodies to neutralize the spike. Such antibodies, elicited by vaccination or as the result of natural infection, are the basis of immune protection against infection.

Moreover, RBD mutations could also, conceivably, impact virus-receptor binding. These facts prompted the current study to identify the mutations and predict their effect on viral transmissibility, pathogenicity, and immune evasion. This prediction is necessarily based on what is known about the earlier identified mutations.

As the virus circulates in a large pool of susceptible individuals, some with antibodies against earlier strains as a result of prior infection or vaccination, mutations that change the shape or behavior of the spike in a manner that benefits the virus tend to be propagated.

For instance, if the mutation facilitates immune evasion or immune escape or allows more rapid infection to take place, it would be more likely to persist and become part of a new variant that may become dominant. For this reason, spike mutations have been the focus of all classification and functional studies of the variants of the virus.

The current study, available on the medRxiv* preprint server, not only analyses the mutations in the Omicron spike variant but classifies various combinations of spike mutations into groups. The Global Initiative for Sharing Avian Influenza Data (GISAID) database now contains over 300 Omicron sequences from African, European, and Asian countries, mostly from South Africa and other nearby countries.

What did the study show?

The researchers mapped the 37 spike mutations of the Omicron variant, which are present in anywhere between 60% to 100% of the sequences available so far. Of these, 29 occur in the S1 domain, comprising 11 in the N-terminal domain (NTD), 15 in the receptor-binding domain (RBD), and 3 in the C-terminal domain (CTD). Of the 15 RBD mutations, ten will be on the receptor-binding motif (RBM). In contrast, eight mutations were on the S2 domain.

Of the 37 mutations, 25 were found to be unique to this strain, while 12 are shared with the Alpha, Beta, Gamma, and Delta VOCs.

The 300-plus strains of the Omicron were classified into 60 groups, each with its own set of mutations. Group 1 and group 2 contain more than half the total number, at 170, containing all 37 mutations and 33 mutations, respectively. Group 1 contains almost 120 of these sequences, and Group 2 about 50.

The remaining ~140 sequences were classified into the remaining 60 groups. The presence of so many groups shows the multiplicity of mutational subtypes of this variant.

Phylogenetically, a new cluster of the Omicron variant, comprising 155 strains, emerged from the GR, Pango B.1.1 or 20B clade of SARS-CoV-2. This cluster is further subdivided into smaller clusters by spike mutation type.

What are the implications?

The presence of 37 mutations in the spike protein, especially affecting the crucial NTD and RBD portions of the S1 subunit of the protein, has raised concerns about a new wave of infections. The 12 overlapping mutations have been shown to cause higher transmissibility, higher binding affinity, or immune evasion. Scientists have predicted that the Omicron variant will continue to show these characteristics. The other 25 unique mutations are still unknown concerning their biological impacts.

The 4 RBD mutations K417N, K477N, T478K, and E484A, have been shown to confer immune evasion capabilities.

Both T478K and E484A affect residues at the immunodominant site of the RBD. The E484K mutation emerges in patients who receive monoclonal antibody or convalescent plasma therapy and confers immune escape capability. Other mutations at this site, such as E484A, E484D, and E484G, also resist antibody-mediated neutralization, while E484Q reduces the titer of serum neutralizing antibodies.

The K477N mutation enables the variant to resist neutralization by monoclonal antibodies but not convalescent plasma. The K417N, previously identified in the Beta and Delta plus variants, makes them partially resistant to neutralization by therapeutic monoclonal antibodies raised against earlier variants.

The fact that these three immune escape mutations are found in the Omicron variant may lead to a heightened potential for immune escape.

The NTD is also immunogenic and contains an antigenic supersite comprising the N-terminal end, a β-hairpin, and loop residues. The Omicron variant contains four mutations within the β-hairpin region, which may enhance immune evasion by this variant.

Four of the 11 mutations in the Omicron RBD, namely, G339D, N440K, T478K, and N501Y, were shown in a recent study to increase ACE2 binding affinity, and the other 11 reduced it.

The most important among these are Q493, Q498, and N501, because they form contact networks including hotspot residues (K31 and K353) on the ACE2 contact surface. If these are replaced by nonpolar amino acids, RBD-ACE2 binding affinity increases. Conversely, replacing glutamine at positions 493 and 498 by the more polar residue arginine may reduce binding affinity.

Thus, the magnitude of interactions between these 11 and 4 mutations with opposing effects will determine the ultimate effect on the receptor binding affinity of the Omicron variant. Meanwhile, the presence of D614G and P681H mutations that mediated high transmissibility in earlier variants means that the Omicron is expected to be highly infectious.

At present, the Delta continues to spread rapidly in susceptible communities and regions, while significant levels of vaccine-induced and natural immunity also exist. Even so, the Omicron variant is causing rapid rises in the number of infections. This seems to suggest that this strain is both highly transmissible and able to cause breakthrough infections.

If the current trend continues, omicron will supplant delta as the most common variation in South Africa and other part of the world very rapidly and may lead to another wave of COVID-19.”

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.


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