The challenges of Omicron

By Dr. Liji Thomas, MDReviewed by Danielle Ellis, B.Sc.Apr 25 2022

The coronavirus disease 2019 (COVID-19) pandemic broke out early in 2020, following the reporting of several cases of pneumonia caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan, China, in December 2019. So far, this disease has claimed more than 6.5 million lives worldwide.

Over the past year, several different variants of the virus have emerged, often with higher transmissibility and immune escape characteristics that make it difficult for the host to resist them even in the presence of immunity elicited by vaccination or infection with the ancestral or earlier strains of the virus. Such variants are called variants of concern (VOCs), and the most recent VOC is Omicron.

A new review published in Reviews in Medical Virology sums up the position of Omicron as a potential threat to human health, especially in the context of controlling this pandemic.

Introduction

The SARS-CoV-2 possesses a number of spike glycoproteins that mediate viral attachment to the host cell and entry into the cell to establish active infection. The attachment is via the viral receptor-binding domain (RBD) on the spike antigen, which binds to the angiotensin-converting enzyme 2 (ACE2) receptor, found on many human cell types.

The virus also carries a nonstructural protein, nsp14, that helps proofread the viral ribonucleic acid (RNA) genome, thus reducing the number of errors or mutations during viral replication. However, new variants have emerged repeatedly, carrying key mutations that promote viral transmission and alter the antigenic sites to allow them to escape neutralization by the corresponding antibodies because they no longer fit the epitopes on these antibodies.

The spike gene is a mutational hotspot, as is the open reading frame (ORF) 6 and ORF 8. In fact, the spike gene appears to show positive selection as part of the viral strategy to become more virulent and more transmissible.

Omicron spike mutations

The Omicron variant most closely resembles the Alpha VOC and is unlike any other variant in its phylogeny. It has over 50 mutations, of which 26 occur only in this variant. In this respect, it exceeds the number of unique mutations found in Delta and Beta variants. It seems to suggest the importance of the role played by the immune milieu in the emergence of adaptive mutations.

Interestingly, the ancestral variant has three more residues than Omicron but is lighter and less basic than the latter. The higher content of arginine, lysine, aspartic acid, and glutamic acid in the Omicron spike stabilizes it by promoting salt bridge formation, while the higher spike core content of nonpolar residues reduces solvent accessibility.

Sharply increased transmissibility

Omicron is now the dominant variant worldwide, with three common lineages, BA.1, BA.2, and BA.3, which have distinct sequences despite belonging to the same line of descent. The first two have 50 differences in sequence, which exceeds the number of mutations separating the earlier VOCs from the ancestral strain.

BA.1 was initially identified as the Omicron variant but was then displaced by BA.2. There is some evidence that the latter should be considered a new strain, though its epidemiology, severity, diagnostic and therapeutic characteristics, and vaccine susceptibility resemble those of BA.1 very closely.

BA.2 and BA.3 are both highly contagious. BA.2 is 1.5 times more contagious than BA.1 and >4 times more contagious than the Delta variant, itself 40-60% more transmissible than the Alpha, which was much more so than the Wuhan variant. This makes BA.2 almost as contagious as “the most contagious disease” known, namely, measles. The Delta variant also doubled the risk of hospitalization, but the Omicron has not shown this trend so far.

Increased binding affinity

All three sublineages have 12 common mutations in the RBD that are associated with high infectivity and immune escape. The spike protein in the Omicron variant has 30 or more mutations along with three deletions and one insertion. This variant shows the highest binding affinity for the ACE2 receptor among all variants, but shows the greatest RBD divergence from other strains.

While many Omicron mutations such as the notorious E484K in the spike protein promote receptor binding, infectivity, and transmissibility, as well as antibody escape, others like G339D, S371 L, and E484A have the opposite effect, reducing spike stability. Thus, the sum of the effects caused by the mutations must be seen to cause the overall biological behavior of the virus.

Immune escape

The RBD and N-terminal domain mutations, especially E484K, are probably responsible for the loss of vaccine efficacy and the high rate of breakthrough infection. Another important contribution is the cluster of mutations at the furin cleavage site, which mediates immune escape and high transmissibility. Finally, mutations in the ORF1 gene also play a role in immune evasion.

Both humoral and T cell immunity may suffer as a result of the Omicron mutations that target epitopes important to both. BA.1 does not seem to induce complete protective immunity against BA.2 infection, and BA.2 shows a higher escape from vaccine-induced immunity than either Delta or BA.1. It has higher infectivity, is more fusogenic, and may pose a higher health threat.

The many mutations on the spike act together, according to some researchers, to evade antibody attachment and neutralization more efficiently than would be possible if they were individually present. BA.2 and BA.3 are almost fully resistant to the neutralizing capacity of vaccine-induced antiserum and to most monoclonal antibodies. Even with sotrovimab, which neutralized most earlier VOCs, BA.2 shows 35% more resistance.

Despite this, highly conserved sarbecovirus epitopes are still available that could be targeted by neutralizing antibodies following prior infection with earlier variants.

Protection against reinfection

The role of a booster dose with a messenger ribonucleic acid (mRNA) vaccine is still in question, though prior to the emergence of Omicron, this was associated with 55-80% protection. With natural infection, too, less than 20% protection was afforded against reinfection after Omicron emerged, compared to the 85% protection for over six months before that.

For immunity associated with prior infection or vaccination, the risk of Omicron reinfection is over five times higher than with Delta. The increased breadth of ACE2 receptor binding with these mutations also makes the reverse transmission from humans to potential reservoir animals in the wild a greater concern.

Lower detection rates?

Diagnostic tests may also be less effective for the Omicron variant, which was first identified in South Africa because of a high proportion of Spike gene target failures. Since the preferred reverse transcription-polymerase chain reaction (RT-PCR) hinges on the detection of the targeted region of the genome, a large number of mutations in this region could markedly reduce the efficiency of detection.

Neurological sequelae?

Finally, though Omicron has been associated with lower rates of severe and fatal disease, it is known that even with a mild infection, neurological injury can occur, causing thinning of the gray matter, shrinking of the brain, and other alterations in brain function. Greater than expected cognitive decline was also reported in the same study. The neurodegeneration observed could be due to neuroinflammation, the entry of the virus via the olfactory pathways, or the loss of sensory pathways as a result of anosmia, and further work is required to establish its reversibility or otherwise.

With the high infection rates of Omicron, the double infection has also become much more common. Recently a study presented the finding of a new “Deltacron” variant possessing the mutations found in both Delta and Omicron VOCs. The high contagiousness of Omicron, its immune escape capability, and the possibility of overwhelming numbers of infections with potential neurological sequelae show that the threat of COVID-19 is far from over with the emergence of this variant. Continuing global surveillance of the virus thus remains a priority, both to track immune escape and viral transmissibility and to identify new mutations as they arise.