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Volume:4 Issue:12 Number:1 ISSN#:2563-559X
OE Original

The Rise of the Omicron SARS-CoV-2 Variant of Concern: Uncertainties Remain, But Readiness Is All

Authored By: OrthoEvidence

December 6, 2021

How to Cite

OrthoEvidence. The Rise of the Omicron SARS-CoV-2 Variant of Concern: Uncertainties Remain, But Readiness Is All. OE Original. 2021;4(12):1. Available from: https://myorthoevidence.com/Blog/Show/160

Highlights


- The World Health Organization (WHO) designated the SARS-CoV-2 B.1.1.529 variant as a variant of concern (VOC) on November 25 with the name -- Omicron.


  • - Among over 50 mutations in the Omicron VOC, some of them (e.g., K417N, N440K, N501Y, S477N) may be associated with high transmissibility and immune escape potential, and therefore being very concerning.


  • - The European Union and European Economic Area (EU/EEA) rates the overall level of risk related to the SARS-CoV-2 Omicron VOC as high to very high. The WHO also determined that the overall global risk associated with the Omicron VOC is very high.


  • - Uncertainties remain about the Omicron variant, such as the transmissibility and immune escape potential of the Omicron VOC and the effectiveness of current available COVID-19 vaccines against the infection, transmission, disease severity, and death related to Omicron.


  • - Appropriate actions should be taken while waiting for further evidence to ensure the readiness if Omicron turns out to be highly transmissible and/or capable of immune escape.





These [e.g., concerns about Omicron being more contagious or evading the protection of vaccines and treatments] are all maybes, but the suggestion is enough. This is something we got to pay really close attention to and be prepared for something that's serious. It may not turn out that way, but you really want to be ahead of it.



Dr. Anthony Fauci, Chief Medical Adviser to the President of the United States (NBC)















A new and potentially more transmissible coronavirus variant (SARS-CoV-2 B.1.1.529 variant), which was first identified in South Africa in a specimen collected on November 9, has raised serious concerns across the world and casted a dark shadow over the approaching holiday season. So far, around 40 countries and regions across continents have reported confirmed cases caused by the SARS-CoV-2 B.1.1.529 variant (Figure 1).


Based on the advice from The Technical Advisory Group on SARS-CoV-2 Virus Evolution (TAG-VE), an independent group of experts responsible for monitoring and assessing the evolution of SARS-CoV-2, The World Health Organization (WHO) has designated the SARS-CoV-2 B.1.1.529 variant as a variant of concern (VOC) on November 25 with the name -- Omicron. An VOC is likely to be associated with significant increase in transmissibility, increase in virulence, and/or decrease in effectiveness of available public health measures, vaccines, and therapeutics.


In this OE Original, we provide evidence-based information on Omicron and explore the implications of this new variant for our battle against the COVID-19 pandemic.








See past OE Originals to know more about SARS-CoV-2 VOCs









* Evidence regarding COVID-19 emerges rapidly. Above OE Originals and Insights can only reflect the best available evidence at the time of publication





# What do we currently know?


According to the WHO, Delta VOC was still the predominant SARS-CoV-2 variant and accounted for about 99.8% (837253/839119) of the sequences uploaded to GISAID (Global Initiative on Sharing Avian Influenza Data) with specimens collected in the last 60 days. Of these sequences, Omicron only accounted for less than 0.1% (159/839119). Although the Omicron VOC is spreading quickly, it is still unclear at current stage whether Omicron would outcompete the Delta VOC.


The Omicron VOC is a highly divergent SARS-CoV-2 variant with a large number of mutations.  Over 30 mutations in the Omicron’s spike protein as opposed to the original SARS-CoV-2, including amino acid changes, small deletions and small insertion, have been identified. (e.g., A67V, ?69-70, T95I, G142D, ?143-145, ?211, 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, L981F) [European Union and European Economic Area (EU/EEA)]. Additionally, around 20 mutations were also detected in genomic regions of Omicron VOC other than its spike protein (EU/EEA).


Some of the mutations may be associated with high transmissibility as well as immune escape potential, and therefore are very worrying (Sarkar et al., 2021). For instance, N501Y might increase the overall binding affinity between the receptor-binding domain (RBD) and the human angiotensin-converting enzyme 2 (ACE2) receptor, increasing the chance of the virus to infect host cells (Luan et al., 2021). A simulation study found that the combination of N501Y and K417N fully abolished the effect of antibodies derived from COVID-19 patients via free energy perturbation calculations (Fratev, 2021).


An affinity and kinetics analysis of the effect of 5 common RBD mutations, including K417N, N501Y, and S477N exhibited in the Omicron VOC, on the RBD/ACE2 interaction suggested that N501Y and S477N mutations might enhance the viral transmission by enhancing the binding between RBD and the ACE2 receptor as well as the K417N/T mutations might facilitate immune escape (Barton et al., 2021).


In a case report, the authors reported a case of reinfection of SARS-CoV-2 in an individual from India. They detected in the patient the presence of N440K in the Spike protein in both episodes of infection, suggesting N440K might be associated with the immune escape of SARS-CoV-2 (Rani et al., 2021). The deletion of amino acids 69 and 70 in the glycoprotein (?69/70) was reported to be associated with the evasion of the human immune response (McCarthy et al., 2021).


Gu et al. (2021) reported 2 Omicrons cases detected in a quarantine hotel in Hongkong, China. The 2 patients were both fully vaccinated travelers. This detection highlighted the concern that the Omicron VOC might have an increased transmissibility and affect the effectiveness of existing vaccines.


A preprint posted in MedRxiv on December 2 examined whether the risk of reinfection (defined as individuals having sequential SARS-CoV-2 positive tests at least 90 days apart) with SARS-CoV-2 had changed over time in the context of the emergence of the Beta, Delta, and Omicron VOCs among over 279000 individuals in South African with laboratory-confirmed SARS-CoV-2 who had a positive test at least 90 days prior to Nov 27, 2021 (Pulliam et al., 2021). Pulliam et al. (2021) found that the risk of reinfection was lower during waves 2 and 3 which were driven by the Beta and Delta variants, respectively, compared to that of the first wave driven by the Alpha variant [hazard ratio (HR) for wave 2 versus wave 1: 0.75, 95% confidence interval (CI): 0.59 to 0.97; HR for wave 3 versus wave 1: 0.71, 95% CI: 0.56 to 0.92]. However, the HR for reinfection during the period from November 1 to 27, 2021 versus wave 1 was 2.39 (95% CI: 1.88 to 3.11), indicating that the Omicron variant might be capable of escaping immunity from prior infection (Pulliam et al., 2021).


Given the probability that the Omicron VOC may have increased transmissibility and immune escape potential, the EU/EEA rates the overall level of risk related to the SARS-CoV-2 Omicron VOC as high to very high. The WHO also determined that the overall global risk associated with the Omicron VOC is very high for similar reasons. In the meantime, the WHO acknowledged that “The evidence for this assessment contains considerable uncertainty and will be updated as more information becomes available.”






Currently, we find ourselves in that place of uncertainty with the omicron variant of SARS-CoV-2. We don’t know whether it will be more transmissible than delta or whether it will result in more severe disease. And we don’t yet know how well the current vaccines will protect us from it… This means that now is the time for the utmost caution.



Salisbury (2021), The BMJ








Many uncertainties remain about the Omicron VOC. As the WHO pointed out, key uncertainties include I) the transmissibility and immune escape potential of the Omicron VOC, II) the effectiveness of current available COVID-19 vaccines against the infection, transmission, disease severity, and death related to the Omicron VOC. Unfortunately, there is little evidence to resolve either of the above uncertainties.


Facing uncertainties does not mean countries and health authorities should wait. There are appropriate actions they can take to be ready. According to the WHO, they should


  • - Try to understand Omicron better by enhancing the surveillance and sequencing efforts;


  • - Further expand and accelerate the COVID-19 vaccination coverage as quickly as they can;


  • - Maintain non-pharmaceutical interventions, such as mask-wearing, physical distancing, avoiding large gathering, hand hygiene, ventilation of indoor space;


  • - Make sure there is an effective early warning system in place so that public health and social measures can be adjusted quickly;


  • - Make sure there are plans in place to maintain essential health services and necessary health care resources to face potential surges in Omicron cases;


  • - Communicate with the public with evidence-based information in a timely and transparent manner.




The Take Home Message


There are still too many uncertainties and unknowns about the SARS-CoV-2 Omicron variant. More evidence is urgently needed. While waiting, we also need to take proper measures to ensure that we are ready if Omicron turns out to be highly transmissible and/or capable of immune escape.






Reference


Barton, M. I., et al. (2021). Effects of common mutations in the SARS-CoV-2 Spike RBD and its ligand, the human ACE2 receptor on binding affinity and kinetics. Elife, 10. doi:10.7554/eLife.70658

Fratev, F. (2021). N501Y and K417N Mutations in the Spike Protein of SARS-CoV-2 Alter the Interactions with Both hACE2 and Human-Derived Antibody: A Free Energy of Perturbation Retrospective Study. J Chem Inf Model. doi:10.1021/acs.jcim.1c01242

Gu, H., et al. (2021). Probable Transmission of SARS-CoV-2 Omicron Variant in Quarantine Hotel, Hong Kong, China, November 2021. Emerg Infect Dis, 28(2). doi:10.3201/eid2802.212422

Luan, B., et al. (2021). Enhanced binding of the N501Y-mutated SARS-CoV-2 spike protein to the human ACE2 receptor: insights from molecular dynamics simulations. FEBS Lett, 595(10), 1454-1461. doi:10.1002/1873-3468.14076

Pulliam, J. R. C., et al. (2021). Increased risk of SARS-CoV-2 reinfection associated with emergence of the Omicron variant in South Africa. medRxiv, 2021.2011.2011.21266068. doi:10.1101/2021.11.11.21266068

Rani, P. R., et al. (2021). Symptomatic reinfection of SARS-CoV-2 with spike protein variant N440K associated with immune escape. J Med Virol, 93(7), 4163-4165. doi:10.1002/jmv.26997

Salisbury, H. (2021). Helen Salisbury: Omicron—panic mongering or appropriate caution? BMJ, 375, n2941. doi:10.1136/bmj.n2941

Sarkar, R., et al. (2021). S glycoprotein diversity of the Omicron Variant. medRxiv, 2021.2012.2004.21267284. doi:10.1101/2021.12.04.21267284



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