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Reports of the latest circulating SARS-CoV-2 variant collided at the end of Nov. 2021 with a pandemic landscape that had become almost exclusively dominated by one, highly transmissible Delta variant (B.1.617.2). Only 2 days after these early reports were publicized,  bestowed the newly classified variant of concern (VOC) with a name befitting its ominous preceding reputation—Omicron.

By mid-Dec. (less than a month later), Omicron had spread not only throughout South Africa, where it was first identified using robust genomic surveillance during a sharp rise in COVID-19 cases in Gauteng, the country’s most populous province, but also to 77 additional countries in Australia, Africa, Asia, Europe, North and South America. Data indicate that the  occurred in a patient with a history of international travel and symptom onset as early as Nov. 15, and by Dec. 25, the new variant accounted for 

Furthermore, with upwards of 50 mutations in its genome, 30 of which exist in the gene encoding Spike—the SARS-CoV-2 surface protein responsible for binding to human ACE2 receptors to facilitate infection, and the immunogen used in all vaccines currently authorized for general use—significant concerns about increased transmissibility and immune escape have been raised. Research is beginning to address those concerns.

How Contagious Is Omicron? 

WHO has acknowledged that , but there are still many questions about how much of a growth rate and/or transmission advantage Omicron has over the other VOCs. According to , Omicron demonstrated exponential growth over a 4-week period in Gauteng (Nov. 8-Dec.5, 2021) and spread with an estimated doubling time of 3.2-3.6 days. This is larger than, but comparable to, the doubling times of the first COVID-19 outbreaks, which occurred in spring 2020 when prior immunity was nonexistent and intervention methods were not yet in place.

 reported that Omicron pseudovirus multiplied 70 times faster than Delta and the original SARS-CoV-2 strain in human bronchus tissue in the lab. Yet it replicated nearly 10 times less efficiently in lung tissue than the original strain, which may be an indicator of lower disease severity.
 
Another South African study, based on 35,670 suspected reinfections among 2,796,982 laboratory-confirmed SARS-CoV-2 cases,  to be 2.39-fold higher during a wave of suspected Omicron outbreak (Nov. 1-Nov. 27, 2021) than during the first wave of SARS-CoV-2 infection. Furthermore, Omicron is spreading rapidly in areas such as Denmark and the U.K., which have vaccination rates of 69% and 77%, respectively, suggesting that vaccine breakthrough infections are more common with this variant.

The fact that Omicron has continued to spread in areas with high prevalence of prior SARS-CoV-2 infection and in well-vaccinated areas is particularly concerning and has led scientists to conclude that it is possible that Omicron will outcompete Delta and (at least temporarily) become the dominant strain of SARS-CoV-2 across the globe.

Will Vaccines Remain Protective Against Omicron?

On the whole,    have demonstrated that Omicron is capable of extensive, but incomplete, escape from neutralizing antibodies in vaccinated and convalescent sera. One study, found that pseudotyped Omicron virus was  by sera collected from 28 individuals who had previously been infected and recovered from SARS-CoV-2. In comparison, pesudotyped Alpha, Beta, Gamma and Delta viruses were found to be 1.2-4.5-fold less susceptible to neutralization.

, which tested serum samples from 88 individuals who received the Moderna COVID-19 vaccine, 111 who received the Pfizer COVID-19 vaccine and 40 who received the Johnson & Johnson COVID-19 vaccine against wild type, Delta and Omicron pseudoviruses, reported nearly undetectable neutralization activity against Omicron. However, serum samples from individuals who had been boosted with mRNA vaccines demonstrated restored neutralization activity that was only 4-6-fold lower against Omicron than against the wild type pseudovirus.

, which corroborated findings of reduced efficacy against Omicron after 2 doses of vaccine and demonstrated significant restoration of serum neutralizing activity with an additional vaccine dose. Serum collected from individuals 3 weeks after receiving the second dose of the Pfizer COVID-19 vaccine demonstrated a greater than 25-fold mean reduction in neutralization titers against pseudotyped Omicron virus. However, samples collected from individuals 4 weeks after receiving a third dose of the mRNA vaccine significantly increased neutralization titers by 25-fold.

Discovery Health, South Africa's largest private health insurer, conducted analysis of more than 211,000 COVID-19 positive test results, providing the first insight about . 41% of the samples that were evaluated in this study were collected from adult participants who had received 2 doses of Pfizer vaccine, and Omicron was identified as the cause of 78,000 of those cases, leading researchers to conclude that 2 doses of the Pfizer vaccine were only 33% protective against Omicron infection. However, severe disease remained rare in vaccinated patients. 70% protection against hospitalization was reported, demonstrating that vaccines remain the best defense against all circulating variants, including Omicron.

Do T-Cells Recognize and Protect Against Omicron? 

Combined, these laboratory and real-world data indicate that antibodies developed against the reference strain of SARS-CoV-2 are less capable of neutralizing the Omicron variant, but an additional dose of mRNA vaccine has been repeatedly shown to provide a significant boost to serum neutralizing activity in the lab. Since antibodies function as the gate keepers of the immune system, these data help support the increases in breakthrough Omicron infections that are being observed throughout the world. However, the observed level of protection against severe disease in vaccinated individuals, indicates that a decent amount of immunity is still being retained, and researchers suspect this is where cellular immunity may come into play.

T-cells , and robust T-cell responses have been associated with less severe disease. It is therefore important to understand whether or not anti-SARS-CoV-2 T-cells that were developed from vaccination or prior SARS-CoV-2 infection are capable of recognizing the Omicron variant. One study suggests that they are. An investigation of  revealed that Omicron has not evolved extensive T-cell escape mutations, which fortunately suggests that existing anti-SARS-CoV-2 CD8+ T-cells should be able to recognize and help clear Omicron infections.

Does Omicron Cause More Severe Disease Than Other Variants of Concern?

Increased risk of reinfection and/or breakthrough infection does not necessarily correlate with increased disease severity. While Omicron symptoms ranging from mild to severe, and , the  associated with the first 43 Omicron cases investigated in the U.S. were cough, fatigue, congestion and runny nose.

Notably, the majority (58%) of these cases occurred in people who were young (18-39 years old), vaccinated (79%) and otherwise healthy. And according to Discovery Health's large-scale, real-world analysis, 2-doses of Pfizer vaccination provide  from Omicron infection. Although this is significant, it does represent a drop in protection against severe disease caused by other VOCs. For example, vaccines conferred 90-93% protection against hospitalization from Delta.

The study also revealed that, while adults are 29% less likely to be hospitalized by Omicron than during the first wave of the pandemic, children are 20% more likely to be hospitalized by this variant. Questions about disease severity, especially in more vulnerable populations (i.e. those who are older, unvaccinated and/or have underlying medical conditions) remain under investigation.

Culpable Mutations of Omicron

Throughout its genome, the Omicron variant possesses at least 50 mutations that differentiate it from the SARS-CoV-2 reference strain. Thirty of these occur in the S gene, some of which overlap with mutations that were previously identified in other VOCs (Alpha, Beta, Gamma and Delta), as well a number of mutations that are considered to be unique to Omicron at this time.

The SARS-CoV-2 spike protein is the portion of the virus that recognizes and binds to human ACE2 receptors. It is critical to the virus’s ability to infect human cells and is the main target of COVID-19 vaccines, as well as serum neutralizing antibodies elicited by natural infection. Mutations that cause changes to the structure and/or function of Spike are more likely to render the virus less recognizable to existing (first wave) antibodies, and understanding how the number, location and specificity of amino acid changes in the Omicron genome may be contributing to its enhanced potential for antibody escape is of great importance.

Here we take a look at some of the Omicron mutations that reside in key regions of the S gene, including the receptor binding domain (RBD), furin cleavage site and NTD-antigenic supersite.

Receptor Binding Domain (RBD)

Spike is 1273 amino acids long, in its entirety. RBD, the portion of the protein that binds directly to human ACE2 receptors, is comprised of amino acids 319-541 and is the site of 15 of Omicron’s 30 S gene mutations. Included in the list is a trio of mutations that have raised alarm bells in other VOCs—a lysine to asparagine substitution at position 417 (K417N), a glutamic acid to lysine substitution at position 484 (E484K) and an asparagine to tyrosine substitution at position 501 (N501Y). N501Y, which Omicron has in common with Alpha, Beta and Gamma, is a particularly noteworthy mutation, even by itself, since it has been shown to  and is . Together, these 3 mutations have been shown to induce relatively high conformational changes to the spike protein and facilitate immune escape. Beta and Gamma possess all 3 of these mutations, while Delta has K417N, as well as an additional RBD mutation, a threonine to lysine substitution at position 478 (T478K), in common with Omicron.

The Omicron variant possesses 11 additional RBD mutations, that are under investigation. One of these, a glutamine to arginine substitution at position 498 (Q498R), has been shown to  in combination with N501Y.

Furin Cleavage Site

The spike protein consists of 2 subunits (S1 and S2) that must be separated from one another in order to mediate membrane fusion and cause infection. The  is the junction where that separation takes place. It represents another key element of SARS-CoV-2 pathogenesis, and mutations in this region have been linked to increases in infection and transmissibility.

For example, Alpha, Delta and Omicron all possess a proline to arginine substitution at position 681 (P681H), which reportedly , facilitating cleavage of additional spike proteins and making infection more efficient. Importantly, research shows that this mutation must occur on the background of additional Spike mutations in order have such an effect.

Gamma and Omicron have an additional mutation, a histidine to tyrosine substitution at position 655 (H655Y), that is located near the furin cleavage site and remains under investigation.

NTD-Antigenic Supersite

Certain regions in the N-terminal domain of the spike protein are especially vulnerable to antibody recognition and attack. When mutations accumulate in these antigenic supersites immune escape becomes more likely. Omicron has 4 consecutive mutations located at positions 142-145, which fall within a . One of these, a change in the glycine residue at position 142 (G142-), is also common to Delta.

Notably, just because a mutation is common to multiple variants does not necessarily mean it has the same functional consequences to all of them. Associated phenotypes may be impacted by combined effects of other mutations in a given genetic background, as well as host and environmental factors. Therefore, further study is needed in order to grapple with the effects of Omicron’s unique cocktail of S gene mutations.

What Can Be Done to Control the Spread of Omicron?

Omicron is spreading quickly across the globe, and data support real world observations of increased reinfection and vaccine breakthrough associated with this new variant. While it is unclear whether Omicron inherently causes more severe disease, preliminary data suggest that vaccines are continuing to offer protection against hospitalization from Omicron infection. Furthermore, studies show that an additional dose of mRNA vaccine is largely effective at restoring serum neutralizing antibody activity against all circulating variants. Therefore, vaccination is still the safest and most effective defense against severe complications of COVID-19, regardless of which variant is circulating. However, as the SARS-CoV-2 virus continues to evolve and spread, combining non-pharmaceutical interventions—practicing good hand hygiene, masking in crowded, indoor spaces and social distancing—will also continue to be necessary if we truly hope to slow transmission.

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