A transmission electron microscope image of SARS-CoV-2. Image: Flickr/NIAID CC BY 2.0
Note: What we know and don’t know about the omicron variant of the novel coronavirus is changing rapidly. The following article is confident about its facts up to the time it was published. Details that could change in time may since have changed; please verify them for yourselves.
- At the time of writing this article, the omicron variant had been confirmed in 131 samples and was suspected in 1,057 others – in 13 countries.
- The omicron variant is not a descendant of any of the existing VOCs; instead, it appears to have descended directly from the ‘original’ strain (B.1).
- Its closest evolutionary connection appeared in April 2020, which suggests the variant evolved over an extended period of time before entering the population in its current form.
- There is a striking accumulation of mutations in its spike protein’s S1 domain, which contains the receptor binding domain and the N-terminal domain.
After a 10-hour overnight trip on two flights from Capetown in South Africa, around 600 passengers were detained at the edge of the Netherlands’ Schiphol airport runway on November 26 for four hours. Dutch officials were concerned that the travellers were ‘carrying’ a new variant of the novel coronavirus, which the WHO had recently christened ‘omicron’.
Officials held the passengers in a room with poor ventilation, and it was many hours before they were tested.
This incident typified, and typifies, the state of the world’s response to the omicron variant, the newest variant of concern (VOC).
Since experts in South Africa first detected its existence around November 12-20 in the country’s Gauteng province, its presence has also been reported from samples in Botswana, Hong Kong, Israel, Belgium, the Czech Republic, Italy, Germany, England, Austria and Australia.
At the time of writing this article, the omicron variant had been confirmed in 131 samples and was suspected in 1,057 others – in 13 countries worldwide. The list is surely bound to grow in the coming days. That the omicron variant has been reported from so many countries already says two important things: that the warning from South Africa about the variant’s existence is important and gives us a headstart, and that the variant has already spread to multiple countries.
Many countries have imposed travel bans on the affected countries as a knee-jerk reaction to what they understand to be an impending emergency. And many international health experts and agencies have criticised this move, perhaps rightly so: the virus has already spread, so travel bans may not achieve anything towards limiting the spread of the variant.
This said, many countries are struggling to devise an optimum response, and are swinging between inaction and overreaction.
Strains of the virus
Thousands of variants of the novel coronavirus are circulating across the world. This is nothing unusual. Most RNA viruses are expected to mutate all the time, to achieve their ‘best fit’. But the omicron variant has virologists in particular worried because it seems to be very different from the ‘original’ strain of the virus – the strain that the current COVID-19 vaccines were designed to fight.
The omicron has a long list of mutations, some 50 in all. Of these, 32 pertain to the virus’s spike protein – a vital part that the virus uses to gain entry into host cells, and which is also the target of most COVID-19 vaccines. Speculations are rife that this VOC may have an extraordinary ability to infect humans. The WHO has already said that the omicron variant seems to be spreading seven-times faster than the delta variant did.
As such, the situation on the ground wherever the omicron is present or could be is rapidly evolving. Omicron’s genetic profile has raised legitimate concerns – but at the same time there is a marked shortage of real-world data to make sure. As a result, nobody has the complete picture of what the omicron variant is and isn’t capable of. We don’t know the magnitude of the threat posed by omicron.
Then again, these are still early days. It is too soon for us to expect to know how much of a threat the variant poses. According to a WHO technical brief dated November 28, we don’t know how transmissible the omicron variant is in the real world, whether it can cause more severe disease, and how it might respond to naturally acquired or vaccine-induced immunity.
As such, we will need a few weeks, at least, to get a better sense of the omicron variant’s plans for the COVID-19 pandemic.
Evolution, lineage and key mutations
Some details about the omicron variant are available on the Nextstrain viral genome portal. It has the Pango lineage designation of B.1.1.529.
Interestingly, the omicron variant is not a descendant of any of the existing VOCs – alpha, beta, gamma or delta. Instead, it appears to have descended directly from the ‘original’ strain (B.1). Its closest evolutionary connection appeared in April 2020.
This extremely long branch – longer than one year – suggests that the omicron variant evolved over an extended period of circulation in countries with poor genomic surveillance or through continuous evolution in a chronically infected entity, such as an immunocompromised individual, before spilling back into the population.
According to the African Medical Association, the omicron variant has been present on the African continent for at least two months. Since then, it has changed its genetic form 45 times.
Based on a comparison of different omicron variant genomes, some epidemiologists have estimated that the virus emerged sometime around late September or early October 2021, which in turn suggests it might be spreading more slowly than it appears to have.
The more disturbing aspect of the omicron variant is its large number of mutations, 50 in all, with 30 relating to the spike protein. Of these 30, 15 pertain to the receptor-binding domain (RBD), a part of the spike area that is vital to begin its invasion of cells.
The spike protein mutations are also concentrated in a way that is expected to positively influence the variant’s immune escape and transmissibility. Omicron shares many key mutations with the alpha, beta, gamma and delta variants, of course, but has others as well – a (non-conclusive) sign that they were derived from an immunocompromised host with extensive in vivo evolution.
In the spike protein of the omicron variant, there is a striking accumulation of mutations in the S1 domain, which contains both the RBD and another important area called the N-terminal domain. Multiple mutations in these regions could help the virus resist neutralisation by vaccines and monoclonal antibodies.
Three substitutions in its genetic material could also make the virus a more elusive target for natural or vaccine-induced antibodies. In fact, the effect of this ‘triple mutation’ could be worse for convalescent sera than vaccine sera.
(Antibodies are present in the blood serum, and its plural is sera. ‘Convalescent’ effectively means ‘had COVID-19 and recovered’.)
Second, the combination of the substitutions K417N, S477N, Q489R and N501Y in the omicron variant’s genome is also thought to – but not definitively known to – be able to add to the virus’s ability to evade the immune system.
As this author explained in a previous article for The Wire Science, substitutions are one kind of mutation; the other is deletion. Substitution mutations can be corrected by a proofreading mechanism if there is one, and the novel coronavirus does have one.
Second, ‘K417N’ simply means the ‘K’ at position #417 has been substituted with an ‘N’.
Some in vitro studies have also found that the combination of spike protein mutations Q498R and N501Y could significantly increase the variant’s binding affinity to the ACE2 receptor.
Third, four new substitutions – Q339D, S371L, S373P and S375F – could present additional obstacles to certain antibodies. A cluster of substitutions near the spike’s furin cleavage site could enhance the virus’s ability to be transmitted through more efficient cell entry.
Fourth, the omicron variant has a few key deletions. As the author has written before, “The spike protein of the novel coronavirus has a total length of 1,273 amino acids, numbered from 1 to 1,273. Regions on this protein have specific residues – or slots – for different amino acids.” The omicron variant has deletions at the 69 and 70 residues, like the alpha variant also did, and could cause some assays and tests to deliver a ‘negative’ result instead of ‘positive’. This phenomenon – called S-gene target failure (SGTF) – could provide a useful proxy to determine the prevalence of this variant.
However, some PCR tests can also detect this deletion without the need for full-genome sequencing. In fact, this is one bit of good news that we do have: we can easily track the spread of the omicron variant – perhaps easier than we could track the delta – because of the SGTF, which creates a specific pattern in PCR test results.
Additionally, there is a three amino-acid deletion in the non-spike region of the virus. Scientists have observed this deletion in the alpha, beta, gamma and lambda (C.37) variants. And there has been some speculation that this deletion could help the virus with immune evasion, possibly by compromising cells’ ability to degrade viral components.
Next, there are two mutations in the non-spike nucleocapsid protein: R203K and G204R. Though these are ancestral, i.e. not new to this variant, they have been shown to be linked to increased sub-genomic RNA expression and higher viral loads.
This is why scientists have been saying the omicron variant has a spike protein that is ‘dramatically different’ from the one on which current COVID-19 vaccines are based. And the variant’s overall mutational profile suggests a potentially significant transmission advantage – something that we may be beginning to see in the real world, as the omicron overtakes the beta and delta variants in different populations.
Note at this point that it is hard to tell how infectious a virus is based on its mutations alone. The mere presence of several substitutions and/or deletions does not suffice to confer or subtract different attributes. We need to follow the trajectory of this variant over the next few months to be able to comment confidently on its transmission characteristics. All we can say now is that the omicron variant has all the mutations that we do know affect transmissibility.
Some experts believe that the exceptionally large number of mutations in the omicron variant could represent a large number of fixed mutations as well. A fixed mutation is one that the virus finds useful enough to continue to propagate. The extraordinarily large number of mutations in omicron suggests a prolonged period of incubation under some kind of immune attack and which probably wasn’t very effective.
Impact of mutations
In Gauteng province of South Africa, the omicron variant has been rapidly replacing the delta variant, which suggests a transmission advantage. According to Christian Althaus, a computational epidemiologist at the University of Bern, the omicron variant has an estimated growth advantage of 0.38-0.43 per day compared to delta – which translates to a transmissibility of 280% of that of the delta variant. Again, these are early estimates based on limited data.
Assuming the same generation time, the transmission advantage could act at two levels: higher transmissibility and better immune evasion.
If the transmission advantage acted via immune evasion only, there is a formula to estimate the level of immune evasion based on, among other things, the fraction of the population that has fully protective immunity against infection with previous VOCs. If we assumed this fraction to be 75%, the formula spits out the number of 93% – that is, the omicron variant would evade protective immunity in 93% of individuals.
Experts do expect partial immune evasion to be the main driver of the observed dynamics, but at the same time we don’t know enough to rule out increased transmissibility. Developments in South Africa and other countries in the coming days will hopefully allow us a clearer picture on this front.
This said, yet other experts have found such a high transmission rate improbable. Notably, there is some genetic diversity segregating in the omicron variant, with available genomes up to 10 mutations apart. To accumulate such diversity, the variant must have been circulating for at least two to three months. Yet modelling studies currently assume that the variant’s prevalence was ~0% three weeks ago, which seems incorrect. The disagreeing experts believe that there may have been substantial undetected transmission in a geographically isolated place for some months before its existence became apparent.
The omicron variant’s presence has already been picked up in several countries. If we find transmission increasing in these and other countries over the course of the next few weeks, it may be a confirmation of its exceptional transmissibility.
This said, we don’t understand the omicron variant’s actual threats. There is early evidence to suggest it presents a higher risk of reinfection compared to other highly transmissible variants. This means people who contracted COVID-19 and recovered could still catch it again.
And again, it will be weeks before we know if the current crop of COVID-19 vaccines will be similarly efficacious or less efficacious against it.
Prospect of milder disease
There has been some misguided speculation doing the rounds online, that an infection of the omicron variant will be “mild”. We may eventually discover this to be true or we may not – but the point is there is really not enough information to come to this conclusion at this point.
There is no immediate indication as to whether the omicron variant causes more severe disease. As with the other variants, some infected individuals have displayed no symptoms while some have displayed mild disease.
We must also be careful about throwing the term ‘mild’ around, especially when it relates to just the acute illness. Hospitalisation is still rising in the hardest hit omicron-dominant provinces in South Africa. In addition, observations from clinicians on the ground are always important, but we also need to be cautious about jumping on early reports that say ‘all cases with this variant are mild’.
Taken together with the time lag for infections to progress to severe disease and hospitalisation, we should only expect to see the omicron variant’s impact on hospitalisation in the next few weeks. Most of the early spread was among younger people, with outbreaks in universities likely amplifying the spread.
We know that getting a rapid sense of disease severity with the omicron variant – particularly in vaccinated individuals and with the prospect of reinfections – is critical, but it is just too early for any of the extant data to be sufficient or reliable. The WHO’s most recent updates have said experts don’t yet know if the omicron variant is more transmissible or if it could cause more severe disease. There is also little information to suggest that the symptoms it induces are different.
As things stand, there are a lot of unknowns – which is, among other things, a reflection of how quickly scientists in South Africa detected and announced the B.1.1.529’s presence and sequenced its genome. Even though some of the genetic changes appear worrisome, we don’t know enough to be able to say if the variant will render the pandemic worse.
Some previous variants, especially the beta, initially concerned scientists but didn’t spread too much. Perhaps more importantly, the vaccination coverage in some parts of the world has increased by leaps and bounds, and in some others moderately so, since what it was when the delta variant first surged.
We also have two antiviral drugs, paxlovid and molnupiravir, that we didn’t have in the first half of this year (although there have been some doubts of late about the latter). Independent experts told this author that, thus far, there has been no suggestion that the omicron variant’s mutations could blunt their efficacy.
Finally, many “scariants” have come and gone. We will have a much better idea about the actual risks of the omicron variant in two or three weeks, and until then, we need to stay calm. Even if the omicron variant can better evade vaccine- or infection-induced immunity, it’s not like the world will be reset to March 2020. Infections have been rampant and people have been vaccinated – and both will help prevent disease should omicron really take off.
Dr Vipin Vashishtha, MD, FIAP, is a consultant paediatrician at the Mangla Hospital and Research Centre, Bijnor.