The Omicron Variant: a summary of what we know so far (with a focus on what we don’t)
A labeled Omicron spike protein showing all the different amino acid changes in the spike protein. Changes with documented phenotypic effects from literature are colored light orange or cyan for insertions/deletions while others without documented phenotypic effects are colored in green. Via GISAID.
Headlines are awash with doomsday prophecies about the Omicron variant, and the panic has far outpaced the data we have, so I thought it might be useful to give a quick update of what we currently know and what we do not. Everything stated here is current as of the publicly available data on the morning of 11/30/2021 on the eastern seaboard of the US.
In November 2021, a sequence of a SARS-CoV-2 genome was uploaded by a team of scientists in Botswana showing a variant that was then called B.1.1.529 under the Pango lineage nomenclature or 21K under the Nextstrain clade. It was subsequently detected in South Africa and Hong Kong, at the time linked to travel to Southern African countries. The WHO’s Technical Advisory Group on SARS-CoV-2 Virus Evolution (TAG-VE) subsequently met after being alerted to the sequence by South African scientists on November 24, 2021 to discuss the variant and the preliminary data emerging from South Africa showing a concerning rise in cases (which were previously at a very low level). The WHO then declared it a variant of concern (VOC) on November 26, 2021 that was to be called Omicron. This skipped the letters Nu (which is actually pronounced “nee” I am told by native Greek speakers, but was avoided because it is too easily confused with “new variant”) and Xi (which was avoided because it is a common surname in some countries).
The fact that the WHO immediately declared it a VOC was a gesture to member states to take the potential threat of Omicron seriously- but why is Omicron such a threat if it’s such a small number of sequences globally right now? Whenever any new variant emerges, there are 3 key questions to ask:
How well does it spread (especially compared to other variants)?
Does it exhibit resistance to our medical countermeasures or show an increased risk of reinfection?
How severe is disease due to the variant?
The answer to most of these for Omicron is “we don’t know yet.” But there are some properties that are cause for concern. The WHO reports that this variant has already shown a heightened risk of reinfection in South Africa compared with other variants, and examination of its genome shows mutations associated with strong evasion of antibodies, better evasion of innate immunity, enhanced transmission (but also reduced transmission). Because of the number and location of the genetic changes in the spike protein, Omicron is expected to be extremely resistant to antibodies elicited by infection from other variants and vaccination, as well as monoclonal antibodies (though those data are not yet available and need to be confirmed). Though this spike protein does show a lot of changes which are concerning for escape from antibodies individually, there is a key point here: some mutations may counteract each other while others may have synergistic effects. There isn’t a simple way to know without explicitly testing the virus to see what properties it has.
Professor Trevor Bedford has an excellent thread on Twitter describing the probable properties of Omicron in terms of transmission and antibody evasion and I think this figure in particular is instructive (though as an aside, I don’t agree with the placement of Mu in this plot because live virus neutralization studies have shown far less dramatic results than some pseudovirus experiments which also had unusual findings when comparing vaccinee serum vs convalescent serum, but I digress):
This was a slide shared by South Africa’s CDC in a presentation here.
Still, in general, the transmissibility of a variant is more important than its ability to evade antibodies, as we have seen by watching the trajectory of Beta and Delta variants throughout the world (Beta has extremely strong capacity to evade antibodies while Delta doesn’t, and yet Delta successfully displaced Beta in regions where Beta was previously dominant). Of course, there’s no real rule that says you can’t get both strong antibody evasion and high transmissibility, and that represents a very troubling scenario. We don’t know yet if Omicron represents such a case, and as Prof. Bedford explains in the thread, it’s likely that Omicron is not inherently more transmissible than Delta or many other variants but may have an advantage over them in regions where there is a high prevalence of either infection or vaccination because it (likely) can evade antibodies much more effectively. We do also have a critical study that is instructive for expectations for omicron in which antibodies from recovered patients, vaccinated patients, and recovered patients who were vaccinated after recovering were tested against pseudoviruses bearing amino acid changes that had been identified in circulating variants. Eventually a polymutant spike protein (PMS) incorporating about 20 of these mutations was engineered (similar in nature to Omicron). This spike protein was able to escape neutralization completely from both vaccinated and recovered patients’ antibodies- but not those patients who had been infected and were also vaccinated (a point I will return to later). This spike protein did also have more difficulty facilitating infection into cells compared with less mutated spike proteins. This largely supports Prof. Bedford’s predictions (and at this point they are still all just predictions).
Via Genomic surveillance of SARS-CoV-2 in Belgium Report of the National Reference Laboratory (UZ Leuven & KU Leuven) Situation update – 26 of November 2021
B.1.1.529 = Omicron, the red one
Regarding transmissibility, there has been a significant rise in cases and hospitalizations in South Africa after a period where cases were about as low as they had ever been. This, however, complicates the analysis because it makes it really hard to tell whether Omicron has significant transmission advantages over other variants. Sequencing of Omicron however is subject to a pleasant quirk that we also saw with the alpha variant: the S gene does not amplify on the TaqPath COVID-19 PCR (but other genes do) allowing for more rapid readouts because sequences in which this S-gene target failure occurs likely correspond to Omicron. However, this still needs to be confirmed with whole genome sequencing because some isolates of the Delta variant also have this property and a suspected case in Belgium turned out to have the Delta variant on whole genome sequencing (though the other case was Omicron). Because so many cases have been identified (relatively speaking) in South Africa, some countries in response to the threat have enacted travel bans. These travel bans have been essentially universally criticized by infectious disease experts as being political in nature and not evidence-based and furthermore looking at the list of countries included, it’s hard not to call them racist. After all, while most of the cases so far do seem to have a travel history to Southern Africa, the case identified in Belgium had no history of travel, as has a recently identified case in Germany. Furthermore, recently Omicron showed up in sequencing from the Netherlands in the week before it was discovered. The US has not yet found any confirmed Omicron cases, but that doesn’t say much given what our genomic surveillance is like (you can view where cases have been identified via this map on GISAID). In truth, Omicron is likely widespread throughout the world at low levels right now, which means travel bans are not accomplishing what they are intended to, setting aside the fact that they frankly, look racist. Also given that this is likely the case, it doesn’t need to be a headline each time someone finds an Omicron sequence in another country. Furthermore, the travel bans are causing devastating economic consequences for the affected countries, and that has serious issues for all of us. Tulio de Oliveira is a leader in South Africa’s genomic surveillance efforts and notes that they are running low on the reagents they need to run tests on Omicron to determine the scope of the problem this variant poses:
Image via Trevor A Branch on twitter: https://twitter.com/TrevorABranch/status/1465200215275704325?s=20
de Oliveira has also stated that he will not accept chartered planes carrying those reagents because of how devastating the travel ban is to the South African economy. I do not blame him- we are well past the point that a travel ban would be effective, there are other more effective measures that we can take, and right now South Africa needs economic support from the world as it strives to uncover critically important information about Omicron. As for some productive suggestions on measures we can take instead of travel bans, I think Dr. Angela Rasmussen (virologist) summarized it very well:
All of these measures would be far more effective and far more appropriate responses to the potential threat of Omicron.
Another key question about Omicron is the severity of disease caused by it, and I want to state this very explicitly: it is too early to know about this. There are accounts from South African physicians reporting that cases seemingly caused by the variant appear to be milder in nature and that cases are concentrated among the unvaccinated which is potentially reassuring as an indicator of vaccine effectiveness (though of course, a minority of the South African population is vaccinated), but there are a lot of problems here with assuming that Omicron causes mild (or at least milder) disease than other variants. For one thing, it is quite literally too early for most people to have developed severe disease from COVID-19 because that phenomenon occurs mainly in the second week of illness… and it literally has not been that long. The other issue is that the median age of South Africa is 28, and severe COVID-19 is overwhelmingly a phenomenon in the elderly. Having said that, there might be cause for optimism in one indicator: wastewater surveillance shows levels of viral RNA at levels similar to those during the peak of the Delta surge in South Africa- but cases and hospitalizations are far lower. Of course, this could mean that the wastewater is just an advance indicator of what is to come, which is a more disquieting thought.
Omicron doesn’t have to be doomsday
So, having told you all the bad stuff, let me tell you now quite explicitly and in no uncertain terms: we are not in the same position with Omicron as we were in March 2020 even if it completely escapes neutralizing antibodies. Firstly, while I don’t think it’s unlikely that 2 doses of mRNA vaccine are not enough to neutralize Omicron, it’s likely that 3 doses will be. A third dose of mRNA vaccine boosted neutralizing antibody levels to a point past what recovered and then vaccinated patients had, whom we know from studies on the polymutant spike protein generated in a lab were still able to neutralize virus. This means that booster doses might be a good idea to buy time and the CDC, in recognition of the threat of Omicron, has expanded its recommendation for boosters to include all adults. Furthermore, whenever it comes to protection from vaccines we have to ask: against what? Though we see that protection against infection and milder forms of the disease declines over time with our vaccines, in the majority of people, protection against severe disease is far more robust. This is likely attributable to T cells. Patients with B cell deficiencies who have intact T cells do recover from COVID-19 as discussed in this video by Dr. Shane Crotty. Additionally, we have data showing that in mice which are depleted of (most of) their B cells that develop COVID-19, T cells are sufficient to control the infection, though it does take longer. Similar findings have occurred with macaques. Similarly, it is much harder to escape T cell protection than antibody-mediated protection:
The epitope coverage of B cells tends to be concentrated at parts of the spike protein that are important in binding to ACE2 (and those that are not shielded by sugars it picks up from infecting our cells). T cells do not have such a restriction and can target almost the entire spike protein as a result. Source: https://www.medrxiv.org/content/10.1101/2021.07.01.21259833v1.full.pdf
Some have reasonably wondered whether or not it might make sense to wait for an Omicron-specific booster vaccine (should it be needed) as multiple vaccine manufacturers have begun working on it (BioNTech has estimated it could get one out in about 100 days). While this concern is reasonable, I think it would be riskier to do that instead of getting a third dose with the ancestral spike protein-based vaccine as soon as possible (beyond the fact that given what the situation is with Delta across the world, that’s probably warranted anyway). The reason is that a lot can happen in 100 days and the antibody response with each additional dose gets significantly broader and better at neutralizing more unrelated coronaviruses. Because Omicron still (presumably) uses ACE2 to get into cells, at least some of the antibodies we make against the receptor-binding domain of the spike protein should cross-react with it (even if a neutralization assay cannot detect them because of their rarity). A booster dose will enrich the B cells that make such crossreactive antibodies and give you even more memory cells that are ready to evolve and protect you should you encounter Omicron. Indeed, maybe a third dose of the same is all that’s needed for Omicron- it’s too early to know.
Beyond this, there are also more monoclonals forthcoming and antivirals. Additionally, our diagnostic tests should continue to work on the Omicron variant because they mostly focus on the N gene which is not nearly as mutated. We also have a much stronger understanding of how this virus spreads than we did in the beginning of 2020 which means we can take measures against it there too. Omicron’s prevalence right now is still very low- which means that there is a lot of opportunity here to be proactive and get it under control before it becomes a big problem. That starts with strengthening the same precautions we have been taking throughout the pandemic and giving support to vaccine equity and the global South as they work tirelessly to give the world the critical information that it needs to be able to combat this serious threat.
