• Alex Cloherty

Introducing Omicron

Last week, on Tuesday, 23rd November 2021, a new SARS-CoV-2 variant with 32 mutations in its spike protein was detected and reported in South Africa. From there, things moved fast. By 24th November, this new variant was designated as "B.1.1.529", and by 26th November the World Health Organization (WHO) had re-classified the mutated strain as a variant of concern and named it "Omicron". Within a day, South African travelers found that the doors were closed for them to travel into countries like the UK, France, and Singapore. And as of today, November 29th, it has been announced that Omicron cases were detected in the Netherlands and Scotland.

So, what is the deal with Omicron? How worried should we be?

Before we get going, I would like to start with one important note: this is science in real-time. We have had very little time to understand the potential impact of this latest variant of concern, so this article should be treated as an honest first and early attempt to estimate how worried we should be about Omicron, based on less than a week's worth of evidence. Having said that, we do have some important clues already. To create this article, I teamed up with my super-smart boyfriend Robert Englmeier, a structural biologist who created all of the images that you'll see in this post and helped with the background research to make this turn-around as quick and as accurate as possible. Now, with that said, let's dive in.

Omicron has a lot of mutations - about fifty as far as we know as of today - which is what a lot of the concern about this variant comes down to. These mutations refer to differences in the structure of Omicron versus the 'wild-type' SARS-COV-2 strain - the one that was originally detected in Wuhan, China back in early 2020. Mutations are normal, and to be expected. In fact, mutations happen all the time, in everything from viruses and bacteria to humans and moths, and in a totally random way. Any living thing on the face of the earth can mutate at any moment, and it is a total throw of the dice in terms of whether that mutation might benefit the living being in question, be detrimental, or have no effect at all.

Where it gets interesting, is that when mutations are helpful to that virus, moth, or human, they might be passed on to progeny - that mutating living thing's kids. This is not because helpful mutations are any more likely to be passed on to a kid than unhelpful mutations, but rather because if a mutation is helpful, it might help the 'parent' to survive. For instance, at some point one of our ancestors ended up with a mutation that gave him or her some pretty cool, top of the line, never-before-seen opposable thumbs. Those handy digits gave that ancestor a clear advantage in dexterity - s/he was better able to grip tools, for example - and that likely helped him or her survive in a nasty and brutish world. And the longer you survive, the more likely you are to have kids. Lots of kids. And if those kids are lucky, they'll inherit that helpful mutation from mama or papa, and also have lots of their own particularly dextrous kids. As a result, all of us humans around today are probably descended from that one particularly dextrous ancestor.

Mutations work in a similar way for viruses. If a mutation helps one virus survive in its battle against our immune system, it is more likely to successfully brew up some virus babies. In a population of viruses, the ones with beneficial mutations will become more and more common - simply because they are more likely to both 'survive' and to replicate (i.e. have virus babies). This is exactly what we have seen with the Delta variant of concern, which had mutations that made it more transmissible, or better able to jump from person to person. In April 2021 it was a novel variant (a version of the virus) first detected in India, but largely absent across the rest of the world. By July 2021, it was the major variant across most of Europe, thanks to the mutations which gave it the competitive edge. Luckily, our vaccines were still effective against the Delta variant (also known as B.1.617.2), else the world may have been more or less right back at where we started in 2020 - in full lockdown due to a deadly respiratory virus for which we had no effective vaccine.

But let's get back to the present, and to Omicron. Will this play out as with Delta?

As I mentioned before, Omicron has an impressive amount of mutations, and 32 of those are in its Spike Protein, the 'hand' that the virus uses to grab onto and get into your cells. The SARS-CoV-2 spike protein specifically grabs onto another protein on the surface of the cells that it infects, which is called ACE2. Put simply, the virus basically has to grab on to ACE2 in order to get inside your cells and start off on its hijacking business. ACE2 acts as a really fancy doorknob that the virus must grasp and turn to get into the interior of your cells.

Because of how important the spike protein is in the early stages of SARS-CoV-2 infection, and the fact that it decorates the surface of the virus and is thereby fully in view for the immune system, it's a common target for both vaccines and other therapeutics against SARS-CoV-2. As shown in this handy infographic, the mRNA vaccines work by providing your immune system with a blueprint for the SARS-CoV-2 spike protein. Your body can then translate this blueprint into an actual version of the spike protein, which on its own is pretty harmless, but very useful. This spike protein that is produced by the blueprint provided by the vaccine acts as a wanted poster: it gives your immune system the briefing it needs to attack anything that has a similar spike protein.

Ah but there's the rub. A similar spike protein. If the spike protein changes enough, by gathering enough mutations, your immune system will no longer be able to jump into action as well. If a criminal changes his or her appearance after a wanted poster is sent out, they are less likely to be detected. The same goes for SARS-CoV-2.

So now, let's get into the data. Is the Omicron spike protein similar enough to the wild-type (the original SARS-CoV-2 that our current vaccines are designed to protect against) spike protein, that the vaccines, and other therapeutics, might still work?

The image below was created by Robert Englmeier to show you exactly what the spike protein looks like. It is made up of three identical parts (scientists would refer to this as a 'trimer' - a protein made up of three individual but identical 'monomers'), shown here in pale purple, blue, and pink. In yellow, you can see a model of ACE2: that doorknob-like protein on your cells that SARS-CoV-2 must turn to enter and infect. The magenta area is the region of the spike protein that is particularly important for attaching to SARS-CoV-2, and thereby arguably the most important part of the spike protein to mess with in order to protect ourselves from infection. Indeed, that region is the focus for therapeutics. And if you take a look at the bright green dots all over the spike protein, which represent the points at which Omicron or Delta respectively have mutations in comparison to the wild-type SARS-CoV-2 strain, you can clearly see that they cluster in this key area. When the WHO reported, "This variant has a large number of mutations, some of which are concerning," these green dots in the magenta region are the concerning mutations that they are talking about.

Structural models of the Delta and Omicron spike proteins (based on data presented here for Delta and here for Omicron), shown together with ACE2.

Copyright Robert Englmeier, 2021.

On its own, this is not definitive evidence that we are in big doo-doo - so far, there is no hard evidence, i.e. no conclusive laboratory studies - that definitively say that vaccines will be less effective, or that therapeutics like Regeneron (the antibody cocktail that Donald Trump famously received) will not work as well. However, the sheer amount of changes in the structure of the Omicron SARS-CoV-2 spike protein does indeed suggest that there is some potential for us to be in a spot of trouble.

As an example, let's take a look at Regeneron. This treatment comprises a so-called 'cocktail' of antibodies - a mix of two different antibodies, named with the super catchy and memory monikers "REGN10933" and "REGN10987", that can each grab onto and block the action of a different part of the spike protein. As you can see in the image below, where these two antibodies are shown in different shades of blue, they both bind the receptor binding region of the spike protein (magenta). This means that they can block the virus from interacting with ACE2, kind of meeting the outstretched hand of the virus with a handshake to prevent if from grasping the doorknob on your cells, thus blocking infection.

Structural models of the Omicron spike protein, shown together with Regeneron antibodies. Copyright Robert Englmeier, 2021.

And indeed, as you can see, there are mutations in the regions that these antibodies bind, meaning that they may not bind Omicron as tightly as they bound the wild-type SARS-CoV-2 spike protein. In particular, in the most zoomed-in region on the right-hand side of the image above, you can see that there are especially many mutations in the region that the REGN10933 antibody binds to, which definitely has the possibility to mess with its ability to bind and block the spike protein. In the case of REGN10987, though, there are far fewer mutations in its binding site, suggesting that this antibody may still be pretty effective. In other words, depending on the exact parts of the spike protein to which antibodies that are either induced by vaccination or delivered therapeutically post-infection bind, there may or may not be a reduction in that antibody's effectiveness in neutralizing Omicron. But again, I would like to stress that this is an educated guess, and laboratory evidence will be needed to prove this.

So what does this all mean for you, in a more practical sense?

Firstly, this is only a prediction, that Omicron could indeed be slightly less 'susceptible' to our current vaccines and therapeutics. If this is proven to be the case, then I can assure you that scientists around the world - including the team at the Autophagy-directed Immunity group that I'm part of - will be working hard to come up with new and improved ways to stop the latest version of the virus. And my guess is that booster shots will then be fast-tracked, in order to give you the best possible protection against emerging SARS-CoV-2 variants. Perhaps companies will also be updating their existing vaccines to approximate a better 'wanted' poster for the new variants.

Secondly, the vaccines do still help. As mutated as Omicron might be, it's not going to take us back to square one, or back to March 2020. For instance, the latest information out of South Africa indicates that vaccinated people still only experience mild to moderate symptoms upon Omicron infection. As with all the other SARS-CoV-2 variants to date, you're more likely to be in real trouble if you are unvaccinated. If you are unvaccinated, not only will your immune system not be able to best protect you against the virus - because you've given it no wanted poster - but with each new variant there is an increasing possibility that other therapeutics like Regeneron may not be able to help you quite as well either, if you end up on life support in the hospital. Having said that, these therapeutics will likely still retain some efficacy - after all, most of these therapeutics are modeled off of the wild type SARS-CoV-2 spike protein, just like the vaccines. But in the end, vaccines are undeniably the best option and more effective protection than post-infection therapeutics - just look at the ICU data on deaths in vaccinated versus unvaccinated people across the world.

And thirdly, I want to end with a note on vaccination. In the last months, as countries have steadily returned to lockdowns, I have heard the following sentiment several times: "What is the point of getting vaccinated? I got it so that I could return to my normal life again. Now I'm asking, was there even a point, if the vaccines might start to work less well?" I would argue, yes. Aside from the fact that vaccination consistently protects against negative SARS-CoV-2 side effects like death, even against variants of concern that differ from the wild-type strain that the vaccines were originally made to protect against, if you've been vaccinated you've done the socially responsible thing.

Variants like Omicron are most likely to arise when there is pressure for them to mutate in a specific way: when they have something to gain by mutating. And to put it simply, having a population in which a small, but considerable amount of people are unvaccinated is a great way to keep the virus circulating at a relatively high level in the population, and give the virus more opportunities to mutate. Even with a mutating virus, if everybody were vaccinated, sure, some people might indeed still get infected, and experience mild or even moderate symptoms - but fewer would die. And at the moment, over-full intensive care units are the main thing that we're trying to avoid, and the main reason that we are entering back into lockdowns. Viral infections on their own are not necessarily a problem. We don't lock down every winter due to the common cold. It is severe viral infections, like those that we now see primarily in the unvaccinated population, that are the problem, not only because we want to protect people from severe effects of the viral infection, but also because we have limited hospital capacities that must also be available to treat people with any other health concern. The main goal of the current lockdowns is to avoid a situation in which ICUs fill up with severe COVID cases (which, again, are primarily seen in the unvaccinated population) to the point that, again, surgeries, cancer treatments, and treatment of other non-COVID issues must be delayed.

Personally, I think of our current lockdown situation like this: remember back when you were in school, one person in the classroom would do something dumb, and then the whole class would have to pay for it, even if everybody else were behaving? And even if you explained that you'd done everything right, you were still punished for the antisocial actions of your classmate? I guess you can see where I'm going with this. Getting vaccinated is still the way to go. If you've been vaccinated, you've done the right thing, and it's not your fault that other people haven't gotten vaccinated even if you are paying a price for their actions.

Ok, let's get to some more hopeful information now. To finish, there is no evidence that the existing vaccines will suddenly lose their efficacy against Omicron. Vaccines work. Secondly, there are more and more available therapeutics - like Paxlovid, Bamlanivimab, and Molnupiravir - that taken together, will with any luck lighten the load and reduce mortality in ICUs. I also have hope that host-directed therapeutics - therapies that boost your immune response to the virus rather than targeting the virus itself, and thereby are less likely to be rendered less effective as the virus mutates - can help us combat this virus. And if you've been vaccinated, you can rest assured that you've taken the best action in your power to put this pandemic to end.

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