A long time ago, I told you that as SARS-COV-2 mutates to escape the vaccine induced immune response, we would see it rapidly begin to pile on more Spike mutations.
The spike protein has dramatically changed its appearance, so most antibodies that neutralized Delta, don’t neutralize Omicron. Protection is now dependent on a greatly diminished number of antibodies that continue to neutralize the virus. This also means that any individual single mutation to a single codon can now offer the virus a much greater advantage than before.
And that’s what’s now starting to happen. Take a look at this example:
Because BA.2.75 evades so many antibodies, there’s a massive relative advantage to be had from evading the few that still work. And because its ACE2 affinity has jumped up relative to previous variants, it can easily afford to incorporate some new antibody evading mutations that have reduced ACE2 affinity as a trade-off.
Of course the advantage is mainly to be had in those parts of the world where trained innate immunity has lagged behind (see: here and here), where people’s immune systems deal with this virus by focusing on neutralizing antibodies against the Spike protein. And so we see variants like this, that take the BA.2.75 frame and pile on extra Spike mutations, in places like Chile, England, Singapore, Spain and Germany, despite almost all BA.2.75 cases showing up in India.
There is an evolutionary arms race going on, between the population’s innate immunity that is being trained through repeated infections and the increasing capacity of the virus to evade our innate immunity. At some point however it becomes harder to get better at evading innate immunity, which makes avoiding our neutralizing antibodies the more straightforward next step. With the emergence of BA.2 descendants like BA.2.75, that now seems to be where we’re headed. In 2020 or early 2021, a variant like this, that piles on three new Spike mutations, would have been big news. But by now, changes are happening so rapidly that hardly anyone pays attention to it.
As I’ve also explained before, the first Omicron variants were pretty mild. There’s a reason for that. This variant did not evolve directly to evade human antibodies. Rather, its changes are mainly the result of jumping into another species (probably a rodent) with a different ACE2 receptor. Those changes then had the pleiotropic benefit of also evading antibodies in humans, thus giving this variant a big transmission advantage once it popped up in our species again.
However, there would have also been changes it underwent in its animal host, that don’t give it an advantage in humans. Those changes would play a role in the variant having a milder disease course (besides of course the fact that it infected a lot of people who had already been infected by previous variants). In BA.5 you see those changes turned back: L452R and R493Q are mutations in BA.5 that go back to previous pre-Omicron variants. In other words, the birth of Omicron was more a breathing pause than the end of the pandemic.
This is what I warned about half a year ago, when I wrote:
Let’s start with what we know. We don’t really know how this thing came into existence. It could have been an HIV patient, but right now the more likely explanation is that it emerged in mice. That’s what Geert van den Bossche has been warning about for a while now, that it could jump into another animal, change to fit that animal and then jump back into humans.
If this is what happened, that means it had to evolve to bind to a mouse ACE2 receptor, which looks different from a human ACE2 receptor. In that case, the evasion of most human antibodies is primarily a side-effect of the fact that it had to change its Spike protein to fit a different looking ACE2 receptor.
If this is what happened, it’s a far worse scenario than the originally proposed scenario, of an infection in an HIV patient. The reason is because it means some of the changes it inherited from its time in mice that it still has right now are probably detrimental to its adaptation to humans. That may explain why it looks milder. That also means it’s probably going to lose those changes and become more severe in the coming weeks, as it continues to evolve.
And so we’re essentially back to square one now, with new Omicron variants that are just as nasty as the pre-Omicron variants, but now constantly infecting vast swathes of the population instead of a small fraction. When you look at the excess mortality we’re dealing with here in Europe, this becomes immediately apparent. Excess mortality is higher in Europe so far than it was in 2020 and 2021 at this point in time.
The question worth asking is: Why is this virus so nasty? Why doesn’t it just behave like a common cold virus? The answer to that question mostly seems to come down to that massive change in its genome that sets it apart from all of its close relatives: The furin cleavage site. Experimental loss of this furin cleavage site attenuates the disease, but it won’t lose the furin cleavage site, as any variant that loses it also incurs a massive hit to its transmission ability.
Unfortunately, as I’ve also noted a few times, the general pattern is that it continues to adapt to preferentially replicate in the bodies of those people who ended up with a very similar immune response based on neutralizing antibodies against the Wuhan spike protein:
I’m sure you can think of some blogs that have pointed out that BA.5 really overwhelmingly tends to affect the vaccinated. Well, with everything we know we can expect that this pattern will just get worse for the foreseeable future.
Take a look at this chart I made, with the number of spike mutations compared to Wuhan of recent variants:
Alpha – 9
Delta – 7
BA.1 – 34
BA.2 – 28
BA.5 – 30
BA.2.75 – 36
And now with this subvariant, you arrive at 39. And you can expect it’s not just a random fluke that goes nowhere, as it has already shown up in six different countries.
As the number of spike mutations increases, you can expect the efficacy of these vaccines to decline further below zero.
We weren’t supposed to reach this point. In fact, a lot of the people involved in manufacturing these vaccines seem to have mistakenly assumed it couldn’t really evolve much further, that it would quite rapidly run into an evolutionary dead end.
Take a look at this study to see an example. You can see the sort of thinking that goes on here: “Twenty spike mutations? Ha, like that’s ever going to happen!” And then a few months later it happened.
But here’s someone who really was dumb enough to say the quiet part out loud:
They never really properly considered how the virus would evolve after their mass vaccination campaign. They just seem to have assumed they would luck out, that it didn’t really have a lot of evolutionary pathways left to it. This is not a trivial question he’s giving the wrong answer to here.
Of course they were wrong. And the consequences are there for you to see: 2022 has been the deadliest year of the pandemic so far in Europe, cumulative excess mortality so far is higher right now than it was in the previous two years. The Omicron era is an extension of the pandemic, caused by mass vaccination:
There’s a concern to be had that the vaccines themselves damage our immune function, but this is more hypothetical. The Wuhan spike protein contains a superantigen motif (now hopefully gone in the Omicron variants) and the Spike protein is directly toxic to hematopoietic progenitor cells. Rather, what it looks like to me is that the escalating misery we’re seeing, a misery so bad that even mainstream media and governments are now beginning to acknowledge it, is caused by how we stupidly interfered with the evolutionary dynamics of this pandemic.
The reason this virus doesn’t run into an evolutionary dead end is because it’s not just dependent on human genetic variation. As long as we infect other animal species, with other receptors that it can bind to, it gets opportunities to come up with different versions of itself, some of which can then jump into other species, including our species.
With every new version that shows up in our species, there are likely to be some new non-human species that are now susceptible to infection that weren’t susceptible before. And those species, because they will have their own unique version of the ACE2 receptor, will be able to bring into existence variants that had no fitness benefit before. And some of those species can then serve as intermediate steps, towards infection of yet other species that human variants can’t directly infect themselves.
So does that mean the pandemic lasts forever? Not necessarily. Trained immunity increases over time, at least we know it does in those who have not received these vaccines. This makes it more difficult over time for this virus to cause new waves in our population. And of course, every jump requires an infected individual to come into contact with a potential host. If the flame just never meets the keg, it won’t get the chance to give rise to yet another version of itself.
However, what it does mean is that we’re now more than half a year into a prolongation of this pandemic, caused by the administration of vaccines that increase our susceptibility to new variants. This constant mass infection with all sorts of Omicron variants in turn is damaging our immune systems, making us vulnerable to further variants, as well as other pathogens, like monkeypox.
And for this winter, this means we’re going to get another wave from a variant with the BA.2.75 framework, with whatever additional Spike mutations piled on that it needs to avoid the neutralizing antibodies induced by the vaccines. The reason BA.2.75 hasn’t caused a wave yet, is because it shows up in the sort of conditions produced by BA.5. BA.5 in turn, made use of the sort of conditions produced by BA.1 infection in vaccinated individuals.
The mistake many people make is to look at the fact that a new immune response is still produced in vaccinated individuals and to conclude in response that the problems created by this mass vaccination campaign will just resolve themselves. Humanity is in a race with this virus: Our immune systems try to shut down transmission, thereby prohibiting the virus from giving rise to new variants of itself.
If we delay that whole process of shutting down these waves by a year, because our original immune response was wrong, that means the virus has had more time to give rise to new variants and our immune systems have had to deal with more cumulative damage.
Similarly, the apparent success that countries like Taiwan, Australia and New Zealand have had in keeping this virus out for a long time, means they will inevitably take longer to build up the trained immunity necessary to stop transmission. You can see the consequences this has in Scandinavia too, where excess mortality has continued to climb during the past half year in all the countries that kept transmission low before the vaccination campaign, but not in Sweden:
Finland in particular has gone from no excess mortality, to the same excess mortality as Sweden in the course of a year.
It’s nice when geographic isolation keeps pathogens outside of particular regions of the world. As an example, the Americas benefited from the lack of pathogens like malaria and smallpox until Columbus discovered the Americas. On the other hand, when countries use their geographic isolation to keep out a virus for about a year, that just means they delay the point at which they build up sufficient immunity to end the waves, thereby also delaying the point at which the virus can no longer give rise to new versions of itself.
And so in conclusion, I want to take a look at this graph I made a while ago, a true artistic beauty:
I think this is generally still correct. What do I mean with catastrophe? At the time I made the graph, I meant a wave of excess mortality far beyond anything we’ve seen so far. I still expect that’s what’s in store for us this coming winter. We’re constantly getting hit by wave after wave, of Omicron variants that are progressively getting nastier. BA.2 was nastier than BA.1, BA.5 is now nastier than BA.2 and the BA.2.75 descendants promise to be even worse in highly vaccinated populations.
I don’t know exactly how this will look. It could be we get the long prophesied ADE doomsday variant, which is what I originally anticipated. What I didn’t sufficiently consider at the time was the intermediate variants towards complete escape from the Wuhan spike vaccine would induce some degree of immunity in the population.
However, I’m also worried about just a further exacerbation of what we already have: Constant unprecedented massive waves of Omicron infections that damage blood vessels and T cells, leading to the excess mortality that we currently witness. Take a look at Edinburgh, to see what I mean:
If you think BA.5 is somehow intrinsically 80% less damaging than Alpha was (it’s not, but let’s play along), the most recent BA.5 wave was still big enough to be more damaging to people’s health than the Alpha wave in early 2021. It’s not good to have these constant waves of mass infection in the middle of summer, especially as the Omicron variants are steadily becoming as virulent as the pre-Omicron variants again.