What you see with the highly pathogenic influenza viruses we humans produce in our factory farms, where we put sickly deformed chickens together in cages so that the viruses have no need to keep their host alive, is that they end up with a big polybasic Furin cleavage site. That’s part of what makes them so deadly.
All human cells produce small amounts of Furin, so it makes it easy for viruses to get their proteins produced for them when they have a site where Furin binds. This allows these influenza viruses to infect many more cell types than they otherwise could, thereby making them deadlier than the regular influenza normally transmitted by wild migratory birds.
What does such a Furin cleavage site look like? Six or seven Arginines and Lysines:
Furin is ubiquitously expressed in the Golgi apparatus of all cells,5 but generally only at low levels. Furin has a well known role in viral pathogenesis and efficiently cleaves polybasic or multi-basic sites such as those found in influenza virus subtypes H5 and H7. These highly pathogenic avian influenza viruses have therefore served as a model for the role of furin cleavage as a viral virulence factor. Mechanistically, this furin site is created through polymerase slippage during replication and occurs at the interface of the HA1 and HA2 subdomains. Such polybasic sites typically exist as a stretch of 6–7 arginine and lysine residues (eg, RKKRKR|G) that can be efficiently cleaved by furin, thereby allowing systemic spread based on the ubiquitous expression of the protease.6 Without the polybasic cleavage site, infection is restricted on the basis of the localised presence of the trypsin-like proteases activating low pathogenicity influenza viruses. Other influenza viruses (such as H9) modulate the cleavage site sequence through mutation and recombination.
As most people now know, SARS2 has a mysterious Furin cleavage site, that the other viruses in its family don’t have. Many people see this as evidence it came from a lab, but I think there is better evidence for that assertion than the Furin cleavage site.
Either way, what some of you will know is that the SARS2 Furin cleavage site is unusual. Not just for the nucleotides it uses to arrive at Arginine, but also for its unorthodox structure. There are much better ways to make a Furin cleavage site. But with the new BA.2.86 variant, it’s now rapidly improving its Furin cleavage site.
The first improvement to its Furin cleavage site was P681R, which helped make the Delta variant so deadly. It turns a Proline into an Arginine, giving it more Arginines next to each other, making it better at attracting Furin to do its job for it. Omicron lost this improvement, but now the new BA.2.86 has that improvement again.
But now it’s improving the Furin cleavage site even further:
Note that all three of these amino acids it tries out here require double nucleotide mutations. A double nucleotide mutation is pretty rare in itself, so to see it do this three times at the same position, arriving at three different amino acids, suggests it’s under very big pressure to change this position.
Out of these three, the most logical one based off what I’ve so far explained to you would be the Arginine one at the bottom. But time will tell. All three probably carry some benefit.
So as you’ll notice, none of these mutations to the Furin cleavage site have ever been seen before, until BA.2.86. So why is this happening now?
Well, the whole population has antibodies against the Spike protein now. Any virus that wants to infect us, needs to figure out how to deal with those antibodies. When everyone has similar antibodies against a few positions, the easy way to escape those antibodies is by mutating those positions. But eventually, the whole population will have different antibodies against different parts of the Spike protein, due to differing waves of infection. That makes that strategy difficult.
So what happens then? Well, the other way of antibody escape that can work is increasing ACE2 affinity. Bind to the proper receptor, before antibodies get a chance to bind. This is a strategy that works more easily, when antibody concentrations decline.
So when the vanishing act started a few months ago, I warned you the virus would just return more fiercely than before. And it did. A new version managed to establish a foothold in the population once antibody concentrations began to decline this summer, that has the higher ACE2 affinity you would expect, higher than any version of the virus ever seen.
So I think the most likely explanation for why this is now happening, is that the BA.2.86 variant can afford to sacrifice some ACE2 affinity to improve its Furin cleavage site.
We learned from Delta that an improvement to the Furin site increases the virulence. Now that we see further improvements to the Furin cleavage site, I expect we will also see further increases in virulence.
Maybe some of you will arrive at very different conclusions (I’d be happy to hear the arguments), but it looks to me like the Omicron lull is about to come to a dramatic end. As I’ve said before, historically it took generations for corona virus outbreaks in our ancestors to unleash their full potential.