Thread by @shay_fleishon

BA.2.86 may or not become a threat, but what’s for sure is that the π scenario is a real.
In π I refer to a huge saltation successful variant based on past variants such as Δ,Omicrons or something even previous. which may lead to rise in case numbers.

Let's dive in...

Two routes in the virus evolution:
Stepwise- small accumulating mutations due to genetic drift from small infecting size.
Saltation- genetic leaps cause most probably in chronic infection in immunocompromised patients, shaped more by selection (from the intra host environment)

Let's start with the saltations. This phenomenon is known from other viruses but not for leading to successful outcomes.
The most accepted and well-founded explanation is that those are actually gradual steps, but which occurs in the body of an immunocompromised patient along a persistent infection. When infection takes time, and no dilution occur, selection can make an impact. So the advancement is indeed gradual, but it is hiddenn. Only if we’ll sample time and again the same chronic patient will we be exposed to this development. And actually, many scientist do (check the paper I was part of with the @SternLab team).

There were likely thousands of chronic patient­s, but less than 100 saltation variants where successful in some level. Most of the time, these chronic cases remain within the individual patient, sometimes infecting close contacts.
The low successful rate of intra host evolved variants to spread inter hose could be understood using fitness landscape. This term represents the different possibilities for changes in the genome and the impact itll have on an organism fitness. In this landscape, the height corresponds to the fitness or success that a particular genomic state provides to an organism in its specific environment.

The goal of every creature is to reach as high in this landscape, so it climbs. But, If it reachs a local peak, to continue for another higher peak would require it to descend from the current peak, meaning to decrease in its fitness, and therefore it is likely to lose in competition to whoever remains on the peak.

But! In chronic patients (somewhat similar to the transmission from animal to human), the virus faces a different environment and selection pressures and hence a different fitness landscape. The competition on human cell replication mechanism is different the competition over susceptive patients in the community. So it will travel elsewhere on the genomic map (which changed its topology).

Comparing its place in the inter host landscape after the chronic infection to its starting point, that will be some distance in a semi random direction. Mostly that will be a lower place compared to viruses in circulation, and hence the low succession rate. If it will reach by this new position a higher ground, that’s what alert us. Those where α,β,Δ,o and this might be π

Now lets go to the Stepwise route.
This happens by Unequal distribution of genomic diversity in infection from person to person leading to overrepresentation (up to fixation) of one of the viruses that has a specific mutation. Meaning If one of even a million viruses in one patient be mutated in some way, if it will be in the transmitted bunch, it could become dominant in the viral population in the new patient. Just by randomness of this process. This accumulation is usually caused by a constant rate, referred to as molecular clock.

Most of the time these mutations will cause no effect, they will be added like an incrementing barcode for different strains with no advantage. In Δ that was very common. If the first patients of the variant entering one country had specific mutation, it would seem as if this mutation caused it to took over that place, but that was just as they were first.

If a mutation causes a disadvantage, well it will be underrepresented as it will loose in the competition.
In vary rare cases, such a stepwise mutation may lead to an advantage, like with the D614G mutation in Spike in the beginning of the pandemic, causing increase in infectivity. This kind of mutations will cause the succession of the virus in more than one location.

From Omicron, many sub variantsdeveloped in a stepwise manner that seems to actually gave an advantage (they became dominant among the other sub variants circulated that time, although without increasing the cases in the population). And that was repeated time after time, a unique trend in Omicron compared to Δ (for instance).

Omicron sub-lineages appear to gain an advantage through stepwise mutations specifically when those focused on the S1 region and, more specifically, within the RBD. This region is crucial as it is the main target for the immune response and facilitates the virus's entry into cells. Moreover, these mutations have occurred in a convergent manner, meaning they have accumulated independently in different Omicron sub-variants, while such a convergent is not seen outside the spike. All of this evidence suggests a selection pressure, possibly driven by the need to evade the immune response.
This phenomena is quite unique to Omicrons, past VOC’s didn’t accumulate mutations in those area even without conferring advantage, as if changing it has a deleterious effect.

It's important to clarify that mutations in the S1 and RBD regions don't mean only escape from the immune response. There's a reason that the neutralizing immune response is focused on these areas; its important for the virus's activity. The virus arrived to the human body in 2019 in a genomic state that was likely not perfect (after all, it hadn't encountered the human body before), so specific changes in the S1 region might have been required, such as the mutation at position 614 in Spike gene, which led to an increase in infectivity at the beginning of the pandemic, and the few mutations in the RBD that accumulated in the dominant variants before the rise of Omicron.

When Omicron first emerged, there were so many initial changes in the S1 region relating to the dominant Δ at that time, specifically in the RBD. Tests performed on it showed a significant decrease ability of neutralizing antibodies connecting to it. But the speed at which Omicron spread was much greater than its predecessors like Δ and α, and it also reached broader parts of the population, And those 2 epidemiological aspects indicates an increase in intrinsic infectivity (although it's likely that immune escape also had some significance ).

Oh, and it's important to remember one more small thing: there's no such variant called Omicron. It's a name given to five variants, most of them are quite different than the others, but according to phylogenetically analysis they share (an unknown) ancestor. First, BA.1 emerged, led to a certain level of cases, and then BA.2 arrived, defeating BA.1 and getting to greater parts of the population. BA.3 failed fairly quickly in competition. A few months later, BA.4 and BA.5 arose. Than 2nd generation (saltations) over BA.2 variants arise (in much smaller genomic leaps than seen in BA.2.86) like with BA.2.75 and BJ.1 (and those 2 even recombined to create XBB)…
and still all of those are called “Omicron”. Honestly, I think this hides much of the picture.

And BTW, this sibling saltation variant thing (BA.1-BA.5) isn’t just an Omicron thing. It happened with other variants, such as B.1.640, which emerged slightly before Omicron and contained two main variants that developed from it and were very different. In fact, Δ, as I reported in the past together with Adi Stern and Neta Zukerman, comprised of five different variants that emerged together (one of them took over most of the rest after a while). And this is very important, because what we see now might be actually BA.2.86.1 (meaning that BA.2.86.2 may come afterward).

But what does it actually matter if a successful variant arrives with a big leap? Let's analyze.
Let's start with the number of cases. We don't want it to increase, right?
It's important to us that the effective R (Re)remains low (as much below 1 as possible). And it depends on intrinsic infectivity (R0) and escape from the immune response

In terms of infectivity (intrinsic, R0), the chance of breaking the record decreases each time the record is broken, and the record set by the original Omicrons was higher than that of Δ, which was higher than α, which was higher than B.1, which was higher than the original strain from Wuhan.
It's a bit like a running record; each time a world record is broken, the lower the chance of breaking the record to be soon. Usain Bolt's 100-meter record from 2009 is unlikely to be broken soon, and if it will, it won't be by much.

But what about the immune response?
There are several levels to escape from. For a 2nd generation (saltation over saltation) variant with high antigenic distance (e.g. BA.2.86) usually we’ll see first neutralization tests, and basically as the distance is greater the chance for good neutralization with current serra is lower.
But as experts on this matter always remind me, there is more to escape from than just neutralizing antigens.
As I advised before, best follow @jbloom_lab for this.

What should be remembered when analyzing a 2nd gen variants, is that unlike with Δ and original Omicrons, the population that will encounter a new variants today will have a much broader and deeper immune memory. People who have been infected with the virus in various forms, once or more, and have been vaccinated—even with vaccines designed for more than one variant—it will give a much harder start than former variants evolved in such a leap.

But here’s something I think of, extremely speculative -
As mentioned earlier, Omicron has been evolving in its S1 for around a year and a half, mainly to escape the immune response, but probably not without a cost. The essential role of S1 and its RBD in infectivity means changing this region for escape might have damaged the virus's intrinsic infectivity, a cost it was willing to pay for the benefit. In other words, it may have “sacrificed” in R0 to maintain Re.
A new variant might achieve the same intrinsic infectivity as original Omicrons but through different changes, specifiacally in S1. This might make it with or without intention more immune evasive. And all together, that may cause an advantage.
Again. Extremely speculative.

Now – lets look at virulence. What everyone most curious about.
The most important massage, as @ArisKatzourakis stated over the pandemic, virulence does not necessarily decrease over time. That's kind of a myth. And it's even less related to a virus like SARS-COV-2 that infects very early before symptoms even developed (let alone the severe ones that come later in the disease). The virus doesn't 'care' if you die; you're not its enemy. It just needs to infect.

Remember that Alpha was a variant that led to more severe illness than the Wuhan strain, than Delta was more severe than Alpha but Omicron was milder than Delta. The greater the genomic leap, and the more it evolves (under selection) in its spike but even more importantly outside the spike, than virulence can change in any direction.

That's it for now. Follow for more updates.