It is curious that some Corona Viruses bind to sialic acid while others use the ACE2 receptor. (Although I did hear that SARS-CoV-2 still can bind to sialic acid, but perhaps I am remembering it wrongly.)

Curious because it seems that influenza has not needed to explore that avenue of evolution.

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Dec 8, 2022·edited Dec 8, 2022Liked by Brian Mowrey

On aspect I'm still playing with in my head is, that we also should not forget we are looking at variants of concern, from the point of winners. These one turned out to be not just able reaching the end of the THPS game, but also faster than most of the original.

Then the musical chair model I proposed a few weeks ago, mathematically just takes care of the rest. Most people infected, infect nobody outside their household, but those that do often infect many. SO that is the equivalent of having kids walk around a ring of chairs until the music stops, but instead of taking one chair away, we take 90% of them away. And then the 10% winners are allowed to clone 10 times, so we are back at 100% again. Random chance will hence eliminate most mutants, regardless whether they are better or worse at THPS, but if a mutant takes hold and is better, it will be inherently accelerated. This also explains why Delta went away while we still had plenty of non-infected people.

Now that still leaves where these new VOC's came from, as the above only explains how they take hold.

But perhaps they were not that special as we believe and maybe we had 10 more VOC's in the last 3 years, but these all just didn't get a seat. After all we look explicitly at the winners. Also with hundreds millions of infected people even a one in a 10 million chance is not that unlikely.

The counterargument given for at least Alpha is that we should have seen this in the sequencing, but even in high-sequence countries like the UK we still only sample a very small % so I'm not immediately convinced. Plus if you look at the graph we actually did see these. A few far away brown dots do appear.

Third, these graphs are somewhat misleading as they treat every mutation as equally likely and hence calculate distance based on sheer amount of changes. But biochemically mutations are not equal, and more important only some are viable. So a set of chances may be biochemically linked and hence more likely than expected based on total changes. Unfortunately many mutations are biochemically poorly understood, but perhaps the distance between B.1.1 and Alpha is less than it apperas if we would know more.

So all in all, it may also just be that for this virus we see clusters of good THPS moves, but some of these clusters require lots of luck to reach, meaning seeing no in-between variants is actually expected.

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So, why doesn't the vax work? Apparently it does mutate and they're still distributing vax for variants that aren't in wide circulation. A competent medical industry could probably keep up, issuing new vax more frequently, but the insanely corrupt approval process precludes that, so we're stuck with the vax they managed to sneak through, regardless of ineffectiveness. That, and an ample supply of stupid people assures the gravy train continues a while longer, and whatever nefarious motives might be behind it. Maybe they'll find a vax for stupidity. Prosecuting the corruption will wise a lot of them up.

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If the vast majority of intermediates (between variant lines) fall in fitness valleys, then as a null (vs. continuous lab update) hypothesis it would be helpful to be able to estimate the probability of crossing any of those valleys *within a single infected host* given the rate of replication errors and the total number of infections. For example, if - on average, and I'm just making this up - every infected cell produces 1000 virions with no genome changes, 100 virions with a single nucleotide changed, 10 with two changes, all the way out to 10 changes occuring in one out of every ten million infected cells, etc., then we could calculate the probability of new variants arising.

Also, would it be likely that the initial further single-nucleotide changes within a new variant that optimize fitness would occur within the first few hosts, thus causing the variants to *appear* to be stable by the time they are first sequenced?

Finally, it seems to me that - until Omicron - the new variants caused further waves of infection by evading innate, rather than adaptive, immunity - i.e. by infecting people that the previous strains were unable to successfully infect, rather than by reinfecting those who had recovered. It is not surprising to me that it is easier for a virus to find new hosts by increasing infectiousness (ability to overcome innate immunity), and that only once a majority of people have been infected does the more difficult approach of evading innate immunity become the best evolutionary move. That's not to suggest that Omicron or any of the VOCs *weren't * lab releases - only that the observed pattern seems consistent with evolutionary pressures to me, and that (in the absence of abundant sequence data to track and analyze genetic changes) the overall progression of waves of infection and eventual reinfection doesn't seem especially anomalous for a new virus entering the human population.

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