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.
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.
If so, that leads to sort of a paradoxical argument where SARS-CoV-2 is showing an evolutionary pattern (seismic leaps) that doesn't show in less-well-sampled viral genomes, yet the reason for the pattern is because we still aren't sequencing enough. Specifically, if this is how viruses work, it sure isn't what flu does, which is to build incrementally in a very orderly phylogenic pattern that can be reconstructed from archived isolates for both humans and animals without any big gaps, as in the supplemental materials at Smith, et al. https://www.pnas.org/doi/10.1073/pnas.0904991106#supplementary-materials
*edit for further comments: In general, regardless of how well we sequence a given RNA virus, evolution appears faster in close-up than in far away. The reason for this again is stabilizing and purifying selection - most mutations are pruned in the long run (ref here is Simmonds 2019 in this post). So hence why "high dots" should not lead the trend, and indeed they do not. And, SARS-CoV-2 should not be mutating faster in the long term (via seismic leaps) than it is at any point when you follow a given clade in real time.
That's not to rule it out (for example, there are still problems with the "dark age" of flu where it seems like 1918 is an extinct offshoot of the H1 progenitor of both 1918 and the flu that survives going forward to 1933 and beyond), but again the purpose of "Should Variants" is to frame the whole topic in the context where there *is no* precedent for what we are seeing, and yet here we are clearly bringing these expectations "oh of course there will be variants." Well, no, it's not an of course matter.
From that point, begins the argument that the variants should not appear, which has to raise the higher bar of ruling out some kind of unprecedented and likely paradoxical evolutionary pattern.
Agree with your point about weighting mutations for likeliness. The next post will, however, show that the VOCs do not consistently travel to their mutation set by following paths of likely mutations (though it's hardly a clear-cut "synthetic signature" for most).
Flu may also be inherently not representative here. It doesn't have a receptor-binding protein, and hence perhaps doesn't need to make leaps. Similar parainfluenza binds to a sialic acid, not a complex protein.
For RSV family though, it does seem to be stable. But we have very low historical sampling and the strength of RSV is that it can use a wider selection of receptor binding proteins and has been suggested to have decoy mechanisms to have antibodies bind to the wrong things.
And to be fair, we actually are not really sure COVID-19 is unprecedented in the corona family. After all, we barely studied common coronaviruses at this biochemical level. Perhaps they do make leaps too?
So perhaps nature has a few methods to solve the problem of immunity evasion and we should not assume COVID-19 should necessarily follow the same patterns as flu?
Of course, perhaps this is unprecedented. But then also no virus ever in our human history had just under 8 American billion *virgin* hosts to work with. A one in a 10 million chance, can be compensated by throwing simply more hosts at it.
In essence my point is, we should be careful trying to extrapolate based on current knowledge as we really know very little for sure in general, but as you say do assume a lot.
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.
One key reason the mRNA vax doesn't work is because it doesn't trigger cellular immunity. A key fallacy was to claim immunity = antibodies. That was in the early 2020 days when people claimed natural immunity would wane because antibodies wane, but it was also when we prodicted teh mRNA vax works because it produces high antibodies.
CD8+ T cell for instance is barely triggerred. Studies vary a bit from less than natural immunity to 'no CD8 detected at all' which may be caused by study population and time after measurement, but we know for natura infection most CD8+ T cells trigger on N-proteins, while the vax CD8+ cells already being in lesser numbers, trigger exclusively on the spike. We still poorly understand the practical role of CD8+ T cells.
Also clearly CD4 T+ and B-cell immunity isn't working properly. Normally you'd recreate antibodies fast, but vax induced cellular immunity does not. One study I read suggested the balance between effector and non-effector B cells was sub-optimal. But in general there was/is no funding for ant study that indirectly was investigating why the vax does not work, so we have few to go on.
Last humoral shots are poor in producing mucous immunity. We do now that they can trigger some IgA but it is doubtful, they trigger a similar broad immunity as an actual virus landing and replicating in the mucous. We know very little of mucous immunity in general compared to humoral immunity, but it is very likely this is another issue, especially considering Delta en Omicron learned how to replicate directly in the throat in larger numbers than older variants.
My point, even if COVID had not mutated, the mRNA vax likely would have failed as bad as it did now. Or even more clear: I don't think mutations are the cause of failure.
It's likely the manufacturers knew that, but didn't care. They knew weak benefits would enable huge sales. More pernicious, government advisors, even the idiot fauch, knew it wouldn't work, but their goal was fear, not health. Pharma and feds both benefitted from our panic. The most important rule in any fight is don't panic. But they proved that an ignorant population is easy to panic. They'll certainly continue to use it. Maybe we'll learn. Probably not.
I agree. Take the VOCs out, spray some Wuhan virus in the nose of someone more than 3 months after the vax, doesn't matter, they will get infected. VOCs/Delta are not relevant to vax failure, this was basically settled in the Barnstable Co study (end of June 2021).
...or in other words - if you give someone an mRNA 'therapy' that tells their body to make peanut protein with the hope that the resulting peanut protein will cause the body to make antibodies against peanuts - does the now presence of peanut protein antibodies meant that are you "protected" against peanuts into the future? or that you now have a really severe allergy/autoimmune reaction imminent the next time you bump into a Reese's Peanut Butter Cup situation? ("You got your chocolate in my peanut butter, no you got your peanut butter on my chocolate" - old commercial).
Background short story, coronavirus are fought by IgA antibodies in the nose in our normal way to fight them, not with memory B cell antibodies against the spike itself.
Have a mate - semi pro hockey player -- forced to take the rat poison last December to keep playing - serious vascular damage after one shot -- he's improved but still nowhere near normal.
He pings me the other day - 'my one had is shaking uncontrollably' --- doesn't sound good.
I am thinking the spike does not clear after time rather it continues to circulate and perhaps even increases.
My ex neighbour had heart damage after the first two shots -- but was told not the vax so took the booster - the next day her one hand became very weak... that worsened and spread -- she was diagnosed with Lou Gehrig's disease. Still not blaming the vax.
Not sure what's wrong with my mate but hopefully not the same disease.
<IT IS THE VAKS> <- that is top secret information that the depopulators want to keep secret so people are losing jobs, losing medical licenses, etc.
Please spend some time with my document Protocol Collation and Therapy Goals. It may be long, but if a goal is better quality of life and a longer one, than in seems worth spending some time. There are also more condensed graphics for people who just want a "Try These" list of supplements or herbals. A functional health practitioner could help with more individualized guidance. https://docs.google.com/document/d/1RmdgbxBUuJa9nFUmCfSoZdnEB8EPc181WOvhGakAKTU/edit?usp=sharing
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.
Ok, so regarding the first point, the next post is going to drill down into actual mutation signature differences between "natural" and "toward VOC" variants, so it's probably premature to model the generic case for a valley cross before then.
However, regarding both the first and the second point, any proposal of the variant completing its "finishing touches" while still "in the chamber" essentially proposes that the single infected person or chain of infections was basically a torch being carefully passed around in a room full of propane gas. Pre-perfect versions should have spilled out and the result, especially for Alpha were 1/13 of infections were being sequenced at the time, is that there would be reversion sequences reflecting the pre-perfect version and a MRCA clock wouldn't say "1 day before the first sequence." To repeat the Hill et al quote on the topic:
"In a country with an extensive virus genomic surveillance programme like the UK, which includes random and relatively dense sampling (an average of 7.9% of weekly reported cases in Kent and Medway between 24th April 2020 and 19th September 2020 were sequenced), it is unlikely that a precursor lineage was circulating in Kent over the summer of 2020 and was not detected. It is worth noting also that B.1.1.7 was captured by this surveillance programme within at most two days of its origin - the MRCA of the clade is the 19th September 2020 (see above), and the first sample was taken on 20th of the same month"
Finally, regarding the evolution and wave-naturalism arguments, the problem here is that a lot of the VOCs were duds. They didn't actually have any transmission "advantage" at all. But at the same time, despite dying out, they still behave like clades for and this defies the prior pattern of high-mutation outliers that die out instantly. So where do these duds come from, how do they get such a foothold despite no replication advantage, etc. And then again as at the top, do they match natural mutation. Actually I haven't finished the analysis here but it's going to be somewhat murky, not a smoking gun.
Regarding the final point, Bedford's team made a plot of clades according to their calculated growth rates to try to show that dN S1 mutations were associated with better growth. The problem here is that the "correlation" totally dies if you take out Delta. Beta and the "other" VOIs, which are my counter-example to the "variants are explained by fitness" argument, are the blue and gold dots and show very high for dN S1 mutations with no growth advantage in Fig 1b first graph. https://www.biorxiv.org/content/10.1101/2021.09.11.459844v4
I must reply before fully reading again, this time so I don't forget after I walk away from my computer for dinner - "the new variants caused further waves of infection by evading innate, rather than adaptive, immunity"
Indeed, especially for Alpha. But... isn't that exactly the problem someone who released the original virus would want to solve?
Yes, but it's also the problem that natural evolution would want to solve.
You're starting to convince me to be open to "continuous release" theory, but to really shift toward seeing that as likely I would need to see estimates for the probability of natural appearance of particular variants given what we know about replication fidelity (and possibly taking into account treatments like molnupiravir that dramatically decrease replication fidelity). Assuming that any such probability estimates would have very large error bars (due to complex and not-fully-understood systems), natural appearance probabilities in the range of 1 in 1,000 or lower would be rather convincing, *or* any molecular signatures of additional engineering in VOCs such as were uncovered by the RE site analysis.
RE natural evolution against innate immunity, the only problem (it's not huge, but still) is that it isn't clear what natural evolution would predict about high- vs low-adaptive-immunity environments. Why does the virus "decide" to take on innate immunity in super-saturated areas like Brazil (70% sero+) and India at the same time as kids in England still have a measly 7% sero+ (and to what degree is anything really patched up anyway since the result of the Alpha wave only raises that to 17 https://unglossed.substack.com/i/76838100/the-results).
So it seems like natural evolution is behaving a bit artificially. Of course, there's the question about whether seasonality intrinsically alters clonal competition dynamics and creates windows for high-fitness mutants that don't exist in the middle or residue of a wave regardless of adaptive immune response. So you could say that is why Alpha drops early in the winter wave instead of later. But then you are not really being super-parsimonious at that point, and once again what is up with the retro B.1.1 starting point.
So Hill, et al., aren't really wrong when they say that the only (permissible to publish) origin possible is Immunocompromised Ex Machina.
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.
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.
If so, that leads to sort of a paradoxical argument where SARS-CoV-2 is showing an evolutionary pattern (seismic leaps) that doesn't show in less-well-sampled viral genomes, yet the reason for the pattern is because we still aren't sequencing enough. Specifically, if this is how viruses work, it sure isn't what flu does, which is to build incrementally in a very orderly phylogenic pattern that can be reconstructed from archived isolates for both humans and animals without any big gaps, as in the supplemental materials at Smith, et al. https://www.pnas.org/doi/10.1073/pnas.0904991106#supplementary-materials
*edit for further comments: In general, regardless of how well we sequence a given RNA virus, evolution appears faster in close-up than in far away. The reason for this again is stabilizing and purifying selection - most mutations are pruned in the long run (ref here is Simmonds 2019 in this post). So hence why "high dots" should not lead the trend, and indeed they do not. And, SARS-CoV-2 should not be mutating faster in the long term (via seismic leaps) than it is at any point when you follow a given clade in real time.
That's not to rule it out (for example, there are still problems with the "dark age" of flu where it seems like 1918 is an extinct offshoot of the H1 progenitor of both 1918 and the flu that survives going forward to 1933 and beyond), but again the purpose of "Should Variants" is to frame the whole topic in the context where there *is no* precedent for what we are seeing, and yet here we are clearly bringing these expectations "oh of course there will be variants." Well, no, it's not an of course matter.
From that point, begins the argument that the variants should not appear, which has to raise the higher bar of ruling out some kind of unprecedented and likely paradoxical evolutionary pattern.
Agree with your point about weighting mutations for likeliness. The next post will, however, show that the VOCs do not consistently travel to their mutation set by following paths of likely mutations (though it's hardly a clear-cut "synthetic signature" for most).
Good points and I'm looking forward to Pt 4.
Flu may also be inherently not representative here. It doesn't have a receptor-binding protein, and hence perhaps doesn't need to make leaps. Similar parainfluenza binds to a sialic acid, not a complex protein.
For RSV family though, it does seem to be stable. But we have very low historical sampling and the strength of RSV is that it can use a wider selection of receptor binding proteins and has been suggested to have decoy mechanisms to have antibodies bind to the wrong things.
And to be fair, we actually are not really sure COVID-19 is unprecedented in the corona family. After all, we barely studied common coronaviruses at this biochemical level. Perhaps they do make leaps too?
So perhaps nature has a few methods to solve the problem of immunity evasion and we should not assume COVID-19 should necessarily follow the same patterns as flu?
Of course, perhaps this is unprecedented. But then also no virus ever in our human history had just under 8 American billion *virgin* hosts to work with. A one in a 10 million chance, can be compensated by throwing simply more hosts at it.
In essence my point is, we should be careful trying to extrapolate based on current knowledge as we really know very little for sure in general, but as you say do assume a lot.
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.
One key reason the mRNA vax doesn't work is because it doesn't trigger cellular immunity. A key fallacy was to claim immunity = antibodies. That was in the early 2020 days when people claimed natural immunity would wane because antibodies wane, but it was also when we prodicted teh mRNA vax works because it produces high antibodies.
CD8+ T cell for instance is barely triggerred. Studies vary a bit from less than natural immunity to 'no CD8 detected at all' which may be caused by study population and time after measurement, but we know for natura infection most CD8+ T cells trigger on N-proteins, while the vax CD8+ cells already being in lesser numbers, trigger exclusively on the spike. We still poorly understand the practical role of CD8+ T cells.
Also clearly CD4 T+ and B-cell immunity isn't working properly. Normally you'd recreate antibodies fast, but vax induced cellular immunity does not. One study I read suggested the balance between effector and non-effector B cells was sub-optimal. But in general there was/is no funding for ant study that indirectly was investigating why the vax does not work, so we have few to go on.
Last humoral shots are poor in producing mucous immunity. We do now that they can trigger some IgA but it is doubtful, they trigger a similar broad immunity as an actual virus landing and replicating in the mucous. We know very little of mucous immunity in general compared to humoral immunity, but it is very likely this is another issue, especially considering Delta en Omicron learned how to replicate directly in the throat in larger numbers than older variants.
My point, even if COVID had not mutated, the mRNA vax likely would have failed as bad as it did now. Or even more clear: I don't think mutations are the cause of failure.
It's likely the manufacturers knew that, but didn't care. They knew weak benefits would enable huge sales. More pernicious, government advisors, even the idiot fauch, knew it wouldn't work, but their goal was fear, not health. Pharma and feds both benefitted from our panic. The most important rule in any fight is don't panic. But they proved that an ignorant population is easy to panic. They'll certainly continue to use it. Maybe we'll learn. Probably not.
I agree. Take the VOCs out, spray some Wuhan virus in the nose of someone more than 3 months after the vax, doesn't matter, they will get infected. VOCs/Delta are not relevant to vax failure, this was basically settled in the Barnstable Co study (end of June 2021).
...or in other words - if you give someone an mRNA 'therapy' that tells their body to make peanut protein with the hope that the resulting peanut protein will cause the body to make antibodies against peanuts - does the now presence of peanut protein antibodies meant that are you "protected" against peanuts into the future? or that you now have a really severe allergy/autoimmune reaction imminent the next time you bump into a Reese's Peanut Butter Cup situation? ("You got your chocolate in my peanut butter, no you got your peanut butter on my chocolate" - old commercial).
Background short story, coronavirus are fought by IgA antibodies in the nose in our normal way to fight them, not with memory B cell antibodies against the spike itself.
Have a mate - semi pro hockey player -- forced to take the rat poison last December to keep playing - serious vascular damage after one shot -- he's improved but still nowhere near normal.
He pings me the other day - 'my one had is shaking uncontrollably' --- doesn't sound good.
I am thinking the spike does not clear after time rather it continues to circulate and perhaps even increases.
My ex neighbour had heart damage after the first two shots -- but was told not the vax so took the booster - the next day her one hand became very weak... that worsened and spread -- she was diagnosed with Lou Gehrig's disease. Still not blaming the vax.
Not sure what's wrong with my mate but hopefully not the same disease.
<IT IS THE VAKS> <- that is top secret information that the depopulators want to keep secret so people are losing jobs, losing medical licenses, etc.
Please spend some time with my document Protocol Collation and Therapy Goals. It may be long, but if a goal is better quality of life and a longer one, than in seems worth spending some time. There are also more condensed graphics for people who just want a "Try These" list of supplements or herbals. A functional health practitioner could help with more individualized guidance. https://docs.google.com/document/d/1RmdgbxBUuJa9nFUmCfSoZdnEB8EPc181WOvhGakAKTU/edit?usp=sharing
With the new McDonalds app, you can order mRNA for all your favorite menu item proteins without even getting out of your car.
haha, and uh oh
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.
Ok, so regarding the first point, the next post is going to drill down into actual mutation signature differences between "natural" and "toward VOC" variants, so it's probably premature to model the generic case for a valley cross before then.
However, regarding both the first and the second point, any proposal of the variant completing its "finishing touches" while still "in the chamber" essentially proposes that the single infected person or chain of infections was basically a torch being carefully passed around in a room full of propane gas. Pre-perfect versions should have spilled out and the result, especially for Alpha were 1/13 of infections were being sequenced at the time, is that there would be reversion sequences reflecting the pre-perfect version and a MRCA clock wouldn't say "1 day before the first sequence." To repeat the Hill et al quote on the topic:
"In a country with an extensive virus genomic surveillance programme like the UK, which includes random and relatively dense sampling (an average of 7.9% of weekly reported cases in Kent and Medway between 24th April 2020 and 19th September 2020 were sequenced), it is unlikely that a precursor lineage was circulating in Kent over the summer of 2020 and was not detected. It is worth noting also that B.1.1.7 was captured by this surveillance programme within at most two days of its origin - the MRCA of the clade is the 19th September 2020 (see above), and the first sample was taken on 20th of the same month"
Finally, regarding the evolution and wave-naturalism arguments, the problem here is that a lot of the VOCs were duds. They didn't actually have any transmission "advantage" at all. But at the same time, despite dying out, they still behave like clades for and this defies the prior pattern of high-mutation outliers that die out instantly. So where do these duds come from, how do they get such a foothold despite no replication advantage, etc. And then again as at the top, do they match natural mutation. Actually I haven't finished the analysis here but it's going to be somewhat murky, not a smoking gun.
Regarding the final point, Bedford's team made a plot of clades according to their calculated growth rates to try to show that dN S1 mutations were associated with better growth. The problem here is that the "correlation" totally dies if you take out Delta. Beta and the "other" VOIs, which are my counter-example to the "variants are explained by fitness" argument, are the blue and gold dots and show very high for dN S1 mutations with no growth advantage in Fig 1b first graph. https://www.biorxiv.org/content/10.1101/2021.09.11.459844v4
I must reply before fully reading again, this time so I don't forget after I walk away from my computer for dinner - "the new variants caused further waves of infection by evading innate, rather than adaptive, immunity"
Indeed, especially for Alpha. But... isn't that exactly the problem someone who released the original virus would want to solve?
Yes, but it's also the problem that natural evolution would want to solve.
You're starting to convince me to be open to "continuous release" theory, but to really shift toward seeing that as likely I would need to see estimates for the probability of natural appearance of particular variants given what we know about replication fidelity (and possibly taking into account treatments like molnupiravir that dramatically decrease replication fidelity). Assuming that any such probability estimates would have very large error bars (due to complex and not-fully-understood systems), natural appearance probabilities in the range of 1 in 1,000 or lower would be rather convincing, *or* any molecular signatures of additional engineering in VOCs such as were uncovered by the RE site analysis.
RE natural evolution against innate immunity, the only problem (it's not huge, but still) is that it isn't clear what natural evolution would predict about high- vs low-adaptive-immunity environments. Why does the virus "decide" to take on innate immunity in super-saturated areas like Brazil (70% sero+) and India at the same time as kids in England still have a measly 7% sero+ (and to what degree is anything really patched up anyway since the result of the Alpha wave only raises that to 17 https://unglossed.substack.com/i/76838100/the-results).
So it seems like natural evolution is behaving a bit artificially. Of course, there's the question about whether seasonality intrinsically alters clonal competition dynamics and creates windows for high-fitness mutants that don't exist in the middle or residue of a wave regardless of adaptive immune response. So you could say that is why Alpha drops early in the winter wave instead of later. But then you are not really being super-parsimonious at that point, and once again what is up with the retro B.1.1 starting point.
So Hill, et al., aren't really wrong when they say that the only (permissible to publish) origin possible is Immunocompromised Ex Machina.