When I googled (although I used bing) "what is a leaky vaccine," what I pulled up was the distinction between a leaky vaccine and an "all or none" vaccine:
""Leaky" vaccines are those for which vaccine-induced protection reduces infection rates on a per-exposure basis, as opposed to "all-or-none" vaccines, which reduce infection rates to zero for some fraction of subjects, independent of the number of exposures. Leaky vaccines therefore protect subjects with fewer exposures at a higher effective rate than subjects with more exposures." https://pubmed.ncbi.nlm.nih.gov/24895500/
So that author does not distinguish between leaky and sterilizing; they distinguish between leaky and "all-or-none." I will now need to read the rest of your paper (which will probably take me weeks) in order to see how this fits with "sterilizing" versus "non-sterilizing."
The first thing that occurs to me from this definition of leaky is that with a leaky vaccine plus incredibly high community prevalence (where I am in CA, the wastewater is worse than it was at the peak of Omicron), you are going to get a lot of leaks.
Finally having a moment to sit down - I read it the same way, it is using "all or none" instead of "sterilizing" but it is saying the same thing. Basically just making the point that a wooden shield might be useful against an arrow but not a flamethrower. In actual practice however humans tend to use a lot of leaky vaccines. Or they are sterilizing but not for long term (the measles vax here probably) but we just get away with it because it's enough to keep the virus from establishing its niche again. I can't speak for what veterinary science thinks about the subject but I haven't seen anything that supports the impression vanden Bossche gives that there is a whole school of Leaky Vaccine Disaster Research.
Your thinking in these matters continues to parallel mine. My background, however, is in computer science (BSCS plus 50+ years in the field; couldn't find a use for an advanced degree). There is a surprising degree of overlap. I became interested in the mechanisms of protein synthesis about 10 years ago, and it may have saved my life in 2021, if you see what I mean.
I can't pause for a lengthy reply today, but I'll challenge you with one question: Could your view of viral behavior offer a clue that they may have been _designed_ this way? It's surprising what can pop out when you revise your assumptions.
It's fascinating, and a bit spooky, that humans worked out what DNA is and how to sequence it at the same time that PCs came about, that genomic analysis would essentially be impossible without computers, and that the line between the two essentially blurs once you are dealing with plasmids and vectors.
Also purely cool how all organisms build gene regulation logic out of events that, if humans were trying to design the system, would just be interpreted as bugs. "Oh, the ribosome skips over my polyprotein stop codon 1/4 the time - great, now I can program in a 4/1 protein output ratio," thinks the coronavirus.
Designed by? And "they" meaning all viruses or the SARS-CoV-2 family?
Sorry, my reply was rushed. Calm is returning now, and I guess I have some time to write. I saw the problem with "they" when I re-read the comment. "They" could be as broad as all viruses that operate in the manner that you are suggesting.
Something that fascinates me is that of all species (not to mention non-lifeforms), we appear to be the only ones that design stuff, for fun or profit, to create, maintain, or destroy. And while everything we do builds upon what was already there, nothing else appears to build upon it those special ways. (I could try to be more precise, but I'll leave it there for brevity.)
That is interesting enough in itself, but then in the process of employing what is already here, we begin to look more deeply into its nature as well. Oddly enough, it displays patterns not unlike our own patterns of creativity. But it also exhibits patterns -- what we might even understand to be design patterns -- that we hadn't thought of. Discovering those, we may then incorporate them in what we ourselves design and build.
There is some kind of circular relationship peeking out at us here. There are texts, ancient ones, that describe such a relationship, but as "moderns", most people prefer to look elsewhere for understanding. This leads almost inevitably to the idea that higher order designs -- those beyond what we are presently capable of implementing ourselves -- must somehow arise out of random processes.
It's an easy step from there to ever-mutating, ever-changing life (and now the idea that it will soon spiral out of control and self-destruct if we don't change our ways and take actions that are utterly absurd). But does any of this reflect reality? Whatever became of entropy? How many trillions of years does it take for random to become non-random, and does anybody think the universe has been around that long?
Take one decent-sized, critical enzyme, think of its amino acids in terms of 6 bit numbers (or base 64 or base 20 or somewhere in between, it doesn't matter too much), concatenate those, and imagine how many random permutations it would take to come up with that numerical value or another equivalent that works, and how long that would take. (I credit Brian M. Schiller, author of _Origin of Life: The 5th Option_ as my source for that idea.)
I think it is time to back up a bit and take a fresh look at what we know from the past. I appreciate the many problems with religious traditions. I've spent nearly half my life -- about 35 years out of 72 -- staying as far away from the traditions I was brought up in as I possibly could, while retaining the moral principles, and while exploring other traditions that proved no better. I still do battle with those traditions, but I have had to backtrack, validate, and re-accept a good portion of what I rejected. Otherwise, nothing makes sense.
That's what I am hearing today. Nothing makes sense. There's paradox and now absurdity as far as the eye can see. There is a reason for that. Paradox is a signal. Absurdity is a very loud alarm. Our beliefs are out of touch with reality. It's time to reexamine those beliefs.
It is certainly fair to say that the "accidental" etiology myth operates more like a dogma than any religious one. Essentially, humans passed through a brief window where it might have been fair, given the evidence, to consider a materialist universe apparent, and refuses to acknowledge that further discoveries went and made a beyond-materialist universe apparent again. So ancient societies and authors were being honest / authentic when they proposed that life had been made by something; and that is what current society and authors would propose if being honest / authentic.
This is true on the micro level as well. A lot of what goes on with genes cannot be explained in the logic of algorithms, especially in the virus, embryogenesis, and insect metamorphosis realms. The only real explanation would be that nucleotide polymers have consciousness and will. Of course, we would simply reject that. Because "thinking" happens in nerves, not molecules. But as we are learning more about how nucleotide polymers can act as multidimensional arrays of self-interactions maybe we will stop being so obstinate here.
The obvious problem for a "accidental" universe world-view would still remain, of course: How could it possibly be an "accident" that such a small collection of the fundamental building blocks of matter could perform "thought"?
And then the next step is to consider the recursive nature of the genetic code - that it is how DNA describes how to build molecules that edit DNA. And then the next step brings still more problems. And so on and so on. So it's problems all the way up, for the accidental universe!
If we could just acknowledge that for higher and higher orders of matter and energy, some kind of "input" is required, I think it would become clearer how certain things are possible. Nucleotide polymers don't need to possess their own consciousness if they are being guided by something/somebody else toward that entity's goals.
That might sound religious, but I am a database and software developer and I engage in something like this myself almost every day. My schemas, queries, and code don't think for themselves or improve themselves. I modify them iteratively (often incorporating design patterns) until they produce the results that I am seeking, at which point they cease to "mutate" until a need for change arises again.
To an observer with a limited view, during the iterative phase, it might appear that the process is random, but it is not -- it is goal-directed. I am the "input" that increases the order.
And this..... don't forget that this was a single epitope vaccine. There's the question of sterilizing vs non-sterilizing, but also the question of how broad the viral epitope coverage is. I am guessing that, in reality, the mRNA's were always much less sterilizing vs. for instance Polio.
"The spike protein receptor-binding domain (RBD) of SARS-CoV-2 is the molecular target for many vaccines and antibody-based prophylactics aimed at bringing COVID-19 under control. Such a narrow molecular focus raises the specter of viral immune evasion as a potential failure mode for these biomedical interventions. With the emergence of new strains of SARS-CoV-2 with altered transmissibility and immune evasion potential, a critical question is this: how easily can the virus escape neutralizing antibodies (nAbs) targeting the spike RBD? To answer this question, we combined an analysis of the RBD structure-function with an evolutionary modeling framework. Our structure-function analysis revealed that epitopes for RBD-targeting nAbs overlap one another substantially and can be evaded by escape mutants with ACE2 affinities comparable to the wild type, that are observed in sequence surveillance data and infect cells in vitro. This suggests that the fitness cost of nAb-evading mutations is low. We then used evolutionary modeling to predict the frequency of immune escape before and after the widespread presence of nAbs due to vaccines, passive immunization or natural immunity. Our modeling suggests that SARS-CoV-2 mutants with one or two mildly deleterious mutations are expected to exist in high numbers due to neutral genetic variation, and consequently resistance to vaccines or other prophylactics that rely on one or two antibodies for protection can develop quickly -and repeatedly- under positive selection. Predicted resistance timelines are comparable to those of the decay kinetics of nAbs raised against vaccinal or natural antigens, raising a second potential mechanism for loss of immunity in the population. Strategies for viral elimination should therefore be diversified across molecular targets and therapeutic modalities"
So that basically slots in the "vaccines fail for other reasons" file. Loading up antibodies to spike protein only temporarily prevents infection and transmission. So these injections failed because circulating antibodies to a coronavirus are not immunity, that's all. It never had anything to do with the (natural or not) mutation of the virus.
Then you have the claim that the first wave of VOCs had "altered immune evasion potential." Well, no, because natural immunity -- which is the only real kind in the context of this coronavirus -- worked just fine against Delta. So it was just the "antibodies=immunity" assumption being recycled again.
"With a total of 835,792 Israelis known to have recovered from the virus, the 72 instances of reinfection amount to 0.0086% of people who were already infected with [SARS-CoV-2]. By contrast, Israelis who were vaccinated were 6.72 times more likely to get infected after the shot than after natural infection, with over 3,000 of the 5,193,499, or 0.0578%, of Israelis who were vaccinated getting infected in the latest wave." <- early Delta wave https://www.israelnationalnews.com/News/News.aspx/309762
"Could some vaccines drive the evolution of more virulent pathogens? Conventional wisdom is that natural selection will remove highly lethal pathogens if host death greatly reduces transmission. Vaccines that keep hosts alive but still allow transmission could thus allow very virulent strains to circulate in a population. Here we show experimentally that immunization of chickens against Marek's disease virus enhances the fitness of more virulent strains, making it possible for hyperpathogenic strains to transmit. Immunity elicited by direct vaccination or by maternal vaccination prolongs host survival but does not prevent infection, viral replication or transmission, thus extending the infectious periods of strains otherwise too lethal to persist. Our data show that anti-disease vaccines that do not prevent transmission can create conditions that promote the emergence of pathogen strains that cause more severe disease in unvaccinated hosts."
Herpes viruses have genes that appear to limit tropism. And like bacterial viruses they presumably have some sort of sophisticated "timer" system to regulate dormancy - the genes for how chicken pox "decides" to stop replicating in your nerves before it kills you. So there's some pretty sophisticated host-virus co-evolution there, and as such, we should be worried about a Marek's effect if we keep using chicken pox vaccines for decades. *edit: forgot to link to my post on it https://unglossed.substack.com/p/crackpot-corner-marekspocalypse-edition
On the other hand, it might not be the same since veterinary vaccination arbitrarily keeps immunity so regular. And since there's also the danger to the host's immune response becoming *weaker* from lack of yearly natural "boosters," we could actually be pushing chicken pox in two directions at once. Maybe it will be a wash. I would prefer we banned chicken pox vaccines as well as others, and yes, "because evolution" - but the reason is because it only takes one disaster, not because every time you do it there is a disaster, in other words. It's a black ball in the sack problem.
This was sort of discussed with Crawford. However, don't know if it will actually happen. Meanwhile I might try my own video presentation, and so part of the motivation for this post is to get some graphics up, though they won't be of a very high production value haha.
I also wouldn't say it's necessary for any individual person to think about or understand both models. But for anyone who finds Couey's not convincing, or too extreme in suggesting that no RNA viruses can spread with fidelity, ok, here is an alternate take. So like I say the argument for multiple releases won't have all its eggs in one basket.
I honestly hope that you and JJ will find a way to discuss things and keep hypotheses open. This is really interesting,and JJ is hell bend to get his model of the truth as close as possible to what might actually be the truth.
He is very aggressive when he is talking alone and very passionate but I have seen him being part of the conversation ... and he is a humble man, he will give you all the space you need to present your ideas, discuss it together,and come up with new ones.
You two are my favorite biology shamans right now.
Mathew is a favorite & that show was fab and JJ is awesome too. But coming into sciences of biology, virology, immunology & associated Rubrics Cube of mixed & mangled information sources, lots of us are just trying to reduce our confusion & it's a pretty high bar. :~)
I fear you may need to find some other analogy to explain ideas as some of us have never played computer games and haven’t a clue what you’re on about!
On a separate note - I’ve just finished listening to ‘ Inventing the AIDS virus’ which seems to stop around 1995. The only other thing I think I know about HIV is that it infects CD4 T cells. What should I read next to get a better understanding? If it’s a ‘harmless bystander’ then why is everyone so worked up about it having parts incorporated into the SARSCov2 spike? Thanks!
Hm... I am not sure any other analogy is possible. THPS is sheer perfection. It is like riding a bike, in terms of movements becoming automatic after a certain amount of play, only everyone who plays THPS literally is hitting the same buttons, and the buttons can be easily converted to a sequence of codes so that you could actually make a machine that plays a level by punching on the controller to get the highest possible score, if you wanted. Well, I have probably made the whole thing even more confusing!
I am still delinquent on my HIV research, sadly. I'd say at the moment, just based on glimpses of the evidence absorbed by osmosis, I'm leaning more toward HIV at very high initial doses does cause AIDS simply because well, you gave it too much of a head start; similar to a spirochaete bacterium (syphilis etc). It's not something you have to worry about bumping into on the street but it can spread with sex and maybe also be a *marker* for pre-existing immune dysfunction in cases where it spreads more easily. So we should still be very suspicious about the fact that it suddenly would explode out of nowhere. I think there is a mix of HIV causing AIDS and being next to it.
What is it doing on the SARS-CoV-2 spike? Either a back-story involving a coronavirus live HIV vaccine or just an intentional signature of human manipulation. But I don't think there's anything to worry about, it's just some amino acids in a string in the end.
I am not a scientist but I do find this article's theory very interesting so I would like to ask my question even though it might already have been answered in a way I failed to grasp.
So what I am confused about is why there would be one single max fitness for each virus. Wouldn't there be a huge variety of max fitness when you look at virus - host combined? So for instance human cell ace2 expression variation might create subsets of people to whom one coronavirus spike protein mutation would be more fit and less fit for others. Then we have a whole bunch of little fitness 'holes' and when some pressure forces a virus out of one hole it may fall down into another, changing which subset of hosts it is better adapted to. It is still optimal but optimal is contingent on host-virus as a set.
I read about some experiment in chemistry that was related to quantum physics. They could balance some substance on a hill where it was exactly between two states. The slightest nudge including measurement would push it into one or the other. It would resolve to one of the two states and be stuck there. Why wouldn't a virus have a lot of these potential contingent optimal states and immune pressure pushes it up a hill of low fitness where it falls into a new hole of contingent fitness? So isn't optimal a moving target that is also dependent on host-virus subsets?
This gets a bit into the metaphysical questions inherent in sequencing. By definition, when you do a sequence and you are amplifying (copy-pasting) all these scraps of genetic material and using a computer to stitch them back together, any non-consensus results are either going to be discarded or considered putative evidence of co-infection or swarm mutants. If your whole sequence is full of conflicts then your original sample wasn't "hot" enough in terms of having a lot of copies of a single virus genome.
So this creates a favoritism for whatever version of the virus "THPS move set" replicates best in a given host and/or in your cell culture. So as long as those two things overlap with "optimum in the host ecosystem overall" then you are going to see the consensus genes in this sequence reappear in a sequence some years down the line. It is a bit like humans being spoiled, rich bachelors that only see the coolest parties, which only have the same coolest people in the same clothes in them. It doesn't matter what the viruses at the comics and games shop playing D&D at 7pm are up to.
So, the question of "what *is* a non-repeating sequence" is tricky. Was it just an artifact on your one sequence that one time, or a lineage that slipped on the fitness slope and later died out, etc. Generally you can't trust any gene that isn't repeated in another sequence, but at the same time you "know" that dead-end offshoots or background coinfector / "swarm" mutants probably exist at least sometimes. So the only approach here is to be a bit ambivalent about one-off mutant sequences. And if you are doing a phylogenetic analysis you use consensus and read depth markers to make a quality cut-off which hopefully makes artifacts minimal in the overall proportion of samples.
Overall, the further a virus slips down the fitness slope, the less accurately we can reliably see what it even is, and this will be relative in terms of the currently best-at-replicating model in whatever the virus replicates in right before you sequence it.
Yet there appears to be a limit to how "rich" viral diversity really is in that lab- or infection-condition bottlenecks aren't able to find viruses that are more than one or two mutations from the consensus genome going in. Again the example here is the OPV, which bottlenecks during administration due to most copies of the virus being nearly replication incompetent, but the difference is a single mutation. So you find the "swarm" variant when you passage OPV through a human but it was only one gene different.
But even this is subject to limitations due to the wonky metaphysical nature of viral replication. It may simply be that swarm variants need to be present in a certain percentage to tip the scales of clonal interference - where the best "move set" is still out-competed by the suboptimal set by pure starting numbers.
All of this comes into play with SARS-CoV-2 as well.
Regarding host molecular heterogeneity, it should probably be thought of as akin to a host species barrier. So you might have some cross-transmission like for avian to swine/human but outside of those cross-overs it would be like having two viruses.
I didn't really think of the measurement / observer problems inherent in amplification and sequencing either so thanks for bringing that up! It is a lot of food for thought. The limitations and guesswork that sequencing introduces makes virology seem more and more akin to quantum physics.
Lucky is the alternate universe where Japanese Playstation owners were forced to buy Tony Honk due to copyright conflicts. I am just using it partly to be facetious and partly because it really does feel weird to turn a real person's name into a theory about RNA virus evolution. But THPS is the perfect model.
When I googled (although I used bing) "what is a leaky vaccine," what I pulled up was the distinction between a leaky vaccine and an "all or none" vaccine:
""Leaky" vaccines are those for which vaccine-induced protection reduces infection rates on a per-exposure basis, as opposed to "all-or-none" vaccines, which reduce infection rates to zero for some fraction of subjects, independent of the number of exposures. Leaky vaccines therefore protect subjects with fewer exposures at a higher effective rate than subjects with more exposures." https://pubmed.ncbi.nlm.nih.gov/24895500/
So that author does not distinguish between leaky and sterilizing; they distinguish between leaky and "all-or-none." I will now need to read the rest of your paper (which will probably take me weeks) in order to see how this fits with "sterilizing" versus "non-sterilizing."
The first thing that occurs to me from this definition of leaky is that with a leaky vaccine plus incredibly high community prevalence (where I am in CA, the wastewater is worse than it was at the peak of Omicron), you are going to get a lot of leaks.
Finally having a moment to sit down - I read it the same way, it is using "all or none" instead of "sterilizing" but it is saying the same thing. Basically just making the point that a wooden shield might be useful against an arrow but not a flamethrower. In actual practice however humans tend to use a lot of leaky vaccines. Or they are sterilizing but not for long term (the measles vax here probably) but we just get away with it because it's enough to keep the virus from establishing its niche again. I can't speak for what veterinary science thinks about the subject but I haven't seen anything that supports the impression vanden Bossche gives that there is a whole school of Leaky Vaccine Disaster Research.
Apologies in advance for only reading to footnote 1 and chasing a squirrel [imitates Boomhower] GD Internet click click click
The irony of reading that while hearing a commercial on the radio for the variant-killer bivalent booster.
https://www.aps.anl.gov/APS-Science-Highlight/2022-08-01/unraveling-sars-cov-2s-mutagenic-prowess-one-enzyme-at-a-time
A perfect example - the Borg variant narrative again defaults as the most exciting way to frame a cool but boring x-ray study.
Your thinking in these matters continues to parallel mine. My background, however, is in computer science (BSCS plus 50+ years in the field; couldn't find a use for an advanced degree). There is a surprising degree of overlap. I became interested in the mechanisms of protein synthesis about 10 years ago, and it may have saved my life in 2021, if you see what I mean.
I can't pause for a lengthy reply today, but I'll challenge you with one question: Could your view of viral behavior offer a clue that they may have been _designed_ this way? It's surprising what can pop out when you revise your assumptions.
It's fascinating, and a bit spooky, that humans worked out what DNA is and how to sequence it at the same time that PCs came about, that genomic analysis would essentially be impossible without computers, and that the line between the two essentially blurs once you are dealing with plasmids and vectors.
Also purely cool how all organisms build gene regulation logic out of events that, if humans were trying to design the system, would just be interpreted as bugs. "Oh, the ribosome skips over my polyprotein stop codon 1/4 the time - great, now I can program in a 4/1 protein output ratio," thinks the coronavirus.
Designed by? And "they" meaning all viruses or the SARS-CoV-2 family?
Sorry, my reply was rushed. Calm is returning now, and I guess I have some time to write. I saw the problem with "they" when I re-read the comment. "They" could be as broad as all viruses that operate in the manner that you are suggesting.
Something that fascinates me is that of all species (not to mention non-lifeforms), we appear to be the only ones that design stuff, for fun or profit, to create, maintain, or destroy. And while everything we do builds upon what was already there, nothing else appears to build upon it those special ways. (I could try to be more precise, but I'll leave it there for brevity.)
That is interesting enough in itself, but then in the process of employing what is already here, we begin to look more deeply into its nature as well. Oddly enough, it displays patterns not unlike our own patterns of creativity. But it also exhibits patterns -- what we might even understand to be design patterns -- that we hadn't thought of. Discovering those, we may then incorporate them in what we ourselves design and build.
There is some kind of circular relationship peeking out at us here. There are texts, ancient ones, that describe such a relationship, but as "moderns", most people prefer to look elsewhere for understanding. This leads almost inevitably to the idea that higher order designs -- those beyond what we are presently capable of implementing ourselves -- must somehow arise out of random processes.
It's an easy step from there to ever-mutating, ever-changing life (and now the idea that it will soon spiral out of control and self-destruct if we don't change our ways and take actions that are utterly absurd). But does any of this reflect reality? Whatever became of entropy? How many trillions of years does it take for random to become non-random, and does anybody think the universe has been around that long?
Take one decent-sized, critical enzyme, think of its amino acids in terms of 6 bit numbers (or base 64 or base 20 or somewhere in between, it doesn't matter too much), concatenate those, and imagine how many random permutations it would take to come up with that numerical value or another equivalent that works, and how long that would take. (I credit Brian M. Schiller, author of _Origin of Life: The 5th Option_ as my source for that idea.)
I think it is time to back up a bit and take a fresh look at what we know from the past. I appreciate the many problems with religious traditions. I've spent nearly half my life -- about 35 years out of 72 -- staying as far away from the traditions I was brought up in as I possibly could, while retaining the moral principles, and while exploring other traditions that proved no better. I still do battle with those traditions, but I have had to backtrack, validate, and re-accept a good portion of what I rejected. Otherwise, nothing makes sense.
That's what I am hearing today. Nothing makes sense. There's paradox and now absurdity as far as the eye can see. There is a reason for that. Paradox is a signal. Absurdity is a very loud alarm. Our beliefs are out of touch with reality. It's time to reexamine those beliefs.
It is certainly fair to say that the "accidental" etiology myth operates more like a dogma than any religious one. Essentially, humans passed through a brief window where it might have been fair, given the evidence, to consider a materialist universe apparent, and refuses to acknowledge that further discoveries went and made a beyond-materialist universe apparent again. So ancient societies and authors were being honest / authentic when they proposed that life had been made by something; and that is what current society and authors would propose if being honest / authentic.
This is true on the micro level as well. A lot of what goes on with genes cannot be explained in the logic of algorithms, especially in the virus, embryogenesis, and insect metamorphosis realms. The only real explanation would be that nucleotide polymers have consciousness and will. Of course, we would simply reject that. Because "thinking" happens in nerves, not molecules. But as we are learning more about how nucleotide polymers can act as multidimensional arrays of self-interactions maybe we will stop being so obstinate here.
The obvious problem for a "accidental" universe world-view would still remain, of course: How could it possibly be an "accident" that such a small collection of the fundamental building blocks of matter could perform "thought"?
And then the next step is to consider the recursive nature of the genetic code - that it is how DNA describes how to build molecules that edit DNA. And then the next step brings still more problems. And so on and so on. So it's problems all the way up, for the accidental universe!
If we could just acknowledge that for higher and higher orders of matter and energy, some kind of "input" is required, I think it would become clearer how certain things are possible. Nucleotide polymers don't need to possess their own consciousness if they are being guided by something/somebody else toward that entity's goals.
That might sound religious, but I am a database and software developer and I engage in something like this myself almost every day. My schemas, queries, and code don't think for themselves or improve themselves. I modify them iteratively (often incorporating design patterns) until they produce the results that I am seeking, at which point they cease to "mutate" until a need for change arises again.
To an observer with a limited view, during the iterative phase, it might appear that the process is random, but it is not -- it is goal-directed. I am the "input" that increases the order.
Where else might we be seeing patterns like this?
And this..... don't forget that this was a single epitope vaccine. There's the question of sterilizing vs non-sterilizing, but also the question of how broad the viral epitope coverage is. I am guessing that, in reality, the mRNA's were always much less sterilizing vs. for instance Polio.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250780
"The spike protein receptor-binding domain (RBD) of SARS-CoV-2 is the molecular target for many vaccines and antibody-based prophylactics aimed at bringing COVID-19 under control. Such a narrow molecular focus raises the specter of viral immune evasion as a potential failure mode for these biomedical interventions. With the emergence of new strains of SARS-CoV-2 with altered transmissibility and immune evasion potential, a critical question is this: how easily can the virus escape neutralizing antibodies (nAbs) targeting the spike RBD? To answer this question, we combined an analysis of the RBD structure-function with an evolutionary modeling framework. Our structure-function analysis revealed that epitopes for RBD-targeting nAbs overlap one another substantially and can be evaded by escape mutants with ACE2 affinities comparable to the wild type, that are observed in sequence surveillance data and infect cells in vitro. This suggests that the fitness cost of nAb-evading mutations is low. We then used evolutionary modeling to predict the frequency of immune escape before and after the widespread presence of nAbs due to vaccines, passive immunization or natural immunity. Our modeling suggests that SARS-CoV-2 mutants with one or two mildly deleterious mutations are expected to exist in high numbers due to neutral genetic variation, and consequently resistance to vaccines or other prophylactics that rely on one or two antibodies for protection can develop quickly -and repeatedly- under positive selection. Predicted resistance timelines are comparable to those of the decay kinetics of nAbs raised against vaccinal or natural antigens, raising a second potential mechanism for loss of immunity in the population. Strategies for viral elimination should therefore be diversified across molecular targets and therapeutic modalities"
So that basically slots in the "vaccines fail for other reasons" file. Loading up antibodies to spike protein only temporarily prevents infection and transmission. So these injections failed because circulating antibodies to a coronavirus are not immunity, that's all. It never had anything to do with the (natural or not) mutation of the virus.
Then you have the claim that the first wave of VOCs had "altered immune evasion potential." Well, no, because natural immunity -- which is the only real kind in the context of this coronavirus -- worked just fine against Delta. So it was just the "antibodies=immunity" assumption being recycled again.
"With a total of 835,792 Israelis known to have recovered from the virus, the 72 instances of reinfection amount to 0.0086% of people who were already infected with [SARS-CoV-2]. By contrast, Israelis who were vaccinated were 6.72 times more likely to get infected after the shot than after natural infection, with over 3,000 of the 5,193,499, or 0.0578%, of Israelis who were vaccinated getting infected in the latest wave." <- early Delta wave https://www.israelnationalnews.com/News/News.aspx/309762
I don't think there any absolutes here... it depends.... from 2015;
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516275/
"Could some vaccines drive the evolution of more virulent pathogens? Conventional wisdom is that natural selection will remove highly lethal pathogens if host death greatly reduces transmission. Vaccines that keep hosts alive but still allow transmission could thus allow very virulent strains to circulate in a population. Here we show experimentally that immunization of chickens against Marek's disease virus enhances the fitness of more virulent strains, making it possible for hyperpathogenic strains to transmit. Immunity elicited by direct vaccination or by maternal vaccination prolongs host survival but does not prevent infection, viral replication or transmission, thus extending the infectious periods of strains otherwise too lethal to persist. Our data show that anti-disease vaccines that do not prevent transmission can create conditions that promote the emergence of pathogen strains that cause more severe disease in unvaccinated hosts."
Herpes viruses have genes that appear to limit tropism. And like bacterial viruses they presumably have some sort of sophisticated "timer" system to regulate dormancy - the genes for how chicken pox "decides" to stop replicating in your nerves before it kills you. So there's some pretty sophisticated host-virus co-evolution there, and as such, we should be worried about a Marek's effect if we keep using chicken pox vaccines for decades. *edit: forgot to link to my post on it https://unglossed.substack.com/p/crackpot-corner-marekspocalypse-edition
On the other hand, it might not be the same since veterinary vaccination arbitrarily keeps immunity so regular. And since there's also the danger to the host's immune response becoming *weaker* from lack of yearly natural "boosters," we could actually be pushing chicken pox in two directions at once. Maybe it will be a wash. I would prefer we banned chicken pox vaccines as well as others, and yes, "because evolution" - but the reason is because it only takes one disaster, not because every time you do it there is a disaster, in other words. It's a black ball in the sack problem.
Can we vote for a show w you & JJ slow walking this w graphics maybe for folks in the bleachers?
This was sort of discussed with Crawford. However, don't know if it will actually happen. Meanwhile I might try my own video presentation, and so part of the motivation for this post is to get some graphics up, though they won't be of a very high production value haha.
I also wouldn't say it's necessary for any individual person to think about or understand both models. But for anyone who finds Couey's not convincing, or too extreme in suggesting that no RNA viruses can spread with fidelity, ok, here is an alternate take. So like I say the argument for multiple releases won't have all its eggs in one basket.
I honestly hope that you and JJ will find a way to discuss things and keep hypotheses open. This is really interesting,and JJ is hell bend to get his model of the truth as close as possible to what might actually be the truth.
He is very aggressive when he is talking alone and very passionate but I have seen him being part of the conversation ... and he is a humble man, he will give you all the space you need to present your ideas, discuss it together,and come up with new ones.
You two are my favorite biology shamans right now.
Please, please make it happen.
Mathew is a favorite & that show was fab and JJ is awesome too. But coming into sciences of biology, virology, immunology & associated Rubrics Cube of mixed & mangled information sources, lots of us are just trying to reduce our confusion & it's a pretty high bar. :~)
This was very interesting. Your analogies facilitate understanding greatly. Thank you!
Thanks!
I fear you may need to find some other analogy to explain ideas as some of us have never played computer games and haven’t a clue what you’re on about!
On a separate note - I’ve just finished listening to ‘ Inventing the AIDS virus’ which seems to stop around 1995. The only other thing I think I know about HIV is that it infects CD4 T cells. What should I read next to get a better understanding? If it’s a ‘harmless bystander’ then why is everyone so worked up about it having parts incorporated into the SARSCov2 spike? Thanks!
Hm... I am not sure any other analogy is possible. THPS is sheer perfection. It is like riding a bike, in terms of movements becoming automatic after a certain amount of play, only everyone who plays THPS literally is hitting the same buttons, and the buttons can be easily converted to a sequence of codes so that you could actually make a machine that plays a level by punching on the controller to get the highest possible score, if you wanted. Well, I have probably made the whole thing even more confusing!
I am still delinquent on my HIV research, sadly. I'd say at the moment, just based on glimpses of the evidence absorbed by osmosis, I'm leaning more toward HIV at very high initial doses does cause AIDS simply because well, you gave it too much of a head start; similar to a spirochaete bacterium (syphilis etc). It's not something you have to worry about bumping into on the street but it can spread with sex and maybe also be a *marker* for pre-existing immune dysfunction in cases where it spreads more easily. So we should still be very suspicious about the fact that it suddenly would explode out of nowhere. I think there is a mix of HIV causing AIDS and being next to it.
What is it doing on the SARS-CoV-2 spike? Either a back-story involving a coronavirus live HIV vaccine or just an intentional signature of human manipulation. But I don't think there's anything to worry about, it's just some amino acids in a string in the end.
I am not a scientist but I do find this article's theory very interesting so I would like to ask my question even though it might already have been answered in a way I failed to grasp.
So what I am confused about is why there would be one single max fitness for each virus. Wouldn't there be a huge variety of max fitness when you look at virus - host combined? So for instance human cell ace2 expression variation might create subsets of people to whom one coronavirus spike protein mutation would be more fit and less fit for others. Then we have a whole bunch of little fitness 'holes' and when some pressure forces a virus out of one hole it may fall down into another, changing which subset of hosts it is better adapted to. It is still optimal but optimal is contingent on host-virus as a set.
I read about some experiment in chemistry that was related to quantum physics. They could balance some substance on a hill where it was exactly between two states. The slightest nudge including measurement would push it into one or the other. It would resolve to one of the two states and be stuck there. Why wouldn't a virus have a lot of these potential contingent optimal states and immune pressure pushes it up a hill of low fitness where it falls into a new hole of contingent fitness? So isn't optimal a moving target that is also dependent on host-virus subsets?
This gets a bit into the metaphysical questions inherent in sequencing. By definition, when you do a sequence and you are amplifying (copy-pasting) all these scraps of genetic material and using a computer to stitch them back together, any non-consensus results are either going to be discarded or considered putative evidence of co-infection or swarm mutants. If your whole sequence is full of conflicts then your original sample wasn't "hot" enough in terms of having a lot of copies of a single virus genome.
So this creates a favoritism for whatever version of the virus "THPS move set" replicates best in a given host and/or in your cell culture. So as long as those two things overlap with "optimum in the host ecosystem overall" then you are going to see the consensus genes in this sequence reappear in a sequence some years down the line. It is a bit like humans being spoiled, rich bachelors that only see the coolest parties, which only have the same coolest people in the same clothes in them. It doesn't matter what the viruses at the comics and games shop playing D&D at 7pm are up to.
So, the question of "what *is* a non-repeating sequence" is tricky. Was it just an artifact on your one sequence that one time, or a lineage that slipped on the fitness slope and later died out, etc. Generally you can't trust any gene that isn't repeated in another sequence, but at the same time you "know" that dead-end offshoots or background coinfector / "swarm" mutants probably exist at least sometimes. So the only approach here is to be a bit ambivalent about one-off mutant sequences. And if you are doing a phylogenetic analysis you use consensus and read depth markers to make a quality cut-off which hopefully makes artifacts minimal in the overall proportion of samples.
Overall, the further a virus slips down the fitness slope, the less accurately we can reliably see what it even is, and this will be relative in terms of the currently best-at-replicating model in whatever the virus replicates in right before you sequence it.
Yet there appears to be a limit to how "rich" viral diversity really is in that lab- or infection-condition bottlenecks aren't able to find viruses that are more than one or two mutations from the consensus genome going in. Again the example here is the OPV, which bottlenecks during administration due to most copies of the virus being nearly replication incompetent, but the difference is a single mutation. So you find the "swarm" variant when you passage OPV through a human but it was only one gene different.
But even this is subject to limitations due to the wonky metaphysical nature of viral replication. It may simply be that swarm variants need to be present in a certain percentage to tip the scales of clonal interference - where the best "move set" is still out-competed by the suboptimal set by pure starting numbers.
All of this comes into play with SARS-CoV-2 as well.
Regarding host molecular heterogeneity, it should probably be thought of as akin to a host species barrier. So you might have some cross-transmission like for avian to swine/human but outside of those cross-overs it would be like having two viruses.
I didn't really think of the measurement / observer problems inherent in amplification and sequencing either so thanks for bringing that up! It is a lot of food for thought. The limitations and guesswork that sequencing introduces makes virology seem more and more akin to quantum physics.
Which once again demonstrates the virtue of a DNA<>virus infectious clone construct. Plug and play!
Is Tony Honk just a clever clown-world themed parody, or is that the name it was actually released under in some places?
Lucky is the alternate universe where Japanese Playstation owners were forced to buy Tony Honk due to copyright conflicts. I am just using it partly to be facetious and partly because it really does feel weird to turn a real person's name into a theory about RNA virus evolution. But THPS is the perfect model.