I've actually wanted to comment on this for quite some time but I still haven't been able to adequately parse your recent posts. From many of the immunocompromised studies I've looked at, including some of the studies from PAXLOVID and Molnupiravir they note similar mutations occurring, such as the N501Y and the E484K mutation appearing.
Correct, and those mutations appear in regular sequences throughout 2020 as well. This is discussed extensively in the Rambaut paper, I must say - there is a reason I keep citing it!
"N501Y in particular has been monitored throughout the pandemic, due to its ability to increase binding to the ACE2 of human and murine cells. However, it appears that by itself, it is not necessarily enough to create a VOC, as there was a cluster in Wales in late 2020 defined by N501Y, but without the NSP6 deletion, which was rapidly outcompeted by Alpha"
So N501Y is not particularly a "immunocompromised signature" nor does it explain why the VOCs displace ancestral strains. There is therefore no intrinsic fitness justification for multiple other, non-ancestral "passenger" mutations appearing with either mutation.
No, but it was one of the mutations I mention because It's one of the ones I can readily remember. I guess you can guess what the other one is!
There's always an inherent tradeoff with some of these mutations, some mutations may be some compensatory mechanism such as the 69-70 deletion but I think that became contested. I think it just suggests there's a lot we don't know but assume that a mutation that persists is a mutation that inherently benefits the virus.
I thought that you might enjoy this new study, that seems to demonstrate quite "surprisingly" that younger, less wealthy and healthier people who drive more get into more traffic accidents than older, more wealthy and less healthy people who drive less: https://www.amjmed.com/article/S0002-9343(22)00822-1/fulltext
The most interesting thing to me about this study was that the risk of COVID infection among the vaccinated was 4.1% while the risk of COVID infection among the unvaccinated was 3.5%.
It is also very interesting to me how the Canada Research Chair in Medical Decision Sciences, the Canadian Institutes of Health Research, the Graduate Diploma in Health Research at the University of Toronto, and the National Sciences & Engineering Research Council of Canada all somehow managed to come through with the funds to investigate the hypothesis that younger, less wealthy and healthier people who drive more get into more traffic accidents than older, more wealthy and less healthy people who drive less, but somehow never considered funding the exact same sort of study to investigate which populations use hospitals more for health conditions associated with potential adverse effects of vaccines.
It's certainly a funny choice of how to waste one's time, on the part of the authors. They have no idea how much driving either group is doing! The vaxxed were all probably still hiding from Delta.
The 4.1/3.5 is baseline - during the study period they find the "severe Covid" rate higher for the unvaxxed which is fine if they are adjusting for age, I have stopped reading haha.
Brian, the last several posts of yours were exceptionally interesting, but unfortunately I realized that I cannot evaluate their correctness due to not knowing enough. I try my best to follow each of them however.
Have you seen recent, and NOT so recent suggestions that the latest variant soup is driven by molnupiravir?
Do you have evidence of those reports Igor? I've covered Molnupiravir quite a bit in the past and the initial comments were concerned about variants sprouting up. However, as a caveat I don't believe molnupiravir is being prescribed to the same extent as PAXLOVID, although the consternations made by the committee last year (around this time, actually) dumbfounded me.
About a month ago, I saw some convincingly looking tweets that showed a lot of mutated viruses with very high number of meaningless mutations and it looked legit.
I did NOT write about it because I felt unable to fact-check that stuff but it looked newsworthy and based on some evidence -- quality of which I could not properly evaluate.
It makes sense too that mutagenic drug that does not always stop infection would cause propagation of highly mutated viruses.
It was one of the primary concerns during the FDA committee meeting on the drug. As to whether it would come to fruition is something that should be looked out for but doesn't appear to be extensively examined. The clinical trials from Merck showed that the mutations seen were similar to those found in other variants and so they couldn't discern whether it was due to the drug or due to those variants just winning out and gaining prominence in select groups.
There's far too much noise in the data and there should have been many studies done to look into the drug.
It should also be noted that there are mutagenic drugs in use such as Ribavirin, but not to the extent that Molnupiravir is being deployed.
Ironically, when Dr. McCullough went onto Joe Rogan's podcast he mentioned an antiviral used in Japan for the flu but was not used anywhere else and argued we should look into it for COVID.
That drug was Favipiravir, and that itself is also a mutagen and one of the reasons Japan is one of a select few countries that deploys that drug. I made the same arguments critical of that drug as I did with Molnupiravir.
At the end of the day there's so many unknowns but we would hope that evidence comes up to substantiate or refute the idea through rigorous testing.
The scrabble variants are not highly mutated if compared to Alpha to Omicron's "release" builds, which all "parachute in" above the normal trend. At best, the scrabble variants are slightly above trend but that is normal, for sequences in a short-time to overclock versus long term, thanks again to stabilizing/purifying selection (most sequenced mutations do not survive the test of time).
Yikes, that's a throwback. I think a predicted M mutation signature is supposed to be to even further promote C>U, but then half the sources say U>C? At a glance I see a lot of >G> in the scrabble RBD spike mutations, very little C<>U action.
I've actually wanted to comment on this for quite some time but I still haven't been able to adequately parse your recent posts. From many of the immunocompromised studies I've looked at, including some of the studies from PAXLOVID and Molnupiravir they note similar mutations occurring, such as the N501Y and the E484K mutation appearing.
Correct, and those mutations appear in regular sequences throughout 2020 as well. This is discussed extensively in the Rambaut paper, I must say - there is a reason I keep citing it!
"N501Y in particular has been monitored throughout the pandemic, due to its ability to increase binding to the ACE2 of human and murine cells. However, it appears that by itself, it is not necessarily enough to create a VOC, as there was a cluster in Wales in late 2020 defined by N501Y, but without the NSP6 deletion, which was rapidly outcompeted by Alpha"
https://www.biorxiv.org/content/10.1101/2022.03.08.481609v1
So N501Y is not particularly a "immunocompromised signature" nor does it explain why the VOCs displace ancestral strains. There is therefore no intrinsic fitness justification for multiple other, non-ancestral "passenger" mutations appearing with either mutation.
No, but it was one of the mutations I mention because It's one of the ones I can readily remember. I guess you can guess what the other one is!
There's always an inherent tradeoff with some of these mutations, some mutations may be some compensatory mechanism such as the 69-70 deletion but I think that became contested. I think it just suggests there's a lot we don't know but assume that a mutation that persists is a mutation that inherently benefits the virus.
Nice job, as usual, Brian.
I thought that you might enjoy this new study, that seems to demonstrate quite "surprisingly" that younger, less wealthy and healthier people who drive more get into more traffic accidents than older, more wealthy and less healthy people who drive less: https://www.amjmed.com/article/S0002-9343(22)00822-1/fulltext
The most interesting thing to me about this study was that the risk of COVID infection among the vaccinated was 4.1% while the risk of COVID infection among the unvaccinated was 3.5%.
It is also very interesting to me how the Canada Research Chair in Medical Decision Sciences, the Canadian Institutes of Health Research, the Graduate Diploma in Health Research at the University of Toronto, and the National Sciences & Engineering Research Council of Canada all somehow managed to come through with the funds to investigate the hypothesis that younger, less wealthy and healthier people who drive more get into more traffic accidents than older, more wealthy and less healthy people who drive less, but somehow never considered funding the exact same sort of study to investigate which populations use hospitals more for health conditions associated with potential adverse effects of vaccines.
It's certainly a funny choice of how to waste one's time, on the part of the authors. They have no idea how much driving either group is doing! The vaxxed were all probably still hiding from Delta.
The 4.1/3.5 is baseline - during the study period they find the "severe Covid" rate higher for the unvaxxed which is fine if they are adjusting for age, I have stopped reading haha.
I'm laughing quite loudly at the title.
Cool, nice job detective. 🧐
Brian, the last several posts of yours were exceptionally interesting, but unfortunately I realized that I cannot evaluate their correctness due to not knowing enough. I try my best to follow each of them however.
Have you seen recent, and NOT so recent suggestions that the latest variant soup is driven by molnupiravir?
Do you have evidence of those reports Igor? I've covered Molnupiravir quite a bit in the past and the initial comments were concerned about variants sprouting up. However, as a caveat I don't believe molnupiravir is being prescribed to the same extent as PAXLOVID, although the consternations made by the committee last year (around this time, actually) dumbfounded me.
Just wrote an article also linking to you and Brian
Maybe I should write at least something about it...
About a month ago, I saw some convincingly looking tweets that showed a lot of mutated viruses with very high number of meaningless mutations and it looked legit.
I did NOT write about it because I felt unable to fact-check that stuff but it looked newsworthy and based on some evidence -- quality of which I could not properly evaluate.
It makes sense too that mutagenic drug that does not always stop infection would cause propagation of highly mutated viruses.
It was one of the primary concerns during the FDA committee meeting on the drug. As to whether it would come to fruition is something that should be looked out for but doesn't appear to be extensively examined. The clinical trials from Merck showed that the mutations seen were similar to those found in other variants and so they couldn't discern whether it was due to the drug or due to those variants just winning out and gaining prominence in select groups.
There's far too much noise in the data and there should have been many studies done to look into the drug.
It should also be noted that there are mutagenic drugs in use such as Ribavirin, but not to the extent that Molnupiravir is being deployed.
Ironically, when Dr. McCullough went onto Joe Rogan's podcast he mentioned an antiviral used in Japan for the flu but was not used anywhere else and argued we should look into it for COVID.
That drug was Favipiravir, and that itself is also a mutagen and one of the reasons Japan is one of a select few countries that deploys that drug. I made the same arguments critical of that drug as I did with Molnupiravir.
At the end of the day there's so many unknowns but we would hope that evidence comes up to substantiate or refute the idea through rigorous testing.
The scrabble variants are not highly mutated if compared to Alpha to Omicron's "release" builds, which all "parachute in" above the normal trend. At best, the scrabble variants are slightly above trend but that is normal, for sequences in a short-time to overclock versus long term, thanks again to stabilizing/purifying selection (most sequenced mutations do not survive the test of time).
I just posted an article - linking to your year old article and modern discontent article - as food for thought to discuss.
I believe that there is something with the appearance of weirdly mutated variants.
I am also honestly not buying that all variants are lab built - but love your articles as they stimulate thinking and useful discussions.
Yikes, that's a throwback. I think a predicted M mutation signature is supposed to be to even further promote C>U, but then half the sources say U>C? At a glance I see a lot of >G> in the scrabble RBD spike mutations, very little C<>U action.
L452R u>g
N460K c>ag
K444R a>g
R346T g>c
F490S u>c
R346T g>c
F486I u>a
G446S g>a