Thank you for this, I really appreciate your approach ➡️-"It’s easy to look at case rates and make assumptions, but in order to examine the nuances and complexities to suggest that this is a variant of the vaccinated, we need to examine all of the factors required to make such an assumption."
Thanks Nova. I suppose I find it rather strange (or I suppose against my general approach) to look at charts of case rates and extrapolate so much from there. We can't tell much of anything, such as what is happening on an individual, let alone the relationship between a positive case and the course of the disease.
Jul 6, 2022·edited Jul 6, 2022Liked by Modern Discontent
Super job clarifying all the research, ty.
“Reversions” vs BA.2 should be interpreted keeping in mind that all the Omicron siblings have an LCA of B.1 version of SARS-CoV-2, and that these “new” siblings were already sequenced in winter, suggesting they were present in the original viral swarm the same way BA.2 doesn’t make sense as a “descendent” of BA.1. So vs the last pre-sequence ancestor (“BA.2 clade beta build”), BA.2 added Q493R while the others added other stuff.
It may not be the case that they are more fit, given that the Q493R sibling was first after BA.1 to dominate. Instead, it may be that BA.2 had more competition from high levels of BA.1-conferred response which has now waned and provided the other siblings a much less competitive game field.
Paradoxically, 4 and 5 still benefit *vs* BA.2 thanks to residual anti-BA.2 response, even if said response is a huge negative compared to how they would do in a naive population (so a relative benefit but an absolute detriment). The analogy would be an action film (“BA.2”) which was released contemporaneously to one with a similar story (“BA.1 / Omicron”) then being edited with some B-roll footage thrown in and passed off as a “sequel” (“BA.4/5”). BA.2 was disadvantaged by the similar contemporary release of BA.1, and the “sequel” 4/5 wouldn’t do as well as 2 at the box office but would still obviously do better than just releasing un-edited 2 again.
The “fitness” of the 452R would have to be thought of in the context of this shifting field of market novelty. It should also be kept in mind that better fusion / virulence doesn’t necessarily improve transmission so this could be purely a toxicity mutation and once again (as I suggest in Omicron Origins https://unglossed.substack.com/p/omicron-origins-part-1) could have been (along with the rest of the BA.2 clade set) the actual intended-for-release “Omicron” sequence.
Thanks for your insight Brian. It's always appreciated. I haven't looked too extensively into Omicron since I wrote my first piece in January, so I suppose I had a wide gap in knowledge. It does make sense that they likely emerged around a similar point in time. Do you consider this to be an indication of zoonotic emergence (WAIT- nvm I went back to read your origins post!)? There's generally the idea of the immunocompromised individual but that argument just didn't quite fit right.
The Q493R one is actually interesting since I didn't necessarily find a large argument in favor of some sort of enhanced binding, just extrapolated from the emergence of both Q493K and Q493R mutations, although the side chain length of both may be comparable and may be more related to escape from prior immunity.
I'm always fascinated by your analogies Brian. I always assume there's some higher level of cognition going on to create these scenarios. I do understand B-roll, as in I understand it enough to hate it! But I do believe I understand your analogy. Ba.2 and Ba.1 emerged around the same time, but unfortunately Ba.1 won out leaving Ba.2 to have to change itself up to try to compete. However, given a landscape that is aware of Ba.1 and some who are aware of Ba.2 there is an issue with respect to Ba.4/5 being released?
Your remark on L452 is actually interesting. Some of the evidence (although examined rather loosely) suggest that L452R came about in many of the variants before Omicron, and it's supposedly this mutation that is the culprit for Delta's increased virulence. One of the articles suggests an increase in viral replication, although I believe it may be more of a supposition.
Altogether, if the intention was to create a variant with L452R it makes one wonder about the eventual emergence through serial human passage and the relation between the intentional lab design. So I believe your suggestion is that both Ba.1 and Ba.2 may be a result of different lab experiments, but that they may have escaped/released which explains how they are both so distinct from Wuhan and those variants while also being so distinct from each other?
I'm also trying to look at this within the context of OAS, but the biggest issue here is figuring out what to do with Omicron, and my general suspicion is to really treat it as wholly separate from prior variants because the connecting features are seriously lacking here.
Jul 8, 2022·edited Jul 8, 2022Liked by Modern Discontent
Right, Origins Part 1 essentially lays out my reasoning for why natural / zoonotic / clandestine co-evolution of BA.1 and 2 (+4/5) is preposterous whether with a 1.5 year or 4 year (Ethical Skeptic) timeline. So it had to be a lab.
Growing a virus at scale makes it intrinsically hard for there to be just “one” version of the virus. LAV vaccines and the risk of deattenuated-batches are an obvious example, but there are probably all sorts of “variant” viruses in any given vaccine batch (ie a viral swarm) and the only difference is that:
1 - SARS-CoV-2 is transmission competent and so we can catch the initially non-dominate variants once they real-life passage enough to produce a QA-passing sequence, whereas in a vax batch there would be no way to sequence without culturing which introduces observer distortion.
2 - The final dominate sequence was still intentionally being “cooked” (passaged in a high pressure environment) before hypothetical scale-up and release and so it has additional “variant” mutations of its own, and that’s what 493R on BA.2 is. So there’s no reversion, 4 and 5 are just descendants of the pre-release LCA that went a different path.
The fact that 4 and 5 are not something that emerged *from* BA.2 ( as in the post-sequencing/release virus that was infecting humans) is the most important takeaway. They were obscure variants in the initial release that were caught on sequence pretty much the same time as BA.2. I don’t have the dates because I’m on mobile.
OAS, which is not real, would insist that BA.2 has a permanent advantage over 4 and 5 due to having 493R, or that 4 and 5 have a permanent advantage due to 452R, and either way cannot account for why one vs-Wuhan-mutation dominated first and fell into decline.
It's actually really weird how that's not talked about much now. I remember it was such a big thing early on and it sort of died out and now we're acting as if Omicron is just part of the general COVID arc and have just included it into a working model rather than viewing it as being distinct. It's one of the reasons why I don't think OAS actually explains the situation. It also doesn't explain Ba.4/Ba.5 being being a variant of the vaccinated to me.
I'm trying to work on a few remarks about Omicron and a bit about immunity that is at least trying to parse a bit of this information.
We also shouldn’t forget about BA.3 despite that being barely a blip in infections. It was also detected in SA at the same time. BA.3 only has 1 unique mutation I believe but shares all others with either BA.1 or BA.2. Unless some recombination event occurred this brings home the swarm of BA being introduced late 2021. BA.3 is then simply another fork that occurred, or likely one of many more never found.
This was actually already proposed by William A. Haseltine from Forbes back in January, except he assumed a natural evolution and states (without too much math) a March 2021 as BA.0 emergence. (But of course that date does not explain why all this was hidden until December 2022.)
Right, or 3 might have been the result of an early co-infection. There were probably lots of Omicron sibling co-infection-recombs but an early early one might be on a better footing to get out there and get sequenced, even if still dying out ultimately.
I wonder though. I've read multiple times corona viruses can recombine, but how frequent is that? I mean relative to our sequencing rates, it seems we barely saw recombinations. Especially during the UK/alpha-variant era when there was a wide variety of significantly different linages competing, shouldn't we have seen more? I also only remember one French case of Delta-Omicron recombination reported.
But if I simply missed it, by reading the wrong literature, I'm happy to be corrected.
But if not, shouldn't we seen lots more of BA.1 + BA.2 comingling? And now BA.2 and BA.4/5? There are plenty of countries where two or more of such variants are widely available. So compared to our 'sequencing sample' rate it seems the recombination rate is not that high. In that case having a set of BA.3's clustered is interesting, although I admit not conclusive.
But if I'm wrong and recombination is not rare, than it seems these recombinations are not really having much advantage, as they seem to pretty much always die out. And that itself should be interesting, as for instance it seems the BA.1 mutations and BA.2 mutations itself seem pretty beneficial as both strains have or in case of BA.1 had a good run, but the BA.3 combo did not. That should tell us more about the benefits/functions of these mutations.
So early in March there were all of these reports of "Deltacron"- apparently Omicron and Delta recombined into this new variant, although it didn't last long.
I'm not sure how frequent recombination occurs honestly. I haven't looked into the literature too much about this topic. Remember that the story of viral dominance is a story of the victor- we only hear of specific mutations because those variants are the ones that win out in the end. There's likely to be tons of mutations and tons of recombinations out there, however they all didn't make the cut and quickly died off.
I'd need to look into this and more into Omicron to figure this out.
Yes, I believe that was in his article about the lineages which commented about those 3. This is all really fascinating, as we look at Wuhan and the first strain of COVID yet here's Omicron probably with the big alarms of "not natural" via some form of evolutionary blasphemy (as Brian pointed out), but there's no mention about that now for some reason.
I think it's even more interesting given that Monkeypox was somewhat jumped on as being of possible lab origin, yet there's also an idea of zoonotic emergence for Monkeypox as well. Maybe both are of lab origin, maybe both are of animal, or maybe we evaluate based on all possibilities?
I think for Omicron I'm becoming even more skeptical of its animal/natural origins.
I did find this website that has some remarks about Ba.4 and Ba.5, and it does appear to have been detected around January, which is rather interesting. I would like to see if there is evidence right around the time of detection for Ba.1 or Ba.2.
Generally most pieces take several hours. This one I dedicated the whole day to after I abandoned another post that probably would have gone on even longer than this one. It usually depends on how extensively I dip into the papers I read. If I try to read them somewhat thoroughly that may take days. I took a few liberties with this post so I suppose that's why I was able to get it out quicker, although I generally would try not to skim papers. However, a few of these are ones I have cited before so I actually remembered the gist of a few of them (such as the monoclonal papers).
Ah - Currently reading https://www.tandfonline.com/doi/epub/10.1080/22221751.2022.2099305 , another recent Sahin/BioNTech study. Includes interesting results with a F486 reversion BA.4 mutant suggesting that the F486V contributes to vaxx escape. Unfortunately no results reported for natural infection vs the BA.4 mutant.
Ok, I didn't realize this was one of those papers that starts as one page and becomes 20 when you download it! I wasn't sure what you were referring to! The notation is interesting. I'm not sure what the acceptable notation for a reversion is (the Hachmann, et. al. mutational lineage chart just removes the mutation) so seeing this one write it in reverse seems strange. I'm appreciating these plot lines more. They're showing the actual pipeline of antibodies for each individual. It's always interesting to see someone who's immune system is just shot regardless, but then one person who doesn't respond to Wuhan/wildtype but may respond very well to Omicron.
I kind of like the tables the best. Two things that stand out are that the BA.1-spike recomb has really inconsistent results across experiments whereas the other recombs are stable. Maybe BA.1 never had a stable spike. This again correspond with BA.1 being some sort of mutant accident that was never meant to be released as I suggest in my Origins Part 2 fictional "template."
Two is that BA.1 conv's have very low response to everything in Table S2. The reason BA.1 natural infection doesn't generate a good neutralizing response could, again, be because BA.1 spike is too unstable to prompt a highly SHM-enriched response. It is like trying to play a corrupted file.
Do you know if any modeling of the Ba.1 spike has been done? Or any type of X-ray crystallography? I'd wonder what about the Ba.1 spike would be interesting.
Honestly the whole "Deltacron" thing caught me off guard, but supposedly the likes of Eric Topol are calling Ba.4/Ba.5 Deltacron because it's behaving like Delta? I wonder if it's because of the L452R mutation. More evidence is needed, but if the similar pattern is seen with this mutation than we may infer that this could be a culprit. It's surprising why this is furthering additional fear.
Jul 15, 2022·edited Jul 15, 2022Liked by Modern Discontent
*edit: Ok there's cryo in this one, already mentioned in the Forbes and your article I think https://www.nature.com/articles/s41586-022-04980-y_reference.pdf way down in Extended Fig 5 and 9. This one probably has a better explanation than my unstable spike theory, going to give it a read
So I went down a rabbit hole after seeing the phrase “HLA-A24 restricted cellular immunity” cause HLA is basically my entire career (clinical rather than research). I also did that with codon optimization a few weeks ago which wrecked me for a bit as many basic assumptions (we totally just ignore synonymous mutations when determining HLA type - it’s literally in the disclaimer on our clinical reports), but I digress.
I’m not really sure where I want to take this comment other than to say that the immune system is so much more than antibodies! You’ve got innate, cell-mediated & humoral immunity. Whether you believe in intelligent design or evolution you can’t deny that the immune system didn’t “put all its eggs in one basket.” Most of the time when you encounter a pathogen your body takes care of it and you are none-the-wiser.
Seems most of the research being done within an extremely narrow focus of the immune system - they’re missing the forest for the trees. Thank you for giving us & encouraging us to get a big picture view of the research currently happening.
Apologies Heidi, but I actually don't know anything about Evusheld. Doing a cursory look it does appear that it's a dual monoclonal therapy that may have an extended half-life and have some prophylactic use. It appears to be for high risk patients. However, I wasn't able to find any evidence as to where it targets.
There is this excerpt from the NEJM article for the clinical trial that mentions this:
"Tixagevimab and cilgavimab simultaneously bind to distinct, nonoverlapping epitopes of the SARS-CoV-2 spike-protein receptor-binding domain to potently neutralize the virus.22-25 AZD7442 has been shown to neutralize SARS-CoV-2 and its variants of concern in vitro and has prophylactic and therapeutic effects in nonhuman primates.22"
So targeting of the receptor binding domain is something of concern since that's where most of Omicron's mutations reside and are likely to reduce binding of monoclonals.
There is this comment from an article by Keam, S. J. that appears to insinuate that Evusheld may have lost some effectiveness in the wake of Omicron:
"A higher 600 mg dose, consisting of 300 mg of tixagevimab and 300 mg of cilgavimab, may be more appropriate for some SARS-CoV-2 variants (for example, Omicron BA.1, Omicron BA.1.1), based on in vitro neutralisation susceptibility data which show reduced susceptibility for tixagevimab + cilgavimab [9, 10]. "
I would comment that I am not a medical professional so please don't consider my remarks as medical advice. But based on this you may want to discuss this with your son's doctor and see if they can provide you with more information on the subject.
I'll try to look around and skim to see what I can find, but unfortunately I haven't actually spent time looking up this monoclonal in particular.
That's definitely something worth discussing with your son's doctor. I suppose it really comes down to serum levels considering the remarks above indicate a higher dose may be needed. ADE is interesting, but generally for monoclonals I believe there is a concern about autoimmune disease depending upon the type of therapy given. Unfortunately there may not be research until further evidence comes out.
So I went back and skimmed a bit. It appears to be effective against Ba.2, and even though it targets the RBD it does use a conserved region. That does add more to its value, but even with that we may need to see evidence against Ba.4/Ba.5.
So I looked it up, and it did have a lot of promise. It does appear to target the receptor binding domain of the spike protein, although a lot of the evidence appears to have been for Ba.1 so there may be concerns with Ba.4/Ba.5
It's a general concern for monoclonals. I'm not sure how common they are, but they are a possibility. It is providing someone with another person's antibodies, so I suppose there's some concerns about how the body reacts to these antibodies (whether favorably or detrimentally).
I'm sorry for your situation Heidi. I find it rather ridiculous the situation that monoclonals have been put in. I mean, we had people who were touting convalescent plasma therapy since the beginning of the pandemic, yet many people spoke out against monoclonals. What do they think was in the plasma that they were giving people?
It's ridiculous that your son isn't considered high risk or something that would allow him higher priority. All the best to you and your son Heidi. I wish you didn't have to be in the position that you are.
Thank you for this, I really appreciate your approach ➡️-"It’s easy to look at case rates and make assumptions, but in order to examine the nuances and complexities to suggest that this is a variant of the vaccinated, we need to examine all of the factors required to make such an assumption."
Thanks Nova. I suppose I find it rather strange (or I suppose against my general approach) to look at charts of case rates and extrapolate so much from there. We can't tell much of anything, such as what is happening on an individual, let alone the relationship between a positive case and the course of the disease.
Excellent work.
Anxiously awaiting the next.
Oh boy, I'm not sure whether I should quell anticipation, or feign some sort of hubris!
Super job clarifying all the research, ty.
“Reversions” vs BA.2 should be interpreted keeping in mind that all the Omicron siblings have an LCA of B.1 version of SARS-CoV-2, and that these “new” siblings were already sequenced in winter, suggesting they were present in the original viral swarm the same way BA.2 doesn’t make sense as a “descendent” of BA.1. So vs the last pre-sequence ancestor (“BA.2 clade beta build”), BA.2 added Q493R while the others added other stuff.
It may not be the case that they are more fit, given that the Q493R sibling was first after BA.1 to dominate. Instead, it may be that BA.2 had more competition from high levels of BA.1-conferred response which has now waned and provided the other siblings a much less competitive game field.
Paradoxically, 4 and 5 still benefit *vs* BA.2 thanks to residual anti-BA.2 response, even if said response is a huge negative compared to how they would do in a naive population (so a relative benefit but an absolute detriment). The analogy would be an action film (“BA.2”) which was released contemporaneously to one with a similar story (“BA.1 / Omicron”) then being edited with some B-roll footage thrown in and passed off as a “sequel” (“BA.4/5”). BA.2 was disadvantaged by the similar contemporary release of BA.1, and the “sequel” 4/5 wouldn’t do as well as 2 at the box office but would still obviously do better than just releasing un-edited 2 again.
The “fitness” of the 452R would have to be thought of in the context of this shifting field of market novelty. It should also be kept in mind that better fusion / virulence doesn’t necessarily improve transmission so this could be purely a toxicity mutation and once again (as I suggest in Omicron Origins https://unglossed.substack.com/p/omicron-origins-part-1) could have been (along with the rest of the BA.2 clade set) the actual intended-for-release “Omicron” sequence.
Thanks for your insight Brian. It's always appreciated. I haven't looked too extensively into Omicron since I wrote my first piece in January, so I suppose I had a wide gap in knowledge. It does make sense that they likely emerged around a similar point in time. Do you consider this to be an indication of zoonotic emergence (WAIT- nvm I went back to read your origins post!)? There's generally the idea of the immunocompromised individual but that argument just didn't quite fit right.
The Q493R one is actually interesting since I didn't necessarily find a large argument in favor of some sort of enhanced binding, just extrapolated from the emergence of both Q493K and Q493R mutations, although the side chain length of both may be comparable and may be more related to escape from prior immunity.
I'm always fascinated by your analogies Brian. I always assume there's some higher level of cognition going on to create these scenarios. I do understand B-roll, as in I understand it enough to hate it! But I do believe I understand your analogy. Ba.2 and Ba.1 emerged around the same time, but unfortunately Ba.1 won out leaving Ba.2 to have to change itself up to try to compete. However, given a landscape that is aware of Ba.1 and some who are aware of Ba.2 there is an issue with respect to Ba.4/5 being released?
Your remark on L452 is actually interesting. Some of the evidence (although examined rather loosely) suggest that L452R came about in many of the variants before Omicron, and it's supposedly this mutation that is the culprit for Delta's increased virulence. One of the articles suggests an increase in viral replication, although I believe it may be more of a supposition.
Altogether, if the intention was to create a variant with L452R it makes one wonder about the eventual emergence through serial human passage and the relation between the intentional lab design. So I believe your suggestion is that both Ba.1 and Ba.2 may be a result of different lab experiments, but that they may have escaped/released which explains how they are both so distinct from Wuhan and those variants while also being so distinct from each other?
I'm also trying to look at this within the context of OAS, but the biggest issue here is figuring out what to do with Omicron, and my general suspicion is to really treat it as wholly separate from prior variants because the connecting features are seriously lacking here.
Right, Origins Part 1 essentially lays out my reasoning for why natural / zoonotic / clandestine co-evolution of BA.1 and 2 (+4/5) is preposterous whether with a 1.5 year or 4 year (Ethical Skeptic) timeline. So it had to be a lab.
Growing a virus at scale makes it intrinsically hard for there to be just “one” version of the virus. LAV vaccines and the risk of deattenuated-batches are an obvious example, but there are probably all sorts of “variant” viruses in any given vaccine batch (ie a viral swarm) and the only difference is that:
1 - SARS-CoV-2 is transmission competent and so we can catch the initially non-dominate variants once they real-life passage enough to produce a QA-passing sequence, whereas in a vax batch there would be no way to sequence without culturing which introduces observer distortion.
2 - The final dominate sequence was still intentionally being “cooked” (passaged in a high pressure environment) before hypothetical scale-up and release and so it has additional “variant” mutations of its own, and that’s what 493R on BA.2 is. So there’s no reversion, 4 and 5 are just descendants of the pre-release LCA that went a different path.
The fact that 4 and 5 are not something that emerged *from* BA.2 ( as in the post-sequencing/release virus that was infecting humans) is the most important takeaway. They were obscure variants in the initial release that were caught on sequence pretty much the same time as BA.2. I don’t have the dates because I’m on mobile.
OAS, which is not real, would insist that BA.2 has a permanent advantage over 4 and 5 due to having 493R, or that 4 and 5 have a permanent advantage due to 452R, and either way cannot account for why one vs-Wuhan-mutation dominated first and fell into decline.
It's actually really weird how that's not talked about much now. I remember it was such a big thing early on and it sort of died out and now we're acting as if Omicron is just part of the general COVID arc and have just included it into a working model rather than viewing it as being distinct. It's one of the reasons why I don't think OAS actually explains the situation. It also doesn't explain Ba.4/Ba.5 being being a variant of the vaccinated to me.
I'm trying to work on a few remarks about Omicron and a bit about immunity that is at least trying to parse a bit of this information.
We also shouldn’t forget about BA.3 despite that being barely a blip in infections. It was also detected in SA at the same time. BA.3 only has 1 unique mutation I believe but shares all others with either BA.1 or BA.2. Unless some recombination event occurred this brings home the swarm of BA being introduced late 2021. BA.3 is then simply another fork that occurred, or likely one of many more never found.
This was actually already proposed by William A. Haseltine from Forbes back in January, except he assumed a natural evolution and states (without too much math) a March 2021 as BA.0 emergence. (But of course that date does not explain why all this was hidden until December 2022.)
Right, or 3 might have been the result of an early co-infection. There were probably lots of Omicron sibling co-infection-recombs but an early early one might be on a better footing to get out there and get sequenced, even if still dying out ultimately.
I wonder though. I've read multiple times corona viruses can recombine, but how frequent is that? I mean relative to our sequencing rates, it seems we barely saw recombinations. Especially during the UK/alpha-variant era when there was a wide variety of significantly different linages competing, shouldn't we have seen more? I also only remember one French case of Delta-Omicron recombination reported.
But if I simply missed it, by reading the wrong literature, I'm happy to be corrected.
But if not, shouldn't we seen lots more of BA.1 + BA.2 comingling? And now BA.2 and BA.4/5? There are plenty of countries where two or more of such variants are widely available. So compared to our 'sequencing sample' rate it seems the recombination rate is not that high. In that case having a set of BA.3's clustered is interesting, although I admit not conclusive.
But if I'm wrong and recombination is not rare, than it seems these recombinations are not really having much advantage, as they seem to pretty much always die out. And that itself should be interesting, as for instance it seems the BA.1 mutations and BA.2 mutations itself seem pretty beneficial as both strains have or in case of BA.1 had a good run, but the BA.3 combo did not. That should tell us more about the benefits/functions of these mutations.
So early in March there were all of these reports of "Deltacron"- apparently Omicron and Delta recombined into this new variant, although it didn't last long.
I'm not sure how frequent recombination occurs honestly. I haven't looked into the literature too much about this topic. Remember that the story of viral dominance is a story of the victor- we only hear of specific mutations because those variants are the ones that win out in the end. There's likely to be tons of mutations and tons of recombinations out there, however they all didn't make the cut and quickly died off.
I'd need to look into this and more into Omicron to figure this out.
Yes, I believe that was in his article about the lineages which commented about those 3. This is all really fascinating, as we look at Wuhan and the first strain of COVID yet here's Omicron probably with the big alarms of "not natural" via some form of evolutionary blasphemy (as Brian pointed out), but there's no mention about that now for some reason.
I think it's even more interesting given that Monkeypox was somewhat jumped on as being of possible lab origin, yet there's also an idea of zoonotic emergence for Monkeypox as well. Maybe both are of lab origin, maybe both are of animal, or maybe we evaluate based on all possibilities?
I think for Omicron I'm becoming even more skeptical of its animal/natural origins.
I did find this website that has some remarks about Ba.4 and Ba.5, and it does appear to have been detected around January, which is rather interesting. I would like to see if there is evidence right around the time of detection for Ba.1 or Ba.2.
https://www.nicd.ac.za/omicron-lineages-ba-4-and-ba-5-faq/
Wow. How many hours does it take you to write all this up?
Generally most pieces take several hours. This one I dedicated the whole day to after I abandoned another post that probably would have gone on even longer than this one. It usually depends on how extensively I dip into the papers I read. If I try to read them somewhat thoroughly that may take days. I took a few liberties with this post so I suppose that's why I was able to get it out quicker, although I generally would try not to skim papers. However, a few of these are ones I have cited before so I actually remembered the gist of a few of them (such as the monoclonal papers).
Ah - Currently reading https://www.tandfonline.com/doi/epub/10.1080/22221751.2022.2099305 , another recent Sahin/BioNTech study. Includes interesting results with a F486 reversion BA.4 mutant suggesting that the F486V contributes to vaxx escape. Unfortunately no results reported for natural infection vs the BA.4 mutant.
Wow, very interesting! I'll try taking a look at it. If only I kept all my mutation tabs in one place...
I should have warned - mutant BA.4 results are hiding in the pdf at the bottom, starting with Fig S2
Ok, I didn't realize this was one of those papers that starts as one page and becomes 20 when you download it! I wasn't sure what you were referring to! The notation is interesting. I'm not sure what the acceptable notation for a reversion is (the Hachmann, et. al. mutational lineage chart just removes the mutation) so seeing this one write it in reverse seems strange. I'm appreciating these plot lines more. They're showing the actual pipeline of antibodies for each individual. It's always interesting to see someone who's immune system is just shot regardless, but then one person who doesn't respond to Wuhan/wildtype but may respond very well to Omicron.
Individual differences at play here.
I kind of like the tables the best. Two things that stand out are that the BA.1-spike recomb has really inconsistent results across experiments whereas the other recombs are stable. Maybe BA.1 never had a stable spike. This again correspond with BA.1 being some sort of mutant accident that was never meant to be released as I suggest in my Origins Part 2 fictional "template."
Two is that BA.1 conv's have very low response to everything in Table S2. The reason BA.1 natural infection doesn't generate a good neutralizing response could, again, be because BA.1 spike is too unstable to prompt a highly SHM-enriched response. It is like trying to play a corrupted file.
Do you know if any modeling of the Ba.1 spike has been done? Or any type of X-ray crystallography? I'd wonder what about the Ba.1 spike would be interesting.
Honestly the whole "Deltacron" thing caught me off guard, but supposedly the likes of Eric Topol are calling Ba.4/Ba.5 Deltacron because it's behaving like Delta? I wonder if it's because of the L452R mutation. More evidence is needed, but if the similar pattern is seen with this mutation than we may infer that this could be a culprit. It's surprising why this is furthering additional fear.
*edit: Ok there's cryo in this one, already mentioned in the Forbes and your article I think https://www.nature.com/articles/s41586-022-04980-y_reference.pdf way down in Extended Fig 5 and 9. This one probably has a better explanation than my unstable spike theory, going to give it a read
Not sure if any crystallography. https://chemistry-europe.onlinelibrary.wiley.com/doi/full/10.1002/cbic.202100681 models just the RBD, https://covariants.org/variants/21K.Omicron has a GISAID-furnished model, also one at https://www.biorxiv.org/content/10.1101/2021.12.17.473248v2.full. Modeling is only safe when we're sure that cells are able to produce a functional thing in the first place, and sort-of know what the function is. This would be questionable for BA.1.
A great, foundational article! Took me a while to read and was truly a pleasure.
So I went down a rabbit hole after seeing the phrase “HLA-A24 restricted cellular immunity” cause HLA is basically my entire career (clinical rather than research). I also did that with codon optimization a few weeks ago which wrecked me for a bit as many basic assumptions (we totally just ignore synonymous mutations when determining HLA type - it’s literally in the disclaimer on our clinical reports), but I digress.
I’m not really sure where I want to take this comment other than to say that the immune system is so much more than antibodies! You’ve got innate, cell-mediated & humoral immunity. Whether you believe in intelligent design or evolution you can’t deny that the immune system didn’t “put all its eggs in one basket.” Most of the time when you encounter a pathogen your body takes care of it and you are none-the-wiser.
Seems most of the research being done within an extremely narrow focus of the immune system - they’re missing the forest for the trees. Thank you for giving us & encouraging us to get a big picture view of the research currently happening.
Apologies Heidi, but I actually don't know anything about Evusheld. Doing a cursory look it does appear that it's a dual monoclonal therapy that may have an extended half-life and have some prophylactic use. It appears to be for high risk patients. However, I wasn't able to find any evidence as to where it targets.
There is this excerpt from the NEJM article for the clinical trial that mentions this:
"Tixagevimab and cilgavimab simultaneously bind to distinct, nonoverlapping epitopes of the SARS-CoV-2 spike-protein receptor-binding domain to potently neutralize the virus.22-25 AZD7442 has been shown to neutralize SARS-CoV-2 and its variants of concern in vitro and has prophylactic and therapeutic effects in nonhuman primates.22"
Article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9069994/
So targeting of the receptor binding domain is something of concern since that's where most of Omicron's mutations reside and are likely to reduce binding of monoclonals.
There is this comment from an article by Keam, S. J. that appears to insinuate that Evusheld may have lost some effectiveness in the wake of Omicron:
"A higher 600 mg dose, consisting of 300 mg of tixagevimab and 300 mg of cilgavimab, may be more appropriate for some SARS-CoV-2 variants (for example, Omicron BA.1, Omicron BA.1.1), based on in vitro neutralisation susceptibility data which show reduced susceptibility for tixagevimab + cilgavimab [9, 10]. "
Article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9211051/
I would comment that I am not a medical professional so please don't consider my remarks as medical advice. But based on this you may want to discuss this with your son's doctor and see if they can provide you with more information on the subject.
I'll try to look around and skim to see what I can find, but unfortunately I haven't actually spent time looking up this monoclonal in particular.
That's definitely something worth discussing with your son's doctor. I suppose it really comes down to serum levels considering the remarks above indicate a higher dose may be needed. ADE is interesting, but generally for monoclonals I believe there is a concern about autoimmune disease depending upon the type of therapy given. Unfortunately there may not be research until further evidence comes out.
So I went back and skimmed a bit. It appears to be effective against Ba.2, and even though it targets the RBD it does use a conserved region. That does add more to its value, but even with that we may need to see evidence against Ba.4/Ba.5.
So I looked it up, and it did have a lot of promise. It does appear to target the receptor binding domain of the spike protein, although a lot of the evidence appears to have been for Ba.1 so there may be concerns with Ba.4/Ba.5
It's a general concern for monoclonals. I'm not sure how common they are, but they are a possibility. It is providing someone with another person's antibodies, so I suppose there's some concerns about how the body reacts to these antibodies (whether favorably or detrimentally).
I'm sorry for your situation Heidi. I find it rather ridiculous the situation that monoclonals have been put in. I mean, we had people who were touting convalescent plasma therapy since the beginning of the pandemic, yet many people spoke out against monoclonals. What do they think was in the plasma that they were giving people?
It's ridiculous that your son isn't considered high risk or something that would allow him higher priority. All the best to you and your son Heidi. I wish you didn't have to be in the position that you are.