Question: what is going to happen to the BINDING ISOMERIC ANTIBODIES which have been produced by the immune system in response to the cmRNA coding with Pseudouridine? What is the defining factor which will constitute a sufficient condition for these isomeric abs to be activated, that is, to become neurotoxic prion-like T-bacilli proteins?
Want to add my name to the Paxlovid rebound list. Tested positive PCR and antigen, took 5 day regimen of Paxlovid, symptom free by day six, tested negative, two days later, all symptoms returned, tested positive, still positive after ten days, but mostly symptom free.
Potential future one - https://andrewsullivan.substack.com/p/a-personal-note-to-readers - might be an interesting case, since Sullivan reports being "almost done" with the course but still getting faint +'s, so he might be an example that "immune suppression" doesn't drive higher likelihood of rebound, in fact it reduced likelihood of going negative during the course. Who knows.
He also claims to have 110,000 unpaid subscribers and 20,000 paid subscribers. I am proud and happy for him, but recent counts of likes suggests that he has 2,000-3,000 subscribers or there abouts. (unless I misunderstand what "The Dish" he is talking about, I presume he means his substack)
Anyway, he is an interesting case of a HIV positive, but presumably HIV controlled person on paxlovid.
Sullivan has built his online readership over decades, and got an assistant to field feedback long ago, so that's the model he still uses on his substack. It leads to better comment curation than the algorithm. But I am a bit surprised to read that he is still growing (compared to the sub's early start when he was briefly "edgy" thanks to being dropped by NY Mag for upsetting the woke staff).
I had no idea, what did he do to upset the woke staff?
Anyway, I have a close young vaxed relative with long covid. We went to a cardiologist today, he is having heart rhythm problems since his Covid in January (double vaxed in may). He will be getting echo CG soon and MRI in a month.
Since you are a very advanced guy, I wonder what you think about long covid caused by viral persistence, and whether a good antiviral like Ivermectin could help.
I do realize that this specific problem of my relative is complicated, and the decision making involved is uncertain and involves a lot of judgments, but I wanted to see if you have thoughts on long Covid and antivirals.
I know that some people mention improvements after Paxlovid or Ivermectin, but maybe not with heart issues,.
Patterson looked at Ivermectin as Long Covid treatment for a while, but moved away from it. He said it helped with some patients (https://youtu.be/El1rdF8XET4?t=3913). But I agree it seems hard to imagine that applying to a heart issue per se.
Proal, in a chat about the viral persistence theory, supports trying antivirals in LC without predicting if they will prove to work https://youtu.be/8paiY-60118?t=1322
Proal cites Ebola as an example of a virus that seems to take advantage of immune-privileged tissues. For various reasons, I'm skeptical that this explains why only some and not everyone gets LC or that the question of viral persistence is likely to be productive to treatment. But as Proal says, we should probably start by trying and seeing what works anyway. Proal also cites the vagus nerve as a likely origin of many LC symptoms (this could include heart rhythm problems) and possible interaction with the gut microbiome, so at the least it seems like antivirals won't be a silver bullet. Also with any cardiac thing you would probably want to be more careful with trying new medications without consultation...
Hilarious. Like I said in my original reply, the biology for this is really plausible, totally obvious - if only someone with half a brain was in charge of green-lighting antivirals, we could go a few weeks without disaster.
Interesting! But how would you know these are not re-infections instead of flare-ups?
Now, I'm actually not the party-pooper who believes that, but we should ask ourselves if that is possible?
But the real reason I bring it up is because re-infections in general are rare. In any community where a virus rages, you don't see the ones who get it first be reinfected by the later ones. Immunity even though it matures for months is already quite strong right after clearing an illness. So even though in such a community the first one who cleared the virus, will be frequently re-exposed, they do not get re-infected. Killingly, et al. seems to confirm.
So why is it not here? I mean, we pause some virus replication, but most of it is cleared. Then we stop the medication and the remainder is free to replicate again. But at the same time, the body should be high on all the flavours of anti-bodies (IgA, IgM ad IgG) and may have started to produce already some CD8 T memory cells as well. Either way, we just cleared let's say 99% of the virus be it with help of the anti-viral. So why does the immune system have such trouble stopping this let's say 1%? What is different compared to a re-exposure?
It seems that the immune training is impaired as well by the anti-viral!?
Or is this simply an artifact that the ones who get this anti-viral are typically people with poor immune function?
I haven’t discussed it much but already have two ideas on this front. One is that the pause is occurring in already-infected cells, so it’s a barn door after the horses problem. Antibodies can’t do anything to halt lysis in successfully unpaused cells. So external viral shedding is not inhibited by antibodies, even if internal shedding (viremia) is. Cellular immune sniping of unpaused infected cells either 1) isn’t robust enough due to not having let the original infection “play out” 2) isn’t going to be up to the high “virus-containing-barn load” of a synchronized unpause or 3) still results in lots of viral debris, driving false positive tests. 1 and 2 are better fits for the anecdotes of symptomatic rebound, 3 would fit a benign test-only rebound scenario. Obviously we would want to know if return of symptoms was associated with Paxlovid treatment in the trial and that info isn’t available. So as I say in the conclusion the evidence isn’t conclusive yet!
So as someone who used to do PCR testing (well, I did the RNA extracting) the quantification comes down to the instrument and other factors. The rt-PCR instrument needed to be calibrated with a tray containing various concentrations of fluorescence to create a normal curve relative to fluorescence I believe.
For every PCR tray a positive control is added that serves as a reference for all the other testing wells. As for fluorescence, most assays use fluorescent labeled fragments of DNA that are cleaved after a cycle of amplification. Each gene has a different fluorescent tag which is how they differentiate the genes from one another.
Anyways, the PCR test measures at what cycle the fluorescence passes a threshold value. Then the instrument essentially can work retroactively I believe based on an exponential curve, such that:
Fixed viral load = [initial viral load] x base (greater than 1 but less than 2)^Ct
The instrument knows the viral load- it's the threshold that's crossed. The Ct count can be retroactively calculated, and the base value is likely based on the calibration. Plug all of them in and it gives the initial viral load which would tell you whether you are "infectious" using similar measures as outlined in the University of Washington protocol. However, because the initial viral load is related to the Ct count I think they usually stick with the Ct count and it's probably much easier to report.
I've written about my experiences as a COVID tester before. It's floating around in my Substack somewhere but I do remember writing about the sensitivity of these tests. I will tell you that human error is all over the place when doing COVID testing so something to keep in mind when evaluating the results.
As for human error, the Chew et al. control group presumably acts as a semi-negative control that demonstrates that false-positives-by-process shouldn't exceed "4" in the UofW protocol, but the accuracy of their method might shift over time. In general I am pretty impressed with the Berg et al. write-up.
I am a bit confused at how the term "viral load" is being used in your example. I believe you mean the signal strength? But all that measures is primer-duplicated DNA polymers. It's already a measurement of what is only "in the assay," essentially a mathematical construction, and correspondence to actual virus in the real world still requires an outside calibration. So even if the term "viral load" is used in this context to refer to signal strength, the unit "copies/mL" implies a simulated real-world value. So my best attempt to understand the process is that once a result comes out of a quantitative PCR protocol, "viral load" isn't referring to intra-threshold math but rather to Ct-to-IRL calibrated math. In which case, all that matters is the final Ct at threshold...?
*edit: In either case, the "viral load" to Ct plots in Table S1 of Berg, et al. (the Supplementary word doc) all go up and down in lockstep, so that hopefully my conversion table (corrected in an update an hour ago) is accurate. I think the bigger hazard is still the fact that it's not 100% certain that the U of W assay was used. *second edit: Also, I think I need to add +10 to all my conversions to make them match normal reported "Ct"s.
So I should have used the term amplicon as that's the actual term instead of "final viral load". But the same rules still apply- all instruments are likely to use an exponential curve derived from some exponential equation I posted. Most measurements are actually based on the biotech company and their instrument, although their standard curves are created by serial dilutions and may look similar to U of W. For us all samples took 200 uL from the tube of VTM and sample so the volume is known, the amplicon is known, the Ct count is calculated, and therefore the initial viral load concentration is known and that is used to measure if someone is infectious based off of some standard.
This really just confounds the PCR data even further quite honestly. You don't know how a company standardized their methods and how reliable they are as well.
Right, I get that amplification will result in an exponential curve and the threshold is just one spot midway up the curve. But for the "viral load" assay my understanding is that the rest of the curve is scrapped, and the log10 values are derived from parallel calibration via cell culture and dilution.
Right, the standardization is in question - whereas Chew, et al. are careful to plot differences in how specimens were collected, nothing is really known about variability in the Paxlovid trial. Figure 2a in Chew, et al. shows that just swabbing further up will drive a 6log10 increase in some samples, but my guess is that this increase/disparity is only possible if there is a flare-up of viral replication to begin with (as opposed to billions of RNA molecules hanging out in the nose for days on end), and so it's more a false negative hazard and not a false positive hazard. But "negative" in this case wouldn't seem to include "0"s.
I think we're saying similar things but talking in circles between each other and I guess I am confusing myself even further. Anyways the ideas here are rather interesting. It's actually making me wonder how Ivermectin fits into this if it is considered to be a protease inhibitor, as all of the faults of PAXLOVID would be even worse with Ivermectin. I also see people using your hypotheses to either substantiate or invalidate Ivermectin studies. This is creating an interesting scenario.
Fantastic post! Thank you for directing your attention and competence to this. I believe that we are just getting started really looking at paxlovid.
If I recall correctly, paxlovid was tested on unvaccinated people. If vaccinated people are disproportionally getting viral resurgence, this could be due to the following:
- The 5 day PAUSE button that is called Paxlovid, leads to mostly satisfactory results in UNvaccinated people, whose immune system can mount vigorous response during those 5 days, leading to only 20% viral resurgence
- If vaccinated people, due to immune system damage/tolerance to the spike antigen, are unable to create durable immune response during the same 5 day pause, it could explain resurgence in them.
In addition, it may be that Omicron, despite appearing mild, takes more time to clear and a five day PAUSE is not enough. As you or maybe Modern Discontent alluded to, it may be that the protease inhibitor needs to be given for longer (but hopefully not forever as you mentioned)
In addition, it may be that paxlovid trial was rigged, and resurgences were somehow masked by trial protocol.
These trials intentionally excluded vaccinated due to some savior complex of the FDA to argue "well, the vaccinated are WELL protected, so they won't need it! Let's save it for the most vulnerable people!" That was at least a large part of what I got from the FDA press briefing for Molnupiravir.
Well the question wouldn't necessarily be if PAXLOVID doesn't work, but if it provides enough effectiveness to allow for the immune system to carry through with its intended protection. I'm very hesitant to dive deeply into the continuous immunosuppression aspect of the vaccines. We're also probably noticing many things with SARS-COV2 that may actually be common with other viruses, but we may have never noticed because other viruses have never been examined to such an extent as SARS-COV2. At least that's one of my ideas right now.
That touches on some topics I either left out by mistake or intend to follow up on!
Right, the trial excluded the vaxxed. So for now I would say this issue seems to be intrinsic to Paxlovid. I meant to include that in my post.
The patients who are "rebounding" in Figure 2 are having resurgences with percentages that have as many zeros as the difference in the y axis. So a 0 to 7 rebound is a 10000000% rebound. I may be 1 too many or too few 0s in my math. More important is going from ≤2 back over the 4/5 marginal boundary, that's really unusual even after a false negative and suggests true resurgence.
As far as being rigged, the trial had end-points for long term symptomatic follow-up that don't seem to be reported anywhere. And the actual risk groups in the control group turn out to be super-narrow, so for most groups there was no actual efficacy (because severe outcomes did not occur). That'll be in a follow-up post.
Agreed - at least, if I set my contrarian tendency to think that isolation is just “our side’s” fig-leaf embrace of useless containment theatre aside. If viral rebound is both real and consistent with the anecdotes highlighted by Chudov, then Paxlovid given early may improve the virus’s chance of spread by entering the early symptom stage when the host’s behavioral defenses have been lowered. (But once again I don’t strongly buy into the common transmission models that assume high spread early on, I think spread is a lot more random and that isolation doesn’t make much difference.)
Sequences after Day 5 were likely turned over but don't seem to have been used in the FDA analysis. Only subjects with sequences on both 1 and 5 were in the post post hoc cohort and only above-sensitivity-threshold nsp5 mutant-havers on 1 or 5 were deemed Y (red) and non-havers N (grey). Sequence results after day 5 weren't used for the analysis and Figure 2 only reports "viral load" values. Note that the mutant-havers weren't "all mutant" on Day 1 / 5, just some % of reads in the relevant positions were non-wilid-type. Of course the "OUTRT" considers mutation irrelevant, all that matters is how Paxlovid interacts with the normal viral replication cycle.
5 day pause? Sure, but it's much deeper than that. The key to understanding the entire vaccination campaign are the CHIRAL ISOMERS.
https://pubs.acs.org/doi/10.1021/acs.oprd.1c00400 (N4-hydroxycytidine isomer)
https://www.medrxiv.org/content/10.1101/2021.07.28.21261232v1.full (dimethyl-bicyclo[3.1.0] proline isomer)
Question: what is going to happen to the BINDING ISOMERIC ANTIBODIES which have been produced by the immune system in response to the cmRNA coding with Pseudouridine? What is the defining factor which will constitute a sufficient condition for these isomeric abs to be activated, that is, to become neurotoxic prion-like T-bacilli proteins?
More from Twitter (using my alt account as I am blocked for misinformation, pending appeal)
People are getting interested in our paxlovid stuff, without mentioning us of course but whatever
https://twitter.com/EnemyInAState/status/1516588639270092809
https://twitter.com/walidgellad/status/1516040963239653388
https://twitter.com/JFdonoghue1033/status/1515811645515259908 (look at the replies to this one)
https://twitter.com/SteveJoffe/status/1516136976944095247
https://www.coronaheadsup.com/health/treatment/paxlovid/paxlovid-covid-19-infections-rebounding-a-few-days-after-treatment/
https://twitter.com/baby2thfairy/status/1516192113842655243
GOOD ONE: https://twitter.com/TaraL3056/status/1516132283991957514
https://twitter.com/SlightlyUnripe/status/1516566835042287617
https://twitter.com/WoollerEmma/status/1516359610956931080
https://twitter.com/poblematisch/status/1516285346379710469
Apr 21:
https://www.thailandmedical.news/news/urgent-studies-needed-on-paxlovid-does-it-only-help-alleviate-symptoms-and-suppress-viral-load-for-a-while-but-does-not-help-in-total-viral-clearance
https://twitter.com/JeremyLeven1/status/1517264324644982784 <-- he may be a doctor
Want to add my name to the Paxlovid rebound list. Tested positive PCR and antigen, took 5 day regimen of Paxlovid, symptom free by day six, tested negative, two days later, all symptoms returned, tested positive, still positive after ten days, but mostly symptom free.
Potential future one - https://andrewsullivan.substack.com/p/a-personal-note-to-readers - might be an interesting case, since Sullivan reports being "almost done" with the course but still getting faint +'s, so he might be an example that "immune suppression" doesn't drive higher likelihood of rebound, in fact it reduced likelihood of going negative during the course. Who knows.
This guy disabled comments, I wonder why.
He also claims to have 110,000 unpaid subscribers and 20,000 paid subscribers. I am proud and happy for him, but recent counts of likes suggests that he has 2,000-3,000 subscribers or there abouts. (unless I misunderstand what "The Dish" he is talking about, I presume he means his substack)
Anyway, he is an interesting case of a HIV positive, but presumably HIV controlled person on paxlovid.
Wishing him full recovery
Sullivan has built his online readership over decades, and got an assistant to field feedback long ago, so that's the model he still uses on his substack. It leads to better comment curation than the algorithm. But I am a bit surprised to read that he is still growing (compared to the sub's early start when he was briefly "edgy" thanks to being dropped by NY Mag for upsetting the woke staff).
I had no idea, what did he do to upset the woke staff?
Anyway, I have a close young vaxed relative with long covid. We went to a cardiologist today, he is having heart rhythm problems since his Covid in January (double vaxed in may). He will be getting echo CG soon and MRI in a month.
Since you are a very advanced guy, I wonder what you think about long covid caused by viral persistence, and whether a good antiviral like Ivermectin could help.
I do realize that this specific problem of my relative is complicated, and the decision making involved is uncertain and involves a lot of judgments, but I wanted to see if you have thoughts on long Covid and antivirals.
I know that some people mention improvements after Paxlovid or Ivermectin, but maybe not with heart issues,.
Patterson looked at Ivermectin as Long Covid treatment for a while, but moved away from it. He said it helped with some patients (https://youtu.be/El1rdF8XET4?t=3913). But I agree it seems hard to imagine that applying to a heart issue per se.
Proal, in a chat about the viral persistence theory, supports trying antivirals in LC without predicting if they will prove to work https://youtu.be/8paiY-60118?t=1322
Proal cites Ebola as an example of a virus that seems to take advantage of immune-privileged tissues. For various reasons, I'm skeptical that this explains why only some and not everyone gets LC or that the question of viral persistence is likely to be productive to treatment. But as Proal says, we should probably start by trying and seeing what works anyway. Proal also cites the vagus nerve as a likely origin of many LC symptoms (this could include heart rhythm problems) and possible interaction with the gut microbiome, so at the least it seems like antivirals won't be a silver bullet. Also with any cardiac thing you would probably want to be more careful with trying new medications without consultation...
Thanks a lot! Totally agree on the vagus nerve.
Wow, you've 10-timesed the list since last night! I'll have to catch up.
Hilarious. Like I said in my original reply, the biology for this is really plausible, totally obvious - if only someone with half a brain was in charge of green-lighting antivirals, we could go a few weeks without disaster.
I feel like I am living in a clown world. They test Paxlovid on UNvaccinated people.
Then they approve it for ALL people.
Then it turns out that it does not actually work (possibly works for most vaxxed and does not work for most unvaxxed, we do not have the data).
The media is totally silent because it is owned by Pfizer
Anyway, if I find more examples, I will add them to the previous post of mine instead of spamming your responses section.
WE ARE DEFINITELY ON TO SOMETHING BRIAN
Another two
https://www.reddit.com/r/COVID19positive/comments/u61mv9/me_mom_tested_positive_about_almost_2_weeks_ago_2/
https://www.reddit.com/r/COVID19positive/comments/u612zp/viral_rebound_on_day_13_after_taking_paxlovid/
Jessica Rose also wrote about Paxlovid and her article is very interesting.
https://jessicar.substack.com/p/what-is-paxlovid
I saw - I was surprised that it seemed like she hadn't already read your post!
I mostly wanted her to see YOUR post actually
Interesting! But how would you know these are not re-infections instead of flare-ups?
Now, I'm actually not the party-pooper who believes that, but we should ask ourselves if that is possible?
But the real reason I bring it up is because re-infections in general are rare. In any community where a virus rages, you don't see the ones who get it first be reinfected by the later ones. Immunity even though it matures for months is already quite strong right after clearing an illness. So even though in such a community the first one who cleared the virus, will be frequently re-exposed, they do not get re-infected. Killingly, et al. seems to confirm.
So why is it not here? I mean, we pause some virus replication, but most of it is cleared. Then we stop the medication and the remainder is free to replicate again. But at the same time, the body should be high on all the flavours of anti-bodies (IgA, IgM ad IgG) and may have started to produce already some CD8 T memory cells as well. Either way, we just cleared let's say 99% of the virus be it with help of the anti-viral. So why does the immune system have such trouble stopping this let's say 1%? What is different compared to a re-exposure?
It seems that the immune training is impaired as well by the anti-viral!?
Or is this simply an artifact that the ones who get this anti-viral are typically people with poor immune function?
I haven’t discussed it much but already have two ideas on this front. One is that the pause is occurring in already-infected cells, so it’s a barn door after the horses problem. Antibodies can’t do anything to halt lysis in successfully unpaused cells. So external viral shedding is not inhibited by antibodies, even if internal shedding (viremia) is. Cellular immune sniping of unpaused infected cells either 1) isn’t robust enough due to not having let the original infection “play out” 2) isn’t going to be up to the high “virus-containing-barn load” of a synchronized unpause or 3) still results in lots of viral debris, driving false positive tests. 1 and 2 are better fits for the anecdotes of symptomatic rebound, 3 would fit a benign test-only rebound scenario. Obviously we would want to know if return of symptoms was associated with Paxlovid treatment in the trial and that info isn’t available. So as I say in the conclusion the evidence isn’t conclusive yet!
So as someone who used to do PCR testing (well, I did the RNA extracting) the quantification comes down to the instrument and other factors. The rt-PCR instrument needed to be calibrated with a tray containing various concentrations of fluorescence to create a normal curve relative to fluorescence I believe.
For every PCR tray a positive control is added that serves as a reference for all the other testing wells. As for fluorescence, most assays use fluorescent labeled fragments of DNA that are cleaved after a cycle of amplification. Each gene has a different fluorescent tag which is how they differentiate the genes from one another.
Anyways, the PCR test measures at what cycle the fluorescence passes a threshold value. Then the instrument essentially can work retroactively I believe based on an exponential curve, such that:
Fixed viral load = [initial viral load] x base (greater than 1 but less than 2)^Ct
The instrument knows the viral load- it's the threshold that's crossed. The Ct count can be retroactively calculated, and the base value is likely based on the calibration. Plug all of them in and it gives the initial viral load which would tell you whether you are "infectious" using similar measures as outlined in the University of Washington protocol. However, because the initial viral load is related to the Ct count I think they usually stick with the Ct count and it's probably much easier to report.
I've written about my experiences as a COVID tester before. It's floating around in my Substack somewhere but I do remember writing about the sensitivity of these tests. I will tell you that human error is all over the place when doing COVID testing so something to keep in mind when evaluating the results.
As for human error, the Chew et al. control group presumably acts as a semi-negative control that demonstrates that false-positives-by-process shouldn't exceed "4" in the UofW protocol, but the accuracy of their method might shift over time. In general I am pretty impressed with the Berg et al. write-up.
I am a bit confused at how the term "viral load" is being used in your example. I believe you mean the signal strength? But all that measures is primer-duplicated DNA polymers. It's already a measurement of what is only "in the assay," essentially a mathematical construction, and correspondence to actual virus in the real world still requires an outside calibration. So even if the term "viral load" is used in this context to refer to signal strength, the unit "copies/mL" implies a simulated real-world value. So my best attempt to understand the process is that once a result comes out of a quantitative PCR protocol, "viral load" isn't referring to intra-threshold math but rather to Ct-to-IRL calibrated math. In which case, all that matters is the final Ct at threshold...?
*edit: In either case, the "viral load" to Ct plots in Table S1 of Berg, et al. (the Supplementary word doc) all go up and down in lockstep, so that hopefully my conversion table (corrected in an update an hour ago) is accurate. I think the bigger hazard is still the fact that it's not 100% certain that the U of W assay was used. *second edit: Also, I think I need to add +10 to all my conversions to make them match normal reported "Ct"s.
So I should have used the term amplicon as that's the actual term instead of "final viral load". But the same rules still apply- all instruments are likely to use an exponential curve derived from some exponential equation I posted. Most measurements are actually based on the biotech company and their instrument, although their standard curves are created by serial dilutions and may look similar to U of W. For us all samples took 200 uL from the tube of VTM and sample so the volume is known, the amplicon is known, the Ct count is calculated, and therefore the initial viral load concentration is known and that is used to measure if someone is infectious based off of some standard.
This really just confounds the PCR data even further quite honestly. You don't know how a company standardized their methods and how reliable they are as well.
Right, I get that amplification will result in an exponential curve and the threshold is just one spot midway up the curve. But for the "viral load" assay my understanding is that the rest of the curve is scrapped, and the log10 values are derived from parallel calibration via cell culture and dilution.
Right, the standardization is in question - whereas Chew, et al. are careful to plot differences in how specimens were collected, nothing is really known about variability in the Paxlovid trial. Figure 2a in Chew, et al. shows that just swabbing further up will drive a 6log10 increase in some samples, but my guess is that this increase/disparity is only possible if there is a flare-up of viral replication to begin with (as opposed to billions of RNA molecules hanging out in the nose for days on end), and so it's more a false negative hazard and not a false positive hazard. But "negative" in this case wouldn't seem to include "0"s.
I think we're saying similar things but talking in circles between each other and I guess I am confusing myself even further. Anyways the ideas here are rather interesting. It's actually making me wonder how Ivermectin fits into this if it is considered to be a protease inhibitor, as all of the faults of PAXLOVID would be even worse with Ivermectin. I also see people using your hypotheses to either substantiate or invalidate Ivermectin studies. This is creating an interesting scenario.
Fantastic post! Thank you for directing your attention and competence to this. I believe that we are just getting started really looking at paxlovid.
If I recall correctly, paxlovid was tested on unvaccinated people. If vaccinated people are disproportionally getting viral resurgence, this could be due to the following:
- The 5 day PAUSE button that is called Paxlovid, leads to mostly satisfactory results in UNvaccinated people, whose immune system can mount vigorous response during those 5 days, leading to only 20% viral resurgence
- If vaccinated people, due to immune system damage/tolerance to the spike antigen, are unable to create durable immune response during the same 5 day pause, it could explain resurgence in them.
In addition, it may be that Omicron, despite appearing mild, takes more time to clear and a five day PAUSE is not enough. As you or maybe Modern Discontent alluded to, it may be that the protease inhibitor needs to be given for longer (but hopefully not forever as you mentioned)
In addition, it may be that paxlovid trial was rigged, and resurgences were somehow masked by trial protocol.
These trials intentionally excluded vaccinated due to some savior complex of the FDA to argue "well, the vaccinated are WELL protected, so they won't need it! Let's save it for the most vulnerable people!" That was at least a large part of what I got from the FDA press briefing for Molnupiravir.
Yeah, but now a question arises, does paxlovid actually work in the vaccinated.
I feel like I am living in a clown world
Well the question wouldn't necessarily be if PAXLOVID doesn't work, but if it provides enough effectiveness to allow for the immune system to carry through with its intended protection. I'm very hesitant to dive deeply into the continuous immunosuppression aspect of the vaccines. We're also probably noticing many things with SARS-COV2 that may actually be common with other viruses, but we may have never noticed because other viruses have never been examined to such an extent as SARS-COV2. At least that's one of my ideas right now.
Right. So if the immune system can use the 5-day PAUSE to mount an effective response to reappearing virus after cessation of Paxlovid, all is good.
If after 5-7 days, the vaxed cannot provide a speedy immune readjustment, the resurgence could be very significant.
That touches on some topics I either left out by mistake or intend to follow up on!
Right, the trial excluded the vaxxed. So for now I would say this issue seems to be intrinsic to Paxlovid. I meant to include that in my post.
The patients who are "rebounding" in Figure 2 are having resurgences with percentages that have as many zeros as the difference in the y axis. So a 0 to 7 rebound is a 10000000% rebound. I may be 1 too many or too few 0s in my math. More important is going from ≤2 back over the 4/5 marginal boundary, that's really unusual even after a false negative and suggests true resurgence.
As far as being rigged, the trial had end-points for long term symptomatic follow-up that don't seem to be reported anywhere. And the actual risk groups in the control group turn out to be super-narrow, so for most groups there was no actual efficacy (because severe outcomes did not occur). That'll be in a follow-up post.
would love to read your followup post
Agreed - at least, if I set my contrarian tendency to think that isolation is just “our side’s” fig-leaf embrace of useless containment theatre aside. If viral rebound is both real and consistent with the anecdotes highlighted by Chudov, then Paxlovid given early may improve the virus’s chance of spread by entering the early symptom stage when the host’s behavioral defenses have been lowered. (But once again I don’t strongly buy into the common transmission models that assume high spread early on, I think spread is a lot more random and that isolation doesn’t make much difference.)
Sequences after Day 5 were likely turned over but don't seem to have been used in the FDA analysis. Only subjects with sequences on both 1 and 5 were in the post post hoc cohort and only above-sensitivity-threshold nsp5 mutant-havers on 1 or 5 were deemed Y (red) and non-havers N (grey). Sequence results after day 5 weren't used for the analysis and Figure 2 only reports "viral load" values. Note that the mutant-havers weren't "all mutant" on Day 1 / 5, just some % of reads in the relevant positions were non-wilid-type. Of course the "OUTRT" considers mutation irrelevant, all that matters is how Paxlovid interacts with the normal viral replication cycle.