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Posted (edited)

Source is cited within image. Image also clearly shows risk of death, not risk of clot… which even your own source confirms is low and falling lower. 

Edited by iNow
Posted (edited)

The "ABS" link isn't clickable.  I assume that is the Australian Bureau of Statistics? 

It would be helpful if you could provide the direct URL so I can read the entire page.  

 

Looks like Australia is phasing out AZ later this year, according to this article:

Australia plans to shelve AstraZeneca Covid vaccine by October

Controversial vaccine to be given only by request later this year when Moderna and Pfizer will dominate

https://www.theguardian.com/business/2021/jun/23/australia-plans-to-shelve-astrazeneca-covid-vaccine-by-october

Edited by Alex_Krycek
Posted
2 hours ago, iNow said:

Ha.  Very funny.

I already did google that exact information and got a string of irrelevant results.  If you're not going to post the direct URL to your information, I can't debate you.  

 

Screen Shot 2021-06-24 at 22.17.38.png

Posted
6 minutes ago, Alex_Krycek said:

Ha.  Very funny.

I already did google that exact information and got a string of irrelevant results.  If you're not going to post the direct URL to your information, I can't debate you.  

 

Screen Shot 2021-06-24 at 22.17.38.png

If you go to  https://theconversation.com/concerned-about-the-latest-astrazeneca-news-these-3-graphics-help-you-make-sense-of-the-risk-162175

and scroll down about 2/3 of the way, you will find the exact cite given in the article. It's the 2019 version of the links you've shown. If it is not specific enough it's not iNow's fault. Blame the author of the article. (all I did was add "TTS blood clot" to the search to find the article)

 

Posted

And unless he's challenging the validity of the leading causes of death data, it's all moot anyway. The image is based on death counts and shows how the blood clot issue compares. This is why I said, "for scale and context" when posting it. 

Posted
9 minutes ago, Alfred001 said:

Any comments on this:

This was brought up (rather haphazardly) in another thread. Also brought up, in a different thread, was all if the long-lasting symptoms from getting the disease even if it's not fatal to you. 

 

Posted
1 minute ago, swansont said:

This was brought up (rather haphazardly) in another thread. Also brought up, in a different thread, was all if the long-lasting symptoms from getting the disease even if it's not fatal to you. 

 

I think you mistyped something in the last part of the sentence, could you clarify?

Posted
9 minutes ago, Alfred001 said:

I think you mistyped something in the last part of the sentence, could you clarify?

Yes. It should be "all of the long-lasting symptoms"

(and I think the conversation doesn't include erectile disfunction, which I've seen mentioned as a long-term symptom)

Posted
1 minute ago, swansont said:

Yes. It should be "all of the long-lasting symptoms"

But what about the point about the possibility of accumulation of the protein or the vaccine in ovaries, adrenals and bone marrow?

Posted
On 6/21/2021 at 4:12 AM, CharonY said:

Before I talk a bit more on the study itself I want to take a step back and talk a bit how risks in medical interventions are generally evaluated. The key element here is monitoring certain clinical endpoints, including efficacy of the drugs but also specific indicators of morbidity, for example.

In a more general sense, there are no "no effect" endpoints. If you eat a cheeseburger, for example, I could monitor increases in negative biomarkers in your blood, there could be short term shifts in the gene expression of you gut microbiota and so on. However, that tells us little about the risks. As such it would be better to use endpoints such as heart attack and stroke rates and so on. The big issue with long-term effects is that it becomes very difficult to figure out what the causes for a given hard endpoint are, which is why for example nutritional studies, which often are long-term, often do not have clear outcomes.

Trials are looking at such outcomes and from that viewpoint the current the current vaccines are no different from other vaccines or therapeutics. You look at endpoints within a given time frame for a given sample size. The SARS-CoV-2 vaccines all fulfil pretty much the same requirements as you typically do not monitor individuals indefinitely after taking a medication.

So as such, we can be fairly certain that the the the mRNA vaccines do not seem to have any acute effects and we know roughly as much about long-term issues as for other medication.

So what is new regarding our knowledge about concerns regarding this specific vaccine? One risk that folks were concerned years back is the risk that the LNP could distribute their payload throughout the body and enrich in the liver. If the spike protein is formed there, it could result in local inflammation of the organ and liver damage. However, this does not happen. In fact, the Japanese report indicates why, within a relatively short time frame all the mRNA expression is basically gone. So what about the LNP alone? Again, you get a dose, the lipids move through your body and get metabolized. Typically they accumulate in adipose tissue or liver (which for some reason is not plotted, it is higher there than in ovaries, for example). So does this cause harm?

The cited study on direct injection of pure LNP indicate that yes, if given in high concentrations they can cause inflammatory responses. However, this itself is not an indicator for adverse health effects. In fact, the paper argues that these inflammatory responses might be why the current mRNA vaccines are so effective (which was a big worry before, the fact that mRNAs are generally not very immunogenic). I.e. the local inflammation caused by LNPs could have been beneficial for efficacy reasons. We do see lower efficacy in the other vaccines, for example.

While the study is helpful to highlight the potential to elicit inflammatory responses from LNPs alone,  (and therefore nasal delivery is not a good idea) it does not actually suggest health issues. 

Again, it is about endpoints and what the study measured is not helpful to provide evidence of harm in humans.  First,  mice are not a a great model for immune responses in humans (which is a common issue with animal models) and second, they injected a very high amount- 10 ug, IIRC which is a huge amount compared to their body weight relative to the amount found in vaccines and the body weight in humans (we are talking over a thousand fold at least if I got my numbers right).

Moreover, as you know you only get two injections, so there is no chance for long-term accumulation (as opposed to many of the chemicals we use in personal care products, for example). Thus, if inflammation caused by LNPs resulted in adverse effects  you would expect to see most the effects fairly soon (within days) of injection, as the levels after that will gradually decline (rather than increase). The precise rate is not known as they only monitored for two days, but it won't be years. What we do know and expect are inflammation, which are common with most vaccines (as inflammation is the result of the immune system reacting). Mild myocardial inflammation has also been recorded which could be related to LNPs (or the vaccine in general). But again, the endpoints do not suggest significant adverse health effects. Blood clots do not seem to be different between unvaccinated and Pfizer/Moderna vaccinated folks, but seem elevated in certain population subsets in AstraZeneca vaccines, which is likely to related to the adenovirus used (there have been reports in the past for issues with certain adenovirus-based vaccines, but I am not sure what they were in detail and in any case, they are not related to mRNA-based vaccines such as Pfizer/BioNTech.

Meanwhile, there are studies (e.g. https://s3.amazonaws.com/media2.fairhealth.org/whitepaper/asset/A Detailed Study of Patients with Long-Haul COVID--An Analysis of Private Healthcare Claims--A FAIR Health White Paper.pdf) showing that even asymptomatic patients might be at risk of having long COVID symptoms, though it is still about double as high in symptomatic patients.

So again, we have a vaccine that might cause issues in some folks, but protects them from much bigger harm. And on top, they also protect those that are too stubborn to protect themselves.

 

 

But what about their accumulation in other places like adrenals, ovaries and bone marrow? What do you make of the concerns expressed in this thread?

His concern is (and I'm a layperson, so I hope I don't mess it up) that they only studied up to 48 hrs and at that point the LNP is still accumulating in the ovaries and adrenals, so we don't know what happens beyond that point, how much accumulates.

He also says accumulation of the protein and the mRNA wasn't even tested and he's concerned about that, too.

Posted

I have addressed the issues for the most part above already but I can give a more detailed breakdown for clarity. Overall I do not think that the tweet is well informed (but then so are most, I guess).

1) the mRNA in the vaccine is fragile and we know that it degrades over time. In the Pfizer report we see that the test mRNA they used vanished from the liver within 48 hours. In other words, if we expect effects due to the mRNA, they would need to happen before that time frame, and likely need to involve a higher accumulation than in the liver (as liver inflammation does not seem to be a major issue).

2) it can be expected that the LNP and their load seep out from the injection site, and typically eventually reach the liver. Over time, they would be metabolized and eliminated from the body. The Tweet seem to claim that the liver values are stable but that is not necessarily what we expected. Rather we have steady state situation where elimination is balanced with additional accumulation (i.e. likely the liver is doing its work). In fact, between say hour 2 and 48 h we see a loss of ~30% of the total signal. I.e. even if distributions shift, the total levels will obviously go down, rather than up. As such, very long term effects are unlikely to happen due to accumulation of stuff. If anything happens it is more likely due to something stupid our immune system is doing that could affect the body long-term.

3) We see that much of the short-term accumulation happens in the liver (which again, does most of the lipid metabolism) but also spleen (same reason), each of which have about double the concentration than ovaries. The other site to look for for short-term effects (again the mRNA is gone pat 48 hours) could be e.g. also adrenal glands, where quite a bit accumulates in the 24 hours but I have not seen reports that indicate issues here (again, the issue with endpoints, I outlined above).

4) The kinetics are likely going to be different. The rats got a 50 ug dose whereas the Pfizer/BioNTech vaccine is about 30 ug (IIRC). Given that the average human weighs about 240 times more, the elimination is likely going to be faster.

There are a couple of other points I could point out, but I hope that this explains most of it (and let me know if something is unclear (as often I am in a rush and did not proofread it properly). 

Posted (edited)
On 6/25/2021 at 8:43 PM, CharonY said:

I have addressed the issues for the most part above already but I can give a more detailed breakdown for clarity. Overall I do not think that the tweet is well informed (but then so are most, I guess).

1) the mRNA in the vaccine is fragile and we know that it degrades over time. In the Pfizer report we see that the test mRNA they used vanished from the liver within 48 hours. In other words, if we expect effects due to the mRNA, they would need to happen before that time frame, and likely need to involve a higher accumulation than in the liver (as liver inflammation does not seem to be a major issue).

2) it can be expected that the LNP and their load seep out from the injection site, and typically eventually reach the liver. Over time, they would be metabolized and eliminated from the body. The Tweet seem to claim that the liver values are stable but that is not necessarily what we expected. Rather we have steady state situation where elimination is balanced with additional accumulation (i.e. likely the liver is doing its work). In fact, between say hour 2 and 48 h we see a loss of ~30% of the total signal. I.e. even if distributions shift, the total levels will obviously go down, rather than up. As such, very long term effects are unlikely to happen due to accumulation of stuff. If anything happens it is more likely due to something stupid our immune system is doing that could affect the body long-term.

3) We see that much of the short-term accumulation happens in the liver (which again, does most of the lipid metabolism) but also spleen (same reason), each of which have about double the concentration than ovaries. The other site to look for for short-term effects (again the mRNA is gone pat 48 hours) could be e.g. also adrenal glands, where quite a bit accumulates in the 24 hours but I have not seen reports that indicate issues here (again, the issue with endpoints, I outlined above).

4) The kinetics are likely going to be different. The rats got a 50 ug dose whereas the Pfizer/BioNTech vaccine is about 30 ug (IIRC). Given that the average human weighs about 240 times more, the elimination is likely going to be faster.

There are a couple of other points I could point out, but I hope that this explains most of it (and let me know if something is unclear (as often I am in a rush and did not proofread it properly). 

The discussion has kept going on Twitter and it seems like Chris Masterjohn has been able to poke holes in any refutations of his concerns.

The discussion has branched off into too many threads to catalogue here, I'll just post one tweet and anyone interested should look back through the tweets to find the various threads branching off at various points (or go to Chris Masterjohn's timeline and look at his replies, that may be even better):

https://twitter.com/ChrisMasterjohn/status/1409220193683976192

Ok, now, let me try to argue with you based on some of the stuff Chris said on Twitter:

1) Here's his objection to this argument

https://twitter.com/ChrisMasterjohn/status/1409224095011590146

Quote

 

Further the stability of the luciferase mRNA has absolutely nothing to do with the stability of the spike protein mRNA and assuming they are related is total sophistry.


 

Now, this would not be applicable to your point if when you said "test mRNA" you were referring to some other experiment they performed than the one discussed here involving luciferase mRNA. Perhaps you're talking of some experiment where they used test mRNA which is known to have similar stability to the spike protein mRNA, IDK.

2) I'm not sure what you mean by "between say hour 2 and 48 h we see a loss of ~30% of the total signal," the value for liver goes up in that time. Or are you referring to the cumulative value for all the organs?

You say that there appears to be a steady state with elimination balanced out by additional accumulation, but the only timeframe where we see a drop in value that we could take to be elimination is between 8 and 24 hrs and then the value goes up again at the 48 hr mark. Granted it only goes up by 1/5 of what had accumulated in the previous 24 hrs, but we don't know what happens after this very short time frame of 48 hrs and the last observed change is in the upwards direction.

That said, you could be right, it could be that if we had data for an additional 48 hrs that we would se see-sawing and basically a steady state, but that's a hypothesis, we don't know for sure.

3) Well, as I mentioned in relation to 1, we can't be sure the mRNA is gone in 2 days, but also there's the issue of lipid accumulation and I'll post a message from a different covno I'm having where someone mentioned evidence that they might not be being metabolized (and this bears on 2, as well and your hypothesis that they're being eliminated):

E5AQ8dkWUAAQiD8?format=jpg&name=small

Edited by Alfred001
Posted
4 hours ago, Alfred001 said:

Now, this would not be applicable to your point if when you said "test mRNA" you were referring to some other experiment they performed than the one discussed here involving luciferase mRNA. Perhaps you're talking of some experiment where they used test mRNA which is known to have similar stability to the spike protein mRNA, IDK.

His comment is uninformed. There is nothing in the spike protein mRNA that makes it vastly more stable, and the instability of mRNA is well known. It is fairly common to use surrogates for these type of studies. Even if it was much more stable, we would be looking at a couple more days at best, which, unless you are talking about mayflies rarely falls under the moniker of long-term effects.

 

4 hours ago, Alfred001 said:

2) I'm not sure what you mean by "between say hour 2 and 48 h we see a loss of ~30% of the total signal," the value for liver goes up in that time. Or are you referring to the cumulative value for all the organs?

I just quickly calculated the total detectable lipid concentration, which dropped by that amount. So yes, it is cumulative for all organs. Again, it is based on how we generally metabolize lipids. As we are not getting continuous injections, what happens is that the total amount of lipids gets distributed and eventually eliminated. We also know which organs conduct much of the lipid metabolism so I am not sure why at this point we should all pretend not to understand how lipid metabolism works. Again, I think the basic thing that you and the twitter post seem to misunderstand is how compounds, including lipids get metabolized and eliminated. I am sure that if you look at ADME profiles, you will find something for those LNPs.

Moreover, the post seems to be confused about how elimination studies are done. If you want to understand how it is eliminated from the body you would go and measure generally blood and liver values as well as identify those compound in waste (i.e. urine and feces). And guess what, that is what they did and how they estimate elimination rates (some other routine methods involve simple blood plasma analyses. Quickly screening lit has indicate that terminal terminal half life for ALC-0315 and ALC-0159 were ~3 and 8 days, respectively. 

5 hours ago, Alfred001 said:

That said, you could be right, it could be that if we had data for an additional 48 hrs that we would se see-sawing and basically a steady state, but that's a hypothesis, we don't know for sure.

It is not a hypothesis, it is how the liver works. It is how we metabolize things. What you propose is that for some reasons LNPs changes how our organs work. If the liver would simply accumulate harmful substances we would be all dead. A steady state also does not see-saw. If the compound was delivered at a steady rate the concentration would remain steady and then decline slowly as the compound is being eliminated. However drugs can be released in bursts or re-distributed unevenly (e.g. the compound can be released from other organs back into the bloodstream). The main source in this case is leakage from the injection site into the bloodstream.

5 hours ago, Alfred001 said:

3) Well, as I mentioned in relation to 1, we can't be sure the mRNA is gone in 2 days, but also there's the issue of lipid accumulation and I'll post a message from a different covno I'm having where someone mentioned evidence that they might not be being metabolized (and this bears on 2, as well and your hypothesis that they're being eliminated):

Again, not a hypothesis, there is huge body of literature out there showing how liposomes, LNPs and similar compounds pass through our body, get eliminated and/or can get modified to control said elimination. We should not assume that science collectively forgot how basic animal physiology works just because a random guy on twitter doesn't.

Again, there are plenty of studies looking at mRNA as well as LNP degradation and metabolization, as well as basic liver functions. And I want to recall that one of the biggest challenges mRNA vaccines faced are the fact that those were eliminated too quickly to reliably create an immune response. Similarly, early LNPS were cleared too rapidly which added to the issue.

Thus, much of the work surrounded stabilization of mRNA in vivo. So suddenly assuming that it is somehow very stable just goes against all the basic biochemistry we understand regarding those molecules. In addition, the whole molecule is not terribly stable outside of the body, either, which is why they require storage at low temps.

I am not sure why you want to discuss tweets from a person who clearly has no expertise on that matter. Although it does not fall strictly into my area of expertise either, it is easy to see that the author of the tweet has not found it necessary to educate themselves on the subject matter before taking it to the social media (and yes, the irony is not entirely lost on me, considering my postings here).

Take Gregoriadis and Neerjun (https://doi.org/10.1111/j.1432-1033.1974.tb03681.x) which is one of the early papers looking how one could control uptake and elimination. There are tons of advances to control elimination rate, tissue specificity and overall stability in the lit, with detail that goes far beyond my knowledge. So any argument that argues that something mysterious is happening here, is likely based on ignorance. 

So what I think you propose is that for some reasons the main organs for lipid metabolization (and subsequent elimination) will only be active for the first two days or so, then all residual LNPS would magically bypass these organs and mechanism, accumulate in ovaries and stay there forever? So instead on measuring well known excretion routes we should instead focus on something that a random twitter guy does not understand? I would advise you look for some reliable sources. I am not sure whether the person has an agenda or is just badly misinformed, but either way I would urge you to find someone better to follow as neither of us is going to learn anything by feeding trolls.

 

 

Posted
On 6/29/2021 at 7:29 AM, CharonY said:

It is not a hypothesis, it is how the liver works. It is how we metabolize things. What you propose is that for some reasons LNPs changes how our organs work. If the liver would simply accumulate harmful substances we would be all dead.

Well, if it's a foregone conclusion that the LNPs are gonna get eliminated, I don't understand why they measured how much of them gets accumulated in the various organs to begin with and if mRNA is terribly unstable and is only gonna stick around for 2 days max anyway, why did they bother to track where it goes?

 

On 6/29/2021 at 7:29 AM, CharonY said:

I am not sure why you want to discuss tweets from a person who clearly has no expertise on that matter. Although it does not fall strictly into my area of expertise either, it is easy to see that the author of the tweet has not found it necessary to educate themselves on the subject matter before taking it to the social media (and yes, the irony is not entirely lost on me, considering my postings here).

I don't know enough to know who has and hasn't got expertise on the matter, so I have to ask. What I know is that he's engaged in a debate with three people on Twitter who do seem to be acknowledged as experts in the filed and none of them have been able to refute his concerns.

 

On 6/29/2021 at 7:29 AM, CharonY said:

So what I think you propose is that for some reasons the main organs for lipid metabolization (and subsequent elimination) will only be active for the first two days or so, then all residual LNPS would magically bypass these organs and mechanism, accumulate in ovaries and stay there forever? So instead on measuring well known excretion routes we should instead focus on something that a random twitter guy does not understand?

Again I have to ask, if there's no such concern, why did they measure where the LNPs end up to begin with? If it was simply sufficient to measure excretion routes, why did they measure this stuff at all?

And doesn't excretion only tell us that the stuff is being eliminated, but not where from? So it doesn't rule out the possibility that there's somewhere where it's not getting eliminated from and where maybe it would stick around longer.

And, again, I don't have any expertise on this topic and I'm merely asking questions because I want to get educated on the topic, so I don't understand why you have to be hostile about it. I'm not claiming expertise, I'm not claiming to know better than you, I'm asking.

Posted
3 hours ago, Alfred001 said:

Well, if it's a foregone conclusion that the LNPs are gonna get eliminated, I don't understand why they measured how much of them gets accumulated in the various organs to begin with and if mRNA is terribly unstable and is only gonna stick around for 2 days max anyway, why did they bother to track where it goes?

Determination of ADME (absorption, distribution, metabolism, excretion) is standard in pharma. Whenever you produce a drug, you document what happens to it in the body, as it it is critical to assess things like dosages. Moreover, assessing the elimination time also allows monitoring things like acute effects. I.e. if you know stuff ends up in various organs, but is eliminated say in 10 days or so, you know that the time window for monitoring for acute effects might be around 20 days or so. Anything after that are either unlikely to be associated with the drug and/or have to be secondary effects. In other words, it is standard info you provide if you want approval for your drug. It is therefore not surprising nor and indicator of any issues.

Quote

And doesn't excretion only tell us that the stuff is being eliminated, but not where from? So it doesn't rule out the possibility that there's somewhere where it's not getting eliminated from and where maybe it would stick around longer.

That is not generally how things work. The only mechanism would be if it reaches mostly inert tissue or is has properties that take a very long time to eliminate (PCBs and other organohalogens come to mind). If you did those elimination tests there, you won't see clearance at all. Again, most of the stuff circulates and gets redistributed and given how fast things get out (compared to the persisting compounds) there is little reason to believe that a lot can maintain in a given niche.

LNPs and constituents of their lipid shells are quite well investigated and are not known to have these persistent properties. I.e. you (and possibly the twitter user) are proposing an entirely novel mechanism without a shred of evidence at this point.

 

4 hours ago, Alfred001 said:

And, again, I don't have any expertise on this topic and I'm merely asking questions because I want to get educated on the topic, so I don't understand why you have to be hostile about it. I'm not claiming expertise, I'm not claiming to know better than you, I'm asking.

Sorry if I appear hostile, I am more annoyed at the twitter user than you as it seems to me that the question are not honest questions. I can accept that you are not familiar with the standard pharmacological data (and I am only familiar in passing), so it may be something extraordinary to you. But do you accept that if I tell you that this is a standard approach? 

Can you also accept that lipids have a natural way of getting eliminated from the body and that the values are established? Also have you thought about the comment I made earlier that the rats were injected with a much, much higher dose than humans are per weight?

If so, no worries and we can continue to work on your question and figure what you might not understand. But if you are already set in your beliefs, better tell me now, else you would be wasting my time (and then I might get annoyed).

 

Posted (edited)
8 hours ago, CharonY said:

Determination of ADME (absorption, distribution, metabolism, excretion) is standard in pharma. Whenever you produce a drug, you document what happens to it in the body, as it it is critical to assess things like dosages. Moreover, assessing the elimination time also allows monitoring things like acute effects. I.e. if you know stuff ends up in various organs, but is eliminated say in 10 days or so, you know that the time window for monitoring for acute effects might be around 20 days or so. Anything after that are either unlikely to be associated with the drug and/or have to be secondary effects. In other words, it is standard info you provide if you want approval for your drug. It is therefore not surprising nor and indicator of any issues.

But if that is the reason, I don't understand why they monitored for 48 hrs only.

And there's this:

https://twitter.com/TailFirefly/status/1404474619923476484

8 hours ago, CharonY said:

That is not generally how things work. The only mechanism would be if it reaches mostly inert tissue or is has properties that take a very long time to eliminate (PCBs and other organohalogens come to mind). If you did those elimination tests there, you won't see clearance at all. Again, most of the stuff circulates and gets redistributed and given how fast things get out (compared to the persisting compounds) there is little reason to believe that a lot can maintain in a given niche.

LNPs and constituents of their lipid shells are quite well investigated and are not known to have these persistent properties. I.e. you (and possibly the twitter user) are proposing an entirely novel mechanism without a shred of evidence at this point.

Ok, I take your point, but what about this:

https://twitter.com/mrich0312/status/1404399263975608320

https://twitter.com/Wildbranch/status/1404421593049321475

Do the ovaries and bone marrow qualify as inert tissues that you mention might not clear the lipids? To be clear, this is not a rhetorical question, I don't know whether they do. The adrenals also show just a steady climb through 48 hrs.

8 hours ago, CharonY said:

Sorry if I appear hostile, I am more annoyed at the twitter user than you as it seems to me that the question are not honest questions. I can accept that you are not familiar with the standard pharmacological data (and I am only familiar in passing), so it may be something extraordinary to you. But do you accept that if I tell you that this is a standard approach? 

Well, I'm not worried by the fact that they did these studies, I DO accept that this is the standard approach (except, as it turns out, why only 48 hrs), it's more the results that worry me, although I accept your point about liver concentrations not being a cause for concern since it's the filtration organ. It's the bone marrow, ovaries and adrenals that worry me.

Now, again, if you tell me that it's known that those organs clear them, too, I'll accept, but I have to ask the question.

8 hours ago, CharonY said:

Can you also accept that lipids have a natural way of getting eliminated from the body and that the values are established?

Yes, although I'm not sure what you mean by the values being established. The rate of elimination?

8 hours ago, CharonY said:

Also have you thought about the comment I made earlier that the rats were injected with a much, much higher dose than humans are per weight?

Yes, that does assuage my concerns quite a bit.

 

8 hours ago, CharonY said:

If so, no worries and we can continue to work on your question and figure what you might not understand. But if you are already set in your beliefs, better tell me now, else you would be wasting my time (and then I might get annoyed).

I am not set in my beliefs at all, in fact there isn't anything I DO believe yet about this, except the points I've said I accept.

Edited by Alfred001
Posted
6 hours ago, Alfred001 said:

Do the ovaries and bone marrow qualify as inert tissues that you mention might not clear the lipids? To be clear, this is not a rhetorical question, I don't know whether they do. The adrenals also show just a steady climb through 48 hrs.

Accumulation of lipids in adrenal glands, spleen and liver are expected with lipids. Inert tissues tend to be things like adipose tissue where metabolic turnover is low. However, perhaps I have confused you a bit, it is not a function of the tissue alone. To add some detail, elimination of compounds often is connected to metabolic modification. By attaching stuff to a given compounds they could e.g. be made more hydrophilic, which increases the rate in which they eliminated. The liver is one of the core organs for this process. For some compounds this process is for whatever reasons, very slow. But even then bioaccumulation typically only occurs if we get exposed to a compound faster than we can eliminate. If, on the other hand you get exposed only once, the elimination rate determines the time frame where a compound resides in your body. Eventually pretty much everything goes away (via hair, urine or feces, typically) eventually. Stuff that sticks around for a long time (and again, there is no indication that this is true for LNPs) tend to be hydrophobic and often reside in adipose tissue. Ovaries are not a storage organ and have a well-controlled lipid metabolism.

 

6 hours ago, Alfred001 said:

But if that is the reason, I don't understand why they monitored for 48 hrs only.

There is more data out there. Some files available for the vaccines in the EU and US process indicated that the committee has seen 2 weeks of data. The key is not the length, but to provide sufficient data to estimate elimination. I.e. often you do not monitor until the levels are below the detection limit, but rather you measure the rate of elimination and calculate half times based on that. Sometimes folks may ask for final elimination times, I suspect when it is critical to how the drug works, but that is outside my expertise.

For your other question I would prefer if you could transcribe the post and highlight your specific question. I would rather try to help you understand the underlying mechanism rather than argue indirectly with a random twitter person. One thing to keep in mind, and I sense something based on your question, too. The report is not original research trying to find and explain new things. Instead it is based on established pharmacokinetic frameworks. In other words, to fully evaluate the findings one need to understand how those measures are used and how to interpret them. I am not an expert in that area myself, though I have decent knowledge of most of the involved analytical methods (and I have friends that I talk to who are experts).

These data are then provided to a panel who then evaluates things like safety based on the provided information. Folks that seemingly see these type of data the first time in their life and try to make sense out of them simply lack the qualification to interpret them. It is like me trying to figure out general relativity by watching movies involving black holes. 

Posted
3 hours ago, CharonY said:

For your other question I would prefer if you could transcribe the post and highlight your specific question. I would rather try to help you understand the underlying mechanism rather than argue indirectly with a random twitter person.

I thought that the forum might automatically display the links as tweets, as it had done with some of the earlier links I posted, that's why I just left them as tweets.

This is what the first link says:

"Tissue to plasma exposure requires calculation of AUC. The sample period did not go out long enough to calculate it since the Cmax looks like it occurs at >48h . Typically these studies measure out to 7 days."

To be honest with you, I don't even fully understand what they're saying, but they seem to be referencing the fact that peak values for some of the organs are reached after 48 hrs, which did not permit the calculation of AUC, whatever that is. So, my question with regard to that is just if you could explain to me what the person is saying lol

The other two just ask why the lipids are ending up in the ovaries and bone marrow and whether those organs can clear them, but I guess you've answered that, although you didn't specifically address bone marrow, I don't know if anything different than what you've said about the other organs applies to it.

Posted
On 7/7/2021 at 4:38 PM, Alfred001 said:

"Tissue to plasma exposure requires calculation of AUC. The sample period did not go out long enough to calculate it since the Cmax looks like it occurs at >48h . Typically these studies measure out to 7 days."

To be honest with you, I don't even fully understand what they're saying, but they seem to be referencing the fact that peak values for some of the organs are reached after 48 hrs, which did not permit the calculation of AUC, whatever that is. So, my question with regard to that is just if you could explain to me what the person is saying lol

So that argument has some merit from a scientific perspective as they argue that the data provided is too thin to fully assess the pharmacokinetics of the formulation. Fundamentally this criticism has some merit and the context makes  more sense than the posts you have provided earlier. 

But before I get into that, I want to emphasize that in the context of OP long-term effects are not expected. For starters, even with incomplete data we see evidence of some elimination. As noted, the test concentrations was much higher relative to the animal weights as for the human formulation, so especially with hydrophilic compounds, it is likely that clearance will happen slower in rats compared to humans (i.e. more will circulate for a longer time). But more importantly, I want to point out the earlier argument with regard to monitoring health endpoint and its relationship to concentrations.

The rats were injected with 300-1000x the dose of their human counterparts (adjusted for weight) and a basic assumption of the effects of drugs is that they follow a dose-relationship (which is also the rationale behind PK and related analyses). So fundamentally you will expect the stronger effects when the concentration is high. Now with respect to the animal studies this has several implications. One is that the levels are massively higher than a person relative to their weight is going to encounter. I.e. any adverse effects should be pronounced in the animal. Second, clearance will be overall slower, as the small body needs to process a lot of material. For humans the relative dose is much lower.

So going back to the health effects, there were separate studies submitted to the various drug agencies based on injecting rats concentrations between 10-100ug of the drug three times a week apart (followed by a 3 week resting period) and compared to a control group. A snippet of the results is here:

Quote

At post-mortem there were higher absolute and relative spleen weights in vaccinated rats (up to 1.42x in males and to 1.62x in females). There were no other changes in organ weights. Macroscopic findings included enlarged draining lymph nodes and pale/dark firm injection sites in a minority of vaccinated rats. The dosing is reported as tolerated without inducing any systemic toxicity and with all changes consistent with an inflammatory response and immune activation: findings are consistent with those typically associated with dosing of lipid nanoparticle-encapsulated mRNA vaccines. Since this authorisation the manufacturer has provided the final study report which has been reviewed as part of the ongoing assessment for this product and is not discussed here.

In other words, even if injected with over a 1000x of the concentration of the drug several times, there was no indication of serious health effects other than inflammation (which is expected). The increases in the spleen were expected to be related to the inflammatory response, which can lead to the formation of blood cells, which is supported by bone marrow data. This was not the only study, another experiment was presented with more rats at single dose and also looked at organ abnormalities and found none. I.e. the toxicity studies directly look at damages caused by the vaccine components and the conclusion is that even at extremely high concentrations there are no unexpected damages in animal models. Thus, even if LNPs were lingering around, they would be as such low concentration that harmful effects are extremely unlikely. These findings are so far supported by clinical data in humans.

So together the point here is that one should not think that the one report is the full data provided to the drug agencies nor should one expect that any given data point can be easily extrapolated to health issues. Rather, different experiments provide different insights and the panel's job is to look at the full package and make a decision from there.

It would take a bit to explain how area under the curve analyses are conducted and how they are used, but I will for now note that full PK studies are often not required for vaccines. In part because you do not get regular doses of it, so that overdoses and similar events are not an issue. That being said, similar to the tox data, there is also more PK data out there covering about 2 weeks from which they estimated elimination rates:

Quote

Concentrations of ALC-0159 dropped approximately 8000- and >250-fold in plasma and liver, respectively, during this 2-week study. For ALC-0315, the elimination of the molecule from plasma and liver was slower, but concentrations fell approximately 7000- and 4-fold in two weeks for plasma and liver, respectively. Overall, the apparent terminal t½ in plasma and liver were similar in both tissues and were 2-3 and 6-8 days for ALC-0159 and ALC0315, respectively. The apparent terminal t½ in plasma likely represents the re-distribution of the respective lipids from the tissues into which they have distributed as the LNP, back to plasma where they are eliminated.

The public details can be found either on docs provided by the European Medicines Agency, but equivalents should also be found from basically all approving countries. If you are interested in more detail how elimination rates are calculated I could do that if I have a few minutes, but should probably be a different thread.

Posted

Paul Offit, director of the Vaccine Education Center at Children’s Hospital of Philadelphia, called those assertions highly unlikely. In the history of vaccines, he noted, side effects have always appeared within two months of administration.

“There are no long-term effects where you find that one year, two years, later your child or you develop some problem that wasn’t picked up initially,” Offit said. “It has never happened.”

https://www.sandiegouniontribune.com/news/health/story/2021-05-31/misinformation-remains-the-biggest-hurdle-as-vaccination-effort-turns-to-cash-incentives

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