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When will this shit end?


Chrisp1986

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So...OX/AZ, blood clots, suspension of vaccinations, politics, vaccine hesitancy, convoluted data, PR problems, Brexit, EU procurement naivety, poor logistics, national identity...there’s an awful lot of things getting embroiled here!

What’s going on? 

Basically, Oxford, building on decades of prior research, made an excellent vaccine in record time that is easy to distribute and, at the behest of their VC, will provide it to the world at cost price while we are still in a pandemic. Sounds amazing. And it is. 

But...the initial trials were designed by academics. They were designed to test lots of different things, and in reality, they produced an exceptionally rich dataset that allowed the best way to use their vaccine to be determined. However, politics and business meant that others denigrated this approach and pointed to lean, clean efficient trials from competitors and suggested that it was somehow inferior. This is where OX/AZ’s PR problem came from and it was compounded by AZ stating an average efficacy in their press release in an effort to keep up with competitors.  By the time the regulators looked at the data, how the vaccine should be used to gain comparable efficacy to their competitors had been worked out, but it was too late in some places, the narrative had already been established (normally, people aren’t that interested, the academics write their paper, the regulators review the data, it gets approved and the drug company promotes it to professionals, but doesn’t give worldwide press conferences before the data is properly examined...but we’re not in normal times!). That bad PR was perpetuated by idiotic comments from some European politicians who were playing politics with a global public health issue (they weren’t the first, nor will they be the last). 

After efficacy in trials, the next important metric in terms of disease control is effectiveness (how it performs in real world use). On this front OX/AZ has matched or outperformed Pfizer & Moderna...and in some places this has been noted and has changed how the vaccine is used, in others, they have yet to change, not really because they doubt the vaccine, they just don’t have that much of it and have alternatives that they can deploy. 

The next issue with the use of the vaccine is safety. In the trails, as they built through the phases, greater and greater numbers of participants got the vaccine. Adverse events were noted and were almost entirely mild to moderate. Few required medical intervention. Trials were paused to investigate serious events, but deemed to be unrelated to the vaccine, so they continued. In the end, 10s of 1000s of participants got the vaccine and no serious side effects were noted. So far so good. The next phase of safety assessment is the post-authorisation surveillance. This occurs for all medicines and is how we pick up really rare things that you might not see when only a few thousand people get the shot compared to millions or billions. Safety signals for really rare things usually don’t stop a vaccine being used, but they do help identify who should not take it (and if there is an alternative, then they can take that instead). 

Which brings us onto the blood clots. So far in the UK, DVT and other clotting events have been what has been observed. They have occurred at a rate that is no greater than would be expected randomly in the population. Therefore, the conclusion is that they are not related to the vaccine. That is entirely correct. What has happened in Europe over the last week is that a rarer form of clotting has happened in a bunched up way (within a short time post-vaccination). Random stuff can cluster (I used the lotto numbers example before), but it still requires investigation. The next part of the concern is the depletion of blood components associated with these clotting events. This is not usual and, again, needs to be investigated.

I’ll heavily caveat the next part as completely speculative (and indeed, I could be missing key information) but it does maybe give an understanding of why regulators in some countries want an answer...

The genetic vaccines work by delivering the instructions for the spike protein into our cells. The machinery in our cells makes the spike, and we mount an immune response to it. Because it is made in our cells, it is displayed on their surface for our immune system to recognise. This is good in terms of the complexity of the response elicited (we activate T-Cells that teach our B-Cells how to make antibodies to the spike and we also make T-Cells that directly kill the “infected” cell. Next time we encounter the real thing, the entire force of our immune system can be mobilised). It’s an elegant solution and by all evidence, works very well...now, here’s where the possible biological explanation is that needs to be fully answered. Which cells make the spike from the instructions is really important. The aim is that it happens in our muscle cells at the site of the injection. Where the vaccine goes after injection is tested by biodistribution studies during development. In the approval of the Pfizer vaccine, the results of these pre-clinical studies are shown (using a light generating reporter instead of the spike gene so it can be visualised). Light is detected in the muscle cells for about 6 days after injection, suggesting that the muscle cells are making protein for under a week, then it returns to baseline. Light is emitted from the liver for 48 hours after injection, suggesting rapid systematic clearance of any vaccine that gets into circulation. So far so good (rapid clearance prevents our immune system from causing damage elsewhere in our bodies in this case). However, the biodistribution studies for the OX/AZ vaccine weren’t fully completed when the approval was granted (in the approval it says they will be done by end Feb 2021). There are preliminary studies that follow the same pattern as the Pfizer vaccine, but it is a different delivery mechanism and you can’t completely extrapolate (this is the part that I could be missing something on, but I couldn’t find the data in any of the approvals...there’s also years of data on IM administration and systemic distribution to fall back on, so the regulators were probably happy). So, if the vaccine can get into circulation and be taken up by endothelial cells (the cells that line our blood vessels) or platelets (small cells that help our clotting mechanisms among other things), then if they were to make the spike protein and display it on their surface, the immune response would be the same, but the cells destroyed by the T-Cells that were stimulated would be the very ones that are missing from the patients who have had these rare clotting events (though rapid clearance would prevent this). 

Again, this is all conjecture, when I thought of it, I went back to look at the pharmacokinetic and Pharmacodynamic studies that made up the approval submissions for all the vaccines and was generally relieved to see that these things had been looked for, but the final piece of the puzzle was missing for OX/AZ. They may have it by now, the approval was submitted last year, but it would be good to know.

So, how come this isn’t more widespread? Nobody knows. It could just be random (and none of the above happens). Or, the people involved could have a very rare underlying genetic trait that makes them prone to this...normally, 48h would not really be enough time for cytotoxic t-cells and other parts of outer adaptive immune system to be made in order to destroy platelets or endothelial cells. But if these individuals don’t clear the vaccine as quickly, then we don’t really know what happens. The biodistribution studies are generally done in animal models, so it’s possible that there are some really rare slow metabolisers of the vaccine out there that are at risk of this happening...or it could be a manufacturing issue. But that’s exactly what needs to be untangled.

The next thing to note is the difference in approval for OX/AZ in the UK vs Europe. In the EU, under their CMA, AZ are on the hook for any problems. Not so in the UK (the government are). So, AZ will vigorously deny any connection to the vaccine in the EU as they are liable if there is a problem. So, it’s important for the regulators to examine independent data when making sure the vaccine can be safely used. We can’t entirely take AZ’s word for it if they say there is no problem as they have a conflict of interest.

Further to that, OX/AZ is not the principal vaccine is use in much of the EU, so pausing to untangle this poses less of a risk than it would in the UK and elsewhere. That’s partly down to supply, partly down to poor EC procurement, partly down to 27 different Healthcare systems having different capacities and a bunch of other things, but it undoubtedly has played a role in the decision making.

Finally, as has been noted, these are very rare events. Even if it does turn out to be an issue, the vaccine will still be used as the benefits still outweigh the risks. However, I think public confidence in vaccines in general would be harmed by not taking a rigorous approach to safety. I know we are still in a pandemic, but cutting corners does nobody any favours in the long run. There remains a massive amount of communication to be done on the safety of this and other vaccines and that is strengthened by being able to say, we take every event seriously and investigate it and only allow it to be used when we are fully confident it can be done without putting people at risk (and we will mitigate the risk of pausing vaccination by continuing to protect high risk Individuals with other vaccines).

I won’t get into Brexit, the UK/EU relationship, AZ commitments (though you know how I feel about that!), national identity, politics or any of the other aspects that have been dragged into this as I don’t really know much of anything about them.

 

TLDR: the vaccine has been safely used in millions of people. Very rare events are causing some concern. These should be checked and either ruled out as vaccine-related or looked for during future use. We will still use the vaccine as the benefits greatly outweigh the risks.
 

 

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Yeahhhh - 3 weeks today I had my first jab so those lovely antibodies and T cells should now be at a good level.

I am embarrassed to say that I was a little disappointed that it was Pfizer after being so invested in the Oxford-AstraZeneca development but gave myself a good talking to for being so privileged to just have the opportunity for any vaccine.

However, it’s certainly not going to change my behaviour at the moment. No illegal raves for me - not that I’m up to it anyway! I’m sticking with the current lockdown easing. I’ve only got one gig lined up in late July and if it’s still on I’ll certainly be going. Lots of UK campervan trips booked and planned also.

What it has really helped at this point in time is with my young son. My other half had his jab 5 weeks ago and with me now at 3 weeks it has taken so much anxiety away from him. He lives with us and has been working in an engineering company throughout with positive cases. He has been so concerned about catching it and bringing it home. Not so worried about himself but more about us. We’ve reassured him throughout that he would in no way be responsible if he did catch it - s**t happens.

So relieved that he can now relax more and enjoy meeting his friends in the garden/organised football games on the 29th March and outdoor pubs/restaurants on the 12th April 

 

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41 minutes ago, Toilet Duck said:

So...OX/AZ, blood clots, suspension of vaccinations, politics, vaccine hesitancy, convoluted data, PR problems, Brexit, EU procurement naivety, poor logistics, national identity...there’s an awful lot of things getting embroiled here!

What’s going on? 

Basically, Oxford, building on decades of prior research, made an excellent vaccine in record time that is easy to distribute and, at the behest of their VC, will provide it to the world at cost price while we are still in a pandemic. Sounds amazing. And it is. 

But...the initial trials were designed by academics. They were designed to test lots of different things, and in reality, they produced an exceptionally rich dataset that allowed the best way to use their vaccine to be determined. However, politics and business meant that others denigrated this approach and pointed to lean, clean efficient trials from competitors and suggested that it was somehow inferior. This is where OX/AZ’s PR problem came from and it was compounded by AZ stating an average efficacy in their press release in an effort to keep up with competitors.  By the time the regulators looked at the data, how the vaccine should be used to gain comparable efficacy to their competitors had been worked out, but it was too late in some places, the narrative had already been established (normally, people aren’t that interested, the academics write their paper, the regulators review the data, it gets approved and the drug company promotes it to professionals, but doesn’t give worldwide press conferences before the data is properly examined...but we’re not in normal times!). That bad PR was perpetuated by idiotic comments from some European politicians who were playing politics with a global public health issue (they weren’t the first, nor will they be the last). 

After efficacy in trials, the next important metric in terms of disease control is effectiveness (how it performs in real world use). On this front OX/AZ has matched or outperformed Pfizer & Moderna...and in some places this has been noted and has changed how the vaccine is used, in others, they have yet to change, not really because they doubt the vaccine, they just don’t have that much of it and have alternatives that they can deploy. 

The next issue with the use of the vaccine is safety. In the trails, as they built through the phases, greater and greater numbers of participants got the vaccine. Adverse events were noted and were almost entirely mild to moderate. Few required medical intervention. Trials were paused to investigate serious events, but deemed to be unrelated to the vaccine, so they continued. In the end, 10s of 1000s of participants got the vaccine and no serious side effects were noted. So far so good. The next phase of safety assessment is the post-authorisation surveillance. This occurs for all medicines and is how we pick up really rare things that you might not see when only a few thousand people get the shot compared to millions or billions. Safety signals for really rare things usually don’t stop a vaccine being used, but they do help identify who should not take it (and if there is an alternative, then they can take that instead). 

Which brings us onto the blood clots. So far in the UK, DVT and other clotting events have been what has been observed. They have occurred at a rate that is no greater than would be expected randomly in the population. Therefore, the conclusion is that they are not related to the vaccine. That is entirely correct. What has happened in Europe over the last week is that a rarer form of clotting has happened in a bunched up way (within a short time post-vaccination). Random stuff can cluster (I used the lotto numbers example before), but it still requires investigation. The next part of the concern is the depletion of blood components associated with these clotting events. This is not usual and, again, needs to be investigated.

I’ll heavily caveat the next part as completely speculative (and indeed, I could be missing key information) but it does maybe give an understanding of why regulators in some countries want an answer...

The genetic vaccines work by delivering the instructions for the spike protein into our cells. The machinery in our cells makes the spike, and we mount an immune response to it. Because it is made in our cells, it is displayed on their surface for our immune system to recognise. This is good in terms of the complexity of the response elicited (we activate T-Cells that teach our B-Cells how to make antibodies to the spike and we also make T-Cells that directly kill the “infected” cell. Next time we encounter the real thing, the entire force of our immune system can be mobilised). It’s an elegant solution and by all evidence, works very well...now, here’s where the possible biological explanation is that needs to be fully answered. Which cells make the spike from the instructions is really important. The aim is that it happens in our muscle cells at the site of the injection. Where the vaccine goes after injection is tested by biodistribution studies during development. In the approval of the Pfizer vaccine, the results of these pre-clinical studies are shown (using a light generating reporter instead of the spike gene so it can be visualised). Light is detected in the muscle cells for about 6 days after injection, suggesting that the muscle cells are making protein for under a week, then it returns to baseline. Light is emitted from the liver for 48 hours after injection, suggesting rapid systematic clearance of any vaccine that gets into circulation. So far so good (rapid clearance prevents our immune system from causing damage elsewhere in our bodies in this case). However, the biodistribution studies for the OX/AZ vaccine weren’t fully completed when the approval was granted (in the approval it says they will be done by end Feb 2021). There are preliminary studies that follow the same pattern as the Pfizer vaccine, but it is a different delivery mechanism and you can’t completely extrapolate (this is the part that I could be missing something on, but I couldn’t find the data in any of the approvals...there’s also years of data on IM administration and systemic distribution to fall back on, so the regulators were probably happy). So, if the vaccine can get into circulation and be taken up by endothelial cells (the cells that line our blood vessels) or platelets (small cells that help our clotting mechanisms among other things), then if they were to make the spike protein and display it on their surface, the immune response would be the same, but the cells destroyed by the T-Cells that were stimulated would be the very ones that are missing from the patients who have had these rare clotting events (though rapid clearance would prevent this). 

Again, this is all conjecture, when I thought of it, I went back to look at the pharmacokinetic and Pharmacodynamic studies that made up the approval submissions for all the vaccines and was generally relieved to see that these things had been looked for, but the final piece of the puzzle was missing for OX/AZ. They may have it by now, the approval was submitted last year, but it would be good to know.

So, how come this isn’t more widespread? Nobody knows. It could just be random (and none of the above happens). Or, the people involved could have a very rare underlying genetic trait that makes them prone to this...normally, 48h would not really be enough time for cytotoxic t-cells and other parts of outer adaptive immune system to be made in order to destroy platelets or endothelial cells. But if these individuals don’t clear the vaccine as quickly, then we don’t really know what happens. The biodistribution studies are generally done in animal models, so it’s possible that there are some really rare slow metabolisers of the vaccine out there that are at risk of this happening...or it could be a manufacturing issue. But that’s exactly what needs to be untangled.

The next thing to note is the difference in approval for OX/AZ in the UK vs Europe. In the EU, under their CMA, AZ are on the hook for any problems. Not so in the UK (the government are). So, AZ will vigorously deny any connection to the vaccine in the EU as they are liable if there is a problem. So, it’s important for the regulators to examine independent data when making sure the vaccine can be safely used. We can’t entirely take AZ’s word for it if they say there is no problem as they have a conflict of interest.

Further to that, OX/AZ is not the principal vaccine is use in much of the EU, so pausing to untangle this poses less of a risk than it would in the UK and elsewhere. That’s partly down to supply, partly down to poor EC procurement, partly down to 27 different Healthcare systems having different capacities and a bunch of other things, but it undoubtedly has played a role in the decision making.

Finally, as has been noted, these are very rare events. Even if it does turn out to be an issue, the vaccine will still be used as the benefits still outweigh the risks. However, I think public confidence in vaccines in general would be harmed by not taking a rigorous approach to safety. I know we are still in a pandemic, but cutting corners does nobody any favours in the long run. There remains a massive amount of communication to be done on the safety of this and other vaccines and that is strengthened by being able to say, we take every event seriously and investigate it and only allow it to be used when we are fully confident it can be done without putting people at risk (and we will mitigate the risk of pausing vaccination by continuing to protect high risk Individuals with other vaccines).

I won’t get into Brexit, the UK/EU relationship, AZ commitments (though you know how I feel about that!), national identity, politics or any of the other aspects that have been dragged into this as I don’t really know much of anything about them.

 

TLDR: the vaccine has been safely used in millions of people. Very rare events are causing some concern. These should be checked and either ruled out as vaccine-related or looked for during future use. We will still use the vaccine as the benefits greatly outweigh the risks.
 

 

I was just going to say that.

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Cooke says the EMA did initially investigate whether individual batches were possibly causing adverse events, after Austria banned a batch, and that as more events are reported “more batches are involved and therefore it is unlikely it is a batch specific event”.

 

so not a bad batch?

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24 minutes ago, Waterdeep said:

@Toilet Duckthat's really interesting, thanks for sharing. How might the vaccine get into the circulation from the intramuscular injection, is there a small chance of hitting a small vein or could it get there another way?

Howdy, IM injection of most things ends up in the bloodstream, pretty rapidly actually, and quicker than intra-peritoneal and routes other than intravenous (which is obviously straight into the bloodstream!). Our muscles are highly vascularised. The key really is the clearance, the metabolism of the substance and how it gets distributed around the body. These are among the the first things that are looked at in the development of any new drug. There’s lots to work out though!

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9 minutes ago, Ozanne said:

It’s staggers me that he’ll survive this after everything that’s come out.

 

8 minutes ago, steviewevie said:

the people love him, the fucking morons.

100% tories are going to rebound very strong after this once everyone is vaccinated.

Ive been having some serious thoughts recently that once the world re-opens I may relocate and actually give living in another country a shot.

I feel like the U.K. is doing my head in at the moment. I’m really struggling with this overbearing Tory influence on everything - and how getting them out of power just seems like an impossibility. 
 

- policies created for the tabloids 

- tabloid backlash being conflated with public backlash.

It just feels like everything is structured around Tory vision for Britain and there is no valid opposition.

Even america is less tribal than this. At least you see regular changes of power. I’m really sick of the U.K. staring down the barrel of at least another 20 years of Toryism. 

Edited by Matt42
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6 minutes ago, Ozanne said:

It’s staggers me that he’ll survive this after everything that’s come out.

But he got the vaccine out - and all those lab coat photos prove it.

I saw someone rather glibly compare the government response to a last-minute winner in a football match. The fans don’t care how bad the performance was - all they will remember is that feeling when the ball hits the back of the net and the end result. Seems to be happening before our eyes with the poll ratings etc.

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4 minutes ago, Ryan1984 said:

But he got the vaccine out - and all those lab coat photos prove it.

I saw someone rather glibly compare the government response to a last-minute winner in a football match. The fans don’t care how bad the performance was - all they will remember is that feeling when the ball hits the back of the net and the end result. Seems to be happening before our eyes with the poll ratings etc.

Exactly that. It just goes to show how simply pleased vast swathes of the public are. British public will easily forget what they went through this year.

Edited by Matt42
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9 minutes ago, zahidf said:

Cooke says the EMA did initially investigate whether individual batches were possibly causing adverse events, after Austria banned a batch, and that as more events are reported “more batches are involved and therefore it is unlikely it is a batch specific event”.

 

so not a bad batch?

It was already said here that there seems to be no connection between the batch and the nurse, who died (another nurse had health problems). also weird after Austria declared to continue vaccination with AZ yesterday, first county Burgenland declared to stop vaccination for 2 weeks.

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10 minutes ago, Toilet Duck said:

Howdy, IM injection of most things ends up in the bloodstream, pretty rapidly actually, and quicker than intra-peritoneal and routes other than intravenous (which is obviously straight into the bloodstream!). Our muscles are highly vascularised. The key really is the clearance, the metabolism of the substance and how it gets distributed around the body. These are among the the first things that are looked at in the development of any new drug. There’s lots to work out though!

Ah cool, thanks

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56 minutes ago, Zoo Music Girl said:

Ah maybe. Remember it being beautiful throughout lockdown but I've probably edited that a bit.

I just remember the day we closed the hostel down and said goodbye to each other (and shared out the bog roll) the weather and mood seemed very well matched.

Although I also might have edited that for dramatic effect

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23 minutes ago, Matt42 said:

 

100% tories are going to rebound very strong after this once everyone is vaccinated.

Ive been having some serious thoughts recently that once the world re-opens I may relocate and actually give living in another country a shot.

I feel like the U.K. is doing my head in at the moment. I’m really struggling with this overbearing Tory influence on everything - and how getting them out of power just seems like an impossibility. 
 

- policies created for the tabloids 

- tabloid backlash being conflated with public backlash.

It just feels like everything is structured around Tory vision for Britain and there is no valid opposition.

Even america is less tribal than this. At least you see regular changes of power. I’m really sick of the U.K. staring down the barrel of at least another 20 years of Toryism. 

I'm similar to you, Matt. It's just grim to think about the next election and how the Tories will probably walk it. 

Australia was an option for me, but as I'm 30 in a few months I'd have to apply for the Visa very soon and move there before next July (as I think you get a year to enter the country). Not sure I'm quite at the stage where I want to definitely move, so it's tricky.

Somewhere in Europe like Berlin would have been fantastic but unfortunately a large part of the country voted to rip that away from us for no reason. 

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4 minutes ago, km9 said:

Does anybody else worry that @Toilet Duck is just making it all up? 😁

To be honest, the bit about platelets and biodistribution in the post above is completely made up! I have no idea what the answer is (and it’s likely to be something else), but I think there’s a feeling that regulators are making purely political decisions for no good reason, or simply being over cautious and that they are only doing this with AZ because there are other issues, when in reality, they are just doing their jobs. 

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