Ok, I know promised a thread on the fascinating and important new research explaining what happened with the rare, serious side effects of AstraZeneca's and Johnson&Johnson's Covid-19 vaccines.
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(Sorry, I'm realizing this is getting reaaaallly long, but you gotta love the amazing ways that evolution has honed our body's ability to produce so many slightly different molecules to ensure that no matter what microbe nature throws at us we'll be able to produce a matching antibody...)
Amongst the B cells being reactivated were B cells that produced antibodies recognizing a particular protein of the adenovirus called pVII.
And in some people, who had one of those two cards I mentioned, so IGLV3-21*02 or IGLV3-21*3, one tiny change flipped what these antibodies recognize. -
Amongst the B cells being reactivated were B cells that produced antibodies recognizing a particular protein of the adenovirus called pVII.
And in some people, who had one of those two cards I mentioned, so IGLV3-21*02 or IGLV3-21*3, one tiny change flipped what these antibodies recognize.These people had a particular antibody that recognized pVII and in the process of generating mutations in B cells a single amino acid at position 31 switched from a lysine (which is positively charged) to either an aspartic acid or a glutamic acid (both of which are negatively charged).
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These people had a particular antibody that recognized pVII and in the process of generating mutations in B cells a single amino acid at position 31 switched from a lysine (which is positively charged) to either an aspartic acid or a glutamic acid (both of which are negatively charged).
This tiny shift changed what the antibody binds to and suddenly it was not binding to pVII but do PF4, an important protein in our blood clotting system. That led to complexes forming of antibodies with PF4 and those complexes activate platelets (thrombocytes) that then release more PF4. And so on.
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This tiny shift changed what the antibody binds to and suddenly it was not binding to pVII but do PF4, an important protein in our blood clotting system. That led to complexes forming of antibodies with PF4 and those complexes activate platelets (thrombocytes) that then release more PF4. And so on.
The result is both blood clotting and the depletion of platelets that are needed to stop bleeding elsewhere leading to the really striking symptoms that patients with this rare side effect showed.
In our story we simplified the NEJM graphic a little to show what happens.
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The result is both blood clotting and the depletion of platelets that are needed to stop bleeding elsewhere leading to the really striking symptoms that patients with this rare side effect showed.
In our story we simplified the NEJM graphic a little to show what happens.The good news (apart from this thread almost being done):
There is an easy treatment. Doctors can give IVIG (intravenous immunoglobulin). All that means is injecting the patients with other antibodies, essentially flooding their system with a mix of antibodies. -
The good news (apart from this thread almost being done):
There is an easy treatment. Doctors can give IVIG (intravenous immunoglobulin). All that means is injecting the patients with other antibodies, essentially flooding their system with a mix of antibodies.The reason that works? Platelets are activated when the antibodies that are in complexes with PF4 bind to the platelets. But when there are lots of other antibodies that already occupy the binding sites on the platelets then the complexes cannot bind and the platelets are not activated.
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The reason that works? Platelets are activated when the antibodies that are in complexes with PF4 bind to the platelets. But when there are lots of other antibodies that already occupy the binding sites on the platelets then the complexes cannot bind and the platelets are not activated.
It's a little like an asshole billionaire buying up all the houses in his neighborhood so no-one can move in who might aggravate him. Only when doctors do it for our immune system it saves lives...
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It's a little like an asshole billionaire buying up all the houses in his neighborhood so no-one can move in who might aggravate him. Only when doctors do it for our immune system it saves lives...
All of this explains why VITT was so rare and why it could not be picked up in the trials. A lot of things had to come together. The right kind of genetic background with the right kind of antibody and at the end one particular mutation.
There may be other factors too that we don't understand yet. -
All of this explains why VITT was so rare and why it could not be picked up in the trials. A lot of things had to come together. The right kind of genetic background with the right kind of antibody and at the end one particular mutation.
There may be other factors too that we don't understand yet.But with pVII identified as the problem in the adenovirus, researchers can now try to produce a version of it that is different enough that antibodies against it cannot lead to antibodies against PF4. There are a host of adenovirus vaccines in development so this is important.
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But with pVII identified as the problem in the adenovirus, researchers can now try to produce a version of it that is different enough that antibodies against it cannot lead to antibodies against PF4. There are a host of adenovirus vaccines in development so this is important.
One last point: If you have been paying attention it might be clear to you that everything I said could also happen when someone is infected with an adenovirus for a second time instead of getting a vaccine.
And yes! We know now that rarely people get these symptoms after adenovirus infection. -
One last point: If you have been paying attention it might be clear to you that everything I said could also happen when someone is infected with an adenovirus for a second time instead of getting a vaccine.
And yes! We know now that rarely people get these symptoms after adenovirus infection.I feel like a fraud because I didn't really explain the research, just the explanation that came out of it.
But it's a complicated and an important topic and I thought it's the best way to start. If you have questions, send them. I'll try to answer a few tomorrow. -
I feel like a fraud because I didn't really explain the research, just the explanation that came out of it.
But it's a complicated and an important topic and I thought it's the best way to start. If you have questions, send them. I'll try to answer a few tomorrow.@kakape As always, you did a fantastic job explaining a very complex topic. Thanks! Do I understand correctly that this might happen with any adenovirus vaccine? And is there a way to stop it from happening?
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One last point: If you have been paying attention it might be clear to you that everything I said could also happen when someone is infected with an adenovirus for a second time instead of getting a vaccine.
And yes! We know now that rarely people get these symptoms after adenovirus infection.My question exactly while reading this. Keyword is probably "rare". Thanks for summarizing all this.
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