What a fantastic read. The title might be a bit cryptic; the authors propose a convincing hypothesis that explains why Astrazeneca and JNJ vaccines cause rare but fatal blood clotting incidents.
TLDR: mRNA vaccines turn their payload into proteins in the cytosol.
Conversely, DNA vaccines (astrazeneca, JNJ) must first use the nucleus to turn their DNA into mRNA. This incurs so-called post-~translational~ (edit: post-transcriptional) modification to the genetic material prior to protein synthesis.
As it turns out, some of these unforseen modifications create soluble spike protein fragments that bind to epithelial cells. This in turn causes inflammatory, and coagulant, activity, which leads to the lethal side effects that are sometimes observed.
Here is the part I didn't get--they are saying that a mutation of the spike protein causes the binding to epithelial cells. But the real virus, with correct spike proteins, also causes this inflammation. So why does the vaccine only cause it as a result of the mutation? Why do the correctly produced proteins from the vaccine not also cause it?
The real spike proteins are insoluble and stick to certain membranes, like in your lungs. The mutant ones are shorter and more soluble, so they can more easily accumulate elsewhere, e.g. the blood vessels in your brain: hence the vaccine-induced brain blood clots.
They are manufacturing errors more than they are mutations. Since the vaccine and virus use the same machinery to make the proteins, they both result in proteins with errors.
But that is not the case according to the paper. The virus is RNA based whereas the vaccines at issue are DNA based. The problem as described by the paper is:
> the viral piece of DNA [of Adenovirus based vaccines] - deriving from an RNA virus - is not optimized to be transcribed inside of the nucleus. ... Thus, it could well be that the Spike open reading frame of SARS-CoV-2 is potentially disrupted by arbitrary splice events when transcribed inside the nucleus. Most, if not all, of these undesirable splice events would produce shorter protein variants, ... leading to soluble Spike protein variants.
So the error happens during DNA to RNA transcription in the nucleus. The Covid-19 virus is RNA based so how are the same splicing events occurring when it replicates itself in our cells?
Edit: There is further mention in the paper of predicting and then detecting potential splice sites in the "wildtype Spike" (which I think means the RNA of the spike protein of the actual virus) and they found several potential splice sites, but not as many as those predicted / found in the AZ and J&J vaccines. It's still unclear how those splice sites could be activated if the virus replicates entirely outside the nucleus but there is probably some information I'm missing here.
You probably mean post-transcriptional modification; post-translational modification also exists and occurs after protein synthesis for both kinds of vaccines, so it is not relevant here.
The immune response works as follows: Strange new protein in your body -> immunity
mRNA is the blueprint to a protein. You can get the mRNA into your body directly (super cool novel tech) or using a carrier virus that has the blueprint as DNA (eg. a modified chimpanzee cold in astrazeneca's covid vaccine). Here, the body first has to turn DNA into mRNA.
The researchers show that the latter approach gives rise to errors in prodcing proteins, errors that can cause severe side effects.
The J&N and AstraZeneca method (adenovirus-vector) is only barely a "proven technology" - as far as I recall it's only been successfully used once before, in an Ebola vaccine that was created in 2015 and approved in 2020.
As far as I know the vector vaccines were tested on animals. Nothing was skipped.
The issue is more that this side effect is so rare that it didn’t register even during the quite large phase 3 trials. This is to be expected. If side effects are rare enough you just won’t find them during trials. That’s why it’s important to monitor the vaccine rollout for all vaccines.
usually a new drug takes about 10 years to fully be tested as safe and FDA approved. these vaccines were given emergency temporary approval, because of the pandemic.
Also, your statement is highly misleading at best.
No idea what the US did but the EMA in Europe didn’t relax any of its standards and often drug testing is mostly slow because it’s costly. Here cost wasn’t really an issue and things that are usually done sequentially were done in parallel. That saves time.
We don't know the side effects are rare because the reporting mechanism for side effects is nearly non existent.
If you want to use the VAERS data, the side effects, include death, are not really that rare, in fact, these are the most dangerous vaccines ever produced based on that data.
If that data isn't good enough, you'll have to provide data that is.
How would that help when this rare syndrome only affects a very small proportion of people vaccinated. You would have to test it on hundreds of thousands of animals and that's assuming that the animals are a perfect model for humans.
And even if you injected millions of animals, they might happen to be species that deal perfectly fine with the proteins resulting from erroneous transcription.
You know, my father in law had some kind of stroke about 2 weeks after his first shot. I thought maybe it was more than coincidence since there were reports of increased occurence of stroke with the virus. Hard to say if it's just coincidence or not, but this paper is making me wonder if it may have been an adverse event.
The really frustrating part is that most doctors don't report things like this to VAERS. How can we have good data to analyze and find correlations if most doctors do only the legal minimum reporting?! They are only requires to report the types of known adverse events listed in the packet insert. This doesn't help identify new types of adverse events. This is the second time in as many years that I've witnessed something that has the potential to be a rare but serious issue related to vaccines not be entered by the doctors. I had to report one myself, and it looks like this other one will simply go unreported.
I am currently as we speak in Nebraska because my mother-in-law who is in her early sixties, suffered cardiac arrest hours after getting her second shot of Pfizer.
She is now in a coma and it doesn't look like she's going to wake up.
To your point the doctors immediately refuse to say a word about the vaccine or even considerate as a potential causal factor. Only after several days of tests where they determine that there was absolutely nothing wrong with her heart, have they now considered that the vaccine may have been a cause.
And additionally no they have not reported this to VAERS. And with the covid protocols in hospitals not allowing most of us in, my wife and her sister aren't very assertive, and therefore haven't pushed.
My mom refuses to be vaccinated because my grandma’s health tanked (and then she died) after taking the vaccine.
She was old, so, you know - who knows. Certainly it was worth the risk at her age. It’s concerning though that if it does come out at a later date that there are more vaccine complications than we think due to how rushed this is... it will really hurt vaccine confidence.
It’s a shame they were politicized. My mother-in-law keeps on asking if I’ve been vaccinated, even though I had a serious case of COVID in December. She also disapproves of my wife, who is pregnant, not getting the vaccine. I’ve seen YouTube put forward videos on their front page trying to convince pregnant women to be vaccinated.
It’s crazy. Chances are it’d be fine, especially with the mRNA vaccines. But my wife was already exposed when I had it, can still work from home, and confirmed cases are in free fall. It’s like people have completely disregarded risk/reward due to their political affiliation, and that goes both ways.
Well said. The value proposition is different for everyone. I've noticed a bunch of false or misapplied statements from both sides too.
I went to dinner with my in-laws. They were supposed to get an outdoor table but ended up getting an indoor one since they are vaccinated (I think in an effort to pressure me). My father-in-law was giving me all sorts of nonsense about not being vaccinated even though I'm low risk in both lifestyle and comorbidities. I WFH, only go to the food store or distanced outdoor events, I use an N95 mask (that I had from woodworking). I plan to hold off on the vaccine until I go back to the office. At that point there should be a few more month of data for me to look at (even though the data quality in VAERS is abysmal due to lack of reporting). He thought my plan of waiting was stupid.
Even after vaccination, he has a .2% chance of fatality based on age and comorbidities. Unvaccinated I have a .03% chance (likely very much lower but can't find the numbers without comorbidities in my age group). How can he criticize someone with vastly lower risk? There is a point of diminishing return too. If I get the vaccine I eliminate .0285% risk, while it eliminates 3.8% for him. Clearly it provides more value to some than others.
I caught it in mid-February and had virtually no symptoms except for loss of sense of smell.
I have very high levels of antibodies and was advised by my doctor to hold off on getting the vaccine. Several coworkers in mine have insisted that I get the vaccine or they will not participate in a picnic where I am present. They are all vaccinated so I don't really understand the reasoning, but I think there's some strong psychology at play just like your mother-in-law.
I'm pretty racked with guilt at this point because I was strongly encouraging my mother-in-law to get the vaccine so she would stop living like a shut-in.
My wife just came home from the hospital and it's official:
Her brain activity has continued to deteriorate to a point where she is brain dead.
It turns out that there are several cardiac arrest events for every 100,000 shots administered.
So it is a rare event but not as rare as many people think. Obviously the media isn't going to report, because it would cause millions to not get vaccinated. It's understandable, but yeah, my head is exploding right now.....
I don't see how it is understandable for the media not to report the full story. The point of a free press in a democracy is supposed to be for the people to be informed of the issues and decide for themselves.
I'm pretty sure they are legally required to report it if there was a death or near death issue. I'm not sure what the timeframe is for when it stops being required to be reported (I would think same day would be a no brainer).
Are the mechanisms limited to those, or did they only investigate the proteins specific to those vaccines? My understanding is that they only looked at the spike proteins for those vaccines and did not evaluate the others. My understanding is that the proteins in the others have the potential to interact similarly with the ACE2 mechanism but were not evaluated.
The issue seems to be with the DNA -> mRNA transcription required by the adenovirus vector of the J&J and AstraZeneca vaccines, leading to mutated spike proteins which can cause clots. The Pfizer/Moderna shots don't use this mechanism so weren't the subject of the paper.
(This is not my specialty at all, just summarizing the abstract & what other commenters wrote since nobody replied to you yet)
Oh, I see. So similar mutations don't occur with straight mRNA. I think that makes sense. But also I thought the exact spike protein structure could vary with mRNA vaccines too based on the patient's genetic make up because the mRNA only encodes a portion of the spike and the rest of the spike is generated by the host cell.
I don't know, that not my area either. My main two points are that if covid itself can increase risk of stroke and now some covid vaccines can too, then I wonder if other covid vaccines might have contributed to this anecdotal one. The second point plays into the first. I would be less likely to question it if we had better reporting in the VAERS system.
He actually seems fine now, so he recovered quickly.
A stroke within 2 weeks of the shot should be reportable.
The CDC would then compare that event to the background rate to see if it is significant.
Docs are seeing heart inflammation too with the vaccines where a couple of people have died. There were reports out of Israel and then the US military has documented it. The US military has an extremely robust vaccine monitoring program that are the primary evidence. Apparently they had issues in the past with the smallpox vaccine which lead to the new process.
They can report it. The thing is, most simply don't report it because it's not required. (The emergency approval requires it, but doesn't define how long after vaccination it is required)
My kid had an SVT 2 days after receiving 4 simultaneous vaccines. No prior issues, no family history, no cause determined by the doctors. They said that couldn't possibly be related, but when asked for any data/explanation on that theory they had none. (Later doctors said there could be some sort of connection) So they're telling me that they don't know what the cause is, but that it's definitely not the vaccines, even though there's no evidence to rule that out... yeah, ok. There's the possibility of coincidence, but it's astronomically small. The only way to tell one way or the other is to have the data from the larger population, which isn't happening because it's not being reported. I had to submit the report myself in that case.
I wanted to crunch the numbers myself, but the major issue is that even a small number of unreported cases will greatly skew the results when dealing with rare issues. You basically need anonymized medical records (I know, those don't really exist) so that you have a known population size and any medical treatment would have been recorded even if not reported.
We wouldn't have much of an issue of doctors being hush hush if they didn't have to be worried about being sued all the time. If doctors could just do their jobs and not worry, I could see them not caring as much as opposed to when their ass is on the line basically.
In general I agree. The VEARS system shields a lot of the liability for vaccines. There's really no legal reason not to report. In fact, they are required by law to report some types of reactions.
I think the main driver is a lack of understanding and education of how the system should be used.
> How can we have good data to analyze and find correlations if most doctors do only the legal minimum reporting?
We can't, that's the point. It's not like you, random person on the internet, have thought of something the industry and regulators haven't. With all the modern technology at our disposal, the industry has simply chosen not to do this.
They have found first computationally then experimentally, a high number of potential splice sites in genetic code of AstraZeneca and J&J adeno viruses. This means instead of producing Spike protein, its shorter versions may be produced by cells infected with these adenoviruses. Those short proteins can cause rare sever side effects.
Quote: Here, we present first molecular evidence that vector-based vaccines encoding the Spike protein exhibit a problem that is completely absent in mRNA-based vaccines. This is due to the fact that during the vaccination step, the adenoviral DNA enters the nucleus and use the host machinery to transcribe its (trans)genes inside the nucleus. However, RNA viruses have evolved in the absence of any post-transcriptional modification systems that are usually enabled to process the primary RNA transcripts of nuclear encoded genes.
In this study, we experimentally validated our assumption that potential splice events cause the production of Spike protein variants that have lost the important membrane anchor, resulting in secreted, soluble Spike protein variants.
I am way outside my domain here, but the key thing I didn't quite get is why, since 20%+ of the mRNA in the mRNA vaccines is truncated sequences (https://www.bmj.com/content/372/bmj.n627), some of those sequences don't similarly get translated into soluble proteins with similar bad effects.
But I guess it has something to do with particular splice sites causing particular irregular proteins that cause the issue — and since the mechanism of mRNA truncation in the mRNA vaccines is not splicing, I guess there may be a much wider array of random truncated sequences, most of which are harmless?
> Finally, EMA has received reports of Comirnaty recipients developing myocarditis and pericarditis. “There is no indication at the moment that these cases are due to the vaccine,” wrote PRAC.
After my J&J shot, for weeks, my legs and feet would frequently feel “asleep.” Especially on waking but often during the day as well. The effect seems to have diminished (and I think mostly resolved) ~6 weeks later. No idea if it’s related to this.
(This is on top of the usual reaction of chills/fatigue the first night or two. I will say the fatigue seemed to go on for a while at some modestly higher than usual baseline but I can’t really quantify it or prove it. )
Does this only apply to the adenovirus vaccine or could this happen with the mRNA ones too?
It sounds like only the adenovirus, in which case the naming of the syndrome is… unfortunate in the middle of a stalling vaccine rollout. It will sow confusion I think.
It can happen in the mRNA ones too, but this misfolding will happen in the lab rather than in your cells. What percentage of an mRNA shot that is being mass produced is random biological material? We don't know, there's no kind of independent laboratory testing these things.
What I want to know is if the transcription of the spike protein of the SARS-CoV-2 also leads to dangerous C-terminal truncated spike proteins or that SARS-CoV-2 transcription by definition doesn't lead to truncated spike proteins.
If so than catching SARS-CoV-2 is equally risky on this front.
From the abstract:
"..transcription of wildtype and codon-optimized Spike open reading frames enables alternative splice events that lead to C-terminal truncated, soluble Spike protein variants. These soluble Spike variants may initiate severe side effects when binding to ACE2-expressing endothelial cells in blood vessels"
I was asking myself the same question because some of the wording used is quite suggestive to a layman reader like me. But after some Wikipedia my answer is: no, the actual virus carries its blueprint in RNA form that doesn't go through that transcription step where the errors occur.
In JVM lingo, it's as if one was .class and the other was a single-class .jar and somehow certain byte sequences were less reliable during unzip than others. And as a consequence, those byte sequence are avoided by programs routinely distributed as .jar but used quite generously by those distributed as .class. Now they took some snippets from a codebase that is deeply rooted in the ".class" tradition and inserted it into a vector from the ".jar" side and the unzip errors happened to be rare enough to not light up during QA.
Isn't it too be expected that when you train people's immune response by injecting mimicry spike proteins that people will react very similar to when they receive actual spike proteins?
neither mRNA (Pfizer + Moderna) nor viral vector (AZ + J&J) vaccines "inject" spike proteins. They use different delivery mechanisms (lipid nanoparticles or adenoviruses) for the genetic code that is used to create the spike proteins.
The article referenced is suggesting that the rare but serious clotting issues related to the adenovirus vaccines is caused by an errant processing of the spike gene which results in production of truncated spike protein that has soluble properties which results in it being excreted into the body. This soluble spike protein can then cause blood clotting issues when binding to endothelial cells in blood vessels.
So to attempt to answer your question: we expect the vaccine to result in the production of the spike protein in the body which your body then builds an immune response to which protects you from future infection. However, either due to a problem with the vaccine or how the spike protein is created in the body (I'm am not sure which - someone let me know), in rare instances a truncated spike protein can be produced that is slightly different than expected and results in blood clotting issues.
I had reservations about J&J and AZ because of their complicated nature. I had more confidence in mRNA vaccines (Pfizer and Moderna) as simpler and more elegant to produce the desired immune response.
Anytime there are extra steps, there's added risks something can go wrong and cause unknown or horrible side-effects.
What a great example of ridiculousness of web 3.0
researchsquare.com loads and then "An unexpected error has occurred." fullscreen. Disabling JS and CSS makes it worse. So un-scientific.
Can anyone explain how long they expect this potential effect to last? The vaccine DNA presumably breaks down / dissipates after a period of time? And the spike protein fragments too? What might that period of time be?
I had the worst headache of my life a few days after getting the J&J vaccine, and went to the emergency room because my wife was worried I’d had Ana aneurysm or something. The ER visit happened the day before the news broke about blood clots and whatnot. The doctor told me it was absolutely unrelated to the vaccine. They did a scan with some contrast dye, said everything looked fine, and discharged me. I couldn’t do strenuous activity for over a week because I’d feel the headache again, almost like a part of the inside of my skull had been scraped, I don’t know how else to describe it.
TLDR: mRNA vaccines turn their payload into proteins in the cytosol.
Conversely, DNA vaccines (astrazeneca, JNJ) must first use the nucleus to turn their DNA into mRNA. This incurs so-called post-~translational~ (edit: post-transcriptional) modification to the genetic material prior to protein synthesis.
As it turns out, some of these unforseen modifications create soluble spike protein fragments that bind to epithelial cells. This in turn causes inflammatory, and coagulant, activity, which leads to the lethal side effects that are sometimes observed.