The EMA Covid-19 data leak, and what it tells us about mRNA instability
bmj.com
bmj.com
The efficacy data was based on clinical trial batches though, and the challenge seemed to be with lower manufacturing quality in the large scale commercial batches : "changes were made in their processes to ensure that the integrity was improved and brought in line with what was seen for clinical trial batches."
To be honest, we do also have real world data now (Israel mainly) that confirms the benefit/risk balance to be extremely good.
We do what we can with what information is offered to us. Lies, half-truths, and all.
It's all so tiresome…
I could think of half a dozen parties with interest and the means to push this story in either direction. It's axiomatic that a story that's been covered is of interest to anyone. The response to a story implicitly carries on that property. The specific nature of the interests involved are not always clear.
Here, I reserve judgement. Time will tell.
What exactly of the above makes this a "misinformation campaign" (a term so vague as to be misinformation itself)? Nowhere in what you say above says the data are falsified or wrong.
Hackers have leaked data from organizations almost as long as there were computers - and giving them to journalists and/or posting them just as often. People also did it before computers.
The difference being that then we saluted getting access to raw data, whereas now we are being conditioned to consider them "misinformation".
I like this point. I wish it would be reported as an "influence operation" rather than "misinformation". The most effective propaganda is 80% true.
> A closer investigation of the published material has revealed that not all of the documents were published in their integral, original form and may have been taken out of context. Whilst individual emails are authentic, data from different users were selected and aggregated, screenshots from multiple folders and mailboxes have been created and additional titles were added by the perpetrators in a way which could undermine trust in vaccines.
"manipulated data" sounds like Orwellian double speak from the company.
I remember the planned parenthood video, where they where haggling over prices for parts. Planned parenthood claimed it was a manipulated video too. Because it was an excerpt. They even locked up somebody for making the video. Never mind that the full unedited video was also released on the internet.
And a few years earlier I watched a documentary on CBC about a black market in body parts. Little bits and pieces used during surgery. Which this totally corroborated.
If there's actual proof the PP video was legitimate surely it's in that criminal case. Provide specific and high quality proof on specific instances, making wide generalizations does not make it convincing.
I'm not sure where you got your info, but PP was totally vindicated after 15 states investigated.
It sounds like they got people together to go after PP and then it didn't turn out that way.
Doesn't that cut against the dystopia in your imagination where things are predetermined?
Seems like "manipulated" is EMA code-speak for "published the parts that make us look bad".
It could just as likely be a hacker acting out of altruism, similarly to the one who broke into that italian company a few years ago. If someone didn't trust that the megacorp was acting in good faith, what they did here is probably the most effective (though morally ambiguous) way to hold them accountable.
The only question now is, are we going to brush their work aside without examination, blithely labelling it "misinformation", without any further thought?
Setting aside the misinformation / disinformation rhetoric for a moment, a product that gets injected in virtually every human being alive needs to go through a generous amount of scrutiny to ensure it works as intended and does not cause more harm than good.
Biotech is a vastly complex field and taking the stance of "it works, trust me" is not exactly wise.
The leaked information requires analysis to identify the valid and relevant parts which should be treated as feedback for health policies and vaccine development.
Efficacy: the mRNA vaccines have a large margin for error with respect to dose. 55% of several times more than enough is still more than enough.
Danger: suppose the danger of broken-up mRNA to increase linearly with the amount given. Then the increase of danger would be by a factor of (100-55)/(100-78) ~= 2. The substantiated near-term danger of Pfizer is very low. We're at 5.2 million people vaxxed in Israel now… Twice of very low is very low. In order to argue for "too much" danger you have to argue either for non-linearity or for long-term high danger. If you argue for the latter then you already think the danger to be high, so there's no real difference between your view now and your view before. If you want to argue non-linearity of danger then you are arguing for a very remarkable biological coincidence. You also have to explain why the occasional 5x overdoses, which happen when a someone is given a whole vial by mistake, don't seem to be doing any harm. Never mind that it would have come out in the animal trials.
Otherwise, the mRNAs aren’t present in high enough quantities to do significant signaling or silencing things, and it’s going in the deltoid... not really a medically interesting place. You could inject 1mL of dilute HCl there and it wouldn’t be a big problem.
no cytoplasmic nucleotide transport signal and it gets degraded quickly.
“If you want to argue non-linearity of danger then you are arguing for a very remarkable biological coincidence.“
What do you mean here? Can you give a bit more info?
Note, I am pretty well versed on nonlinearities from a mathematical-engineering point of view, but know very very little about biology. (If that’s of any use to know)
There's a specific minimum dosage most people have of allergen before they hit on a life-threatening reaction. You might be okay with trace amount of peanuts, swell up with one peanut, and die with five. It's pretty consistent, and very nonlinear.
That's why you can build up a tolerance to iocane powder too; small doses won't do anything, while large ones are guaranteed to kill. If it was linear, a 1/10th lethal dose would have a 10% chance of killing you.
Chest x-ray is pretty linear within reasonable dosage ranges, for much the same reason I'd expect mRNA damage to be.
This contrast with e.g. sports brain trauma, where one sports brain trauma might be relatively moderate risk, but two might be very high risk (much more than double). Or risk from ibuprofen, where 600mg is has close to zero risk, but an overdose of 60,000mg poses a significant risk of death (much more than 100x the risk of death of a 600mg dose). That's nonlinear.
I'm not sure how risk from mRNA defects would be anything but linear. It would take an extraordinary set of coincidences.
I’m confused so let me try an analogy with DNA: most mutations do nothing. Every now and then, cancer. Sample a large number of mutations for a short duration, and you have proven nothing regarding nonlinearity globally. Roughly speaking.
Another example: I can measure a the air near (but not to near) a shockwave, or just under (By human scale) the free surface of the ocean, and find pretty much linear behavior if no other pathologies are present. The underlying physics however, is not linear, it is only my approximation which is. Maybe it’s valid over configurations of interest. But then I better know something about the limits of my approximation.
If I understand woofie11 correctly, it means that the probability that an error in a single mRNA corresponds with an error in another mRNA to cause a larger perceivable effect is small. The errors would have to be made in the exact same way.
If an mRNA mutation were to make a self-replicating virus, or make something which damages DNA leading to cancer, or something wonky like that, I guess that's in abstract possible. It can make abstract proteins, and we don't know what those will do.
In that case, if I have twice as much mutated mRNA in my body, the odds of that happening almost exactly double. It's like rolling a 1-trillion sided die twice instead of once and seeing if I roll a 1. With one roll, I have a 1-in-a-trillion chance. With two rolls, I have a 2-in-a-trillion chance (minus 1-in-a-septillion of having the same thing happen twice, which we don't know what it would do, but is a small enough possibility we can ignore).
But yeah, unless something really wonky going on, I'm not going to end up with hundreds of strands of mutated mRNA in my body *all doing the same thing*.
The statistics as derived from the dynamics of “how rna works” - yeah that’s compelling.
This:
“If an mRNA mutation were to make a self-replicating virus, or make something which damages DNA leading to cancer, or something wonky like that, I guess that's in abstract possible. It can make abstract proteins, and we don't know what those will do.”
Sounds astronomically I likely, but with unknown error bars. Sounds like our If our cross section test Is large enough going on long enough, we might just get there.
A prion (misfolded protein that causes other proteins to misfold) is more likely, but even then prions need to misfold in specific ways that encourage their replication as well. In all likelihood the error is just going to prevent the ribosome from finishing transcription and we'll have just a fragment of whatever protein the RNA initially encoded for.
Ibuprofen reaches a threshold of toxicity; a level at which our body's ability to manage it gets met and then exceeded. Things go rapidly wrong at that point.
Degraded mRNA just... doesn't work. It'd be a problem if all the mRNA in your cells started suddenly degrading faster than usual, for sure, but that's because you need the resulting protein output to live. If the vaccine degrades too fast, it just doesn't produce the proteins it was supposed to, but we didn't need them to function. Lost efficacy, but you don't wind up growing extra arms.
But I do think this raises some questions around transparency. If the EMA has concerns about the production of these vaccines then I think this is something that should be discussed in public - so the scientific community can weight in and review this issue. If the EMA thinks that this is a solved issue - which the emails imply is what they thought before they authorized the vaccine - then that's what they should communicate.
You know you're in a cult when you must preface your fealty before voicing the softest of logical hardballs. This entire thread is 50% prefacing. We've lost our ability for true discourse.
In any case, it's a matter of weighing risks. Even if there's a 10⁻⁶ probability of complications, giving the vaccine and stopping serious illness/deaths is still a better decision overall. Even if it means hundreds of cases of complications across Europe. And then, the complications might turn out to be statistically difficult to discern from uniform random anyway.
A probability of 10⁻⁶ is difficult to conceptualize so if it is published with scary words, people might interpret it as "will probably happen to me". Then if that affects vaccine roll-out negatively, publishing might be a bad decision.
Millions of people in the UK have received the AZ vaccine, which has demonstrated safety and efficacy.
The efficacy metric means protection against infection, which is not complete. But as far as I've heard, not one person who has received either Pfizer or AZ has become seriously ill or died. In other words, it "flattens the curve" instantly.
Unfortunately we/they are in a damned if you do, damned if you don't situation. If it was published, you can be sure the misinformation around what it meant would be through the roof. Having it hidden, and now come out may end up lending more credence to the conspiracy theories.
And who appointed them as arbiters or censors of truth for "the public's own good" as opposed to researchers that should make their results public whatever they are?
Less fear and doubt than if it gets leaked.
This is another (very very) complex system with a relatively untested technology in an extremely noisy deployment environment. Every user is running a different OS basically, and every deployment corrupts the deployment image to some degree (RNA breakdown). Problems were bound to occur, and yes, the extent of those challenges are likely being downplayed to avoid panic and to get people to take the vaccine.
On the question of motivation: global pandemic, billions in R&D spent, pressure from people on politicians, etc. The usual set of unavoidable human reasons to release products before they are 100% tested (since 100% testing can only really happen in the wild anyway). Combine that with politicization of every topic, and the inability of the public at large to handle any nuance (e.g. "there may be some problems in production, but we believe overall it is worth the risks and won't pose a major problem because of X, Y, and Z.")
Spurious examples aside, the pandemic has highlighted ethnic differences in reactions to both pathogen and vaccine.
And from personal experience in the field, seemingly "random" confounding factors can have drastic effects - supposedly safe gadolinium based contrast agents caused NSF if you happened to have bad kidneys.
Aggregation occludes all nuance, essentially by definition.
Decisions that are correct for the aggregate can often be wrong for the individual.
But I guess that kind of thinking is why the pandemic has been such a crapshoot in the first place.
This is a widely repeated "internet fact" but it's not true. For one thing, a banana has only about 520 million base pairs of DNA, while the Human genome has 3.1 billion.
In reality, depending on the search method used, at most about 24% of human genes have orthologous genes in the banana genome:
https://lab.dessimoz.org/blog/2020/12/08/human-banana-orthol...
I am in general skeptical about some vaccines, especially loading infants up on many vaccines all at once. However, with COVID-19, I think the general risk is worth keeping the global economy from complete collapse (if that is even possible).
We could simply reopen the economy at any point. There are more than enough counterexamples around to demonstrate that lockdowns do not eliminate Covid-19, and that a lack of lockdowns does not lead to endless piles of dead bodies in the streets. Lack of sufficient vaccination is not what is keeping the economy closed -- its usefulness in driving forward certain agendas is. The vaccines aren't even promising anything close to 100% effectiveness, particularly not among the highest risk groups (who were excluded from the clinical trials).
"We can go back to normal soon if everyone just does this one thing" has been the carrot dangled in front of people's noses to get them agreeing to measures of dubious effectiveness since the start of the pandemic. If the virus mutates in the fall and winter and boosters have to be rolled out again, we'll either "have to" shut the economy back down until everyone gets shots in their arms again (in which case these vaccines are a poor preventative against economic damage) or we'll accept the need to live with some amount of endemic Covid spread (in which case it was certainly not lack of vaccines keeping us from reopening).
Citation needed.
Lack of lockdowns does not lead to mass death: Sweden, Florida, South Dakota, vast portions of the Global South.
The US has 500k deaths so far, I consider that pretty massive.
Lockdown _did_ eliminate covid in New Zealand, so there are examples both ways.
It's pretty clear that there's a spectrum of lockdowns and their effectiveness. Personally I would rather you all stayed home for 2 weeks rather than sacrifice my grandparents for the economy.
The lockdowns in much of the western world were pretty weak overall. So many caveats and exceptions. It was "lockdown except for that which is _too_ inconvenient for my voting base"
The lockdowns didn't help your grandparents at all, all they did was destroy the lives of many young people and business owners, and plunge over a hundred million people worldwide into extreme poverty: https://apnews.com/article/lifestyle-health-ap-top-news-addi....
> Personally I would rather you all stayed home for 2 weeks rather than sacrifice my grandparents for the economy.
If you think the life of your grandparents is worth more than a hundred million people in poor countries being able to put food on their table, you're incredibly selfish.
Luckily, CARES aid was so effective it actually reduced poverty.
LA, Sacramento, and every Bay Area County Sheriff publicly announced a focus on “education and voluntary compliance”; virtually all the urban Southern California Sheriffs aside from LA County publicly annouced outright non-enforcement policies (some asserting that the orders were unconstitutional), as did the Sheriffs the counties with the major San Joaquin County cities.
The “most stringent lockdowns” weren’t anything like lockdowns.
Aside from the components that were directly within state or other non-sheriff’s authority to enforce (like the alcohol service components which could be enforced directly by state Alcoholic Beverage Control), there was no enforced lockdown essentially anywhere in the State, and this was publicly announced and widely reported in the media, so people were aware of the nonenforcement.
Travel restrictions are working for AU/NZ/Japan/Korea along with restricting indoor gatherings when necessary. They didn't work for NYC because they didn't restrict European travel.
That's not that much different from the self deceiving mind trick those say who claim this is a "human experiment". Which is, of course it is! I mean the process for testing and certifying a medication has to include a phase where we experiment on humans.
And the whole process is designed with this in mind: increasing number of participants during phase 1-2-3 trials and then it gets released, without being tested "100%", if you will, and it enters phase 4, that is basically tracking it while being "out in the wild". Though you could argue that phase 3 is just as much out in the wild.
I think what you can see from how these vaccines are being tested and released is that these are the most rigorously tested products out there.
With more information (more trials/subjects) we get a better estimate (with less uncertainty) of the associated risk. The properties (safety/risk) of the vaccine don't change. What changes is the uncertainty around our estimations.
This is still a simplification (e.g. there could be unknown unkowns) but I find it a better heuristic than safe/unsafe.
I still plan on getting vaccinated, but I always wondered about the failure modes of the mRNA as it decays and what materials it could produce. I'm hoping prions are not possible, but are they?
The story also asks what happens to the lipid nanoparticles, but I am wondering about another aspect of these crafted mRNA sequences. The "U" in the mRNA has been replaced 1-methyl-3’-pseudouridylyl, denoted by Ψ in their sequences. What happens to the Ψ and its byproducts as it decays or is metabolized?
I had the same question. What I found in a long paper about mRNA vaccines is that they do not really know, but they assume you'll be fine, since they didn't see any immediate effects and because the quantities are tiny.
Ψ is naturally found in tRNA, so its not really something to be concerned about.
Edit: scratch that, confusing pseudouridine with 1-methyl-3’-pseudouridylyl
its not good odds at all to bet on a viral mRNA fragment spontaneously creating a prion protien sequence. this is not beyond the realm of possibilities however the probability nonexistent, compared to the probability that anyone at random could have a nasty interferon mediated cytokine cascade, and sequential inflamatory response to the virus.
these lipid particles are incorporated into the cell membrane during vesicular fusion. Expression of the mRNA results in S protien being expressed on the surface of this cell, Antibodies of complementary clonal type bind to this spike in numerous locations the now adulterated cell is labelled as antigenic thus is destroyed by macrophages, the pieces of this cell are then compared to the self/nonself portfolio of patterns and further antibodies are produced.
all the while this cell is in distress due to the presence of foriegn nucleotides and this incurrs an interferon mediated response that spreads among cells and likewise induces interferon response
Worth noting
Even the Clinton team tried to say the Wikileaks were doctored, despite the vast majority of them having a DKIM signature confirming their authenticity.
The ball is in EMA’s field now: they have to demonstrate the leaks are doctored.
There’s pretty damning information in there, it’s in their interest to demonstrate it’s false.
So the victims of a cyberattack have to prove their data has not been manipulated? Cool
> There’s pretty damning information in there
No, there isn't, unless you're buying manipulated information and believe in 5G vaccines.
The data presented sounds like a regulator doing its job and not rubberstamping every decision (cough cough 737Max)
You might not have seen anything useful in what was presented but it doesn't mean someone else can't. Comparing it to "5G vaccines" to discredit the parents point isn't the right way to challenge their interpretation.
Are you going to question every "data leak" and smear campaign that comes from questionable sources (I think this leak was first published on Rutor - not the first time Russia does something like that)?
> it doesn't mean someone else can't
True, that's what the article addresses. And as you see it's making technical questions not implying they're hiding something.
No, but if they do claim it has been manipulated, then it would be nice to show proof.
> 5G vaccines
No idea what you are talking about, sorry.
Is the EMA suggesting that this isn't the case or are they just telling us that it was editorialised by whoever disseminated it?
Doctored is the word you'd use if the contents have been changed in order to deceive people. However this could be an attempt at damage control if they want people to dispute the veracity of the leak.
Edit: Since I'm questioning the EMA here I'll add that "Vaccines are Good" and that we should await expert opinion before making idle speculation.
What is this, some kind of cult in which nobody dare question?
By the time the correction is published for the doctored material, or the matter is contextualized, the fear will have already spread.
(This is one of the reasons they have very specific handling rules and throw out vaccine that is improperly handled)
> Welcome to Moderna. We believe mRNA is the “software of life." Every cell in the body uses mRNA to provide real-time instructions to make the proteins necessary to drive all aspects of biology, including in human health and disease.
What's the metaphorical software equivalent of "mRNA instability": undefined reference, memory corruption, incomplete download, installation failure, program crash, ...?
Mitochondria won't decode the corrupted mRNA and it will be broken down into constituent parts that are reused by the body.
Edit: Oops, ribosomes, not mitochondria.
(The actual estimate is 10 million billion...)
Edit following my other edit: each cell has something like 10 million ribosomes.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791314/
> Given the central role of RNA in many fundamental biological processes, including translation and splicing, changes to its chemical composition can have a detrimental impact on cellular fitness, with some evidence suggesting that RNA damage has roles in diseases such as neurodegenerative disorders. We are only just beginning to learn about how cells cope with RNA damage, with recent studies revealing the existence of quality-control processes that are capable of recognizing and degrading or repairing damaged RNA.
“This shitty app doesn’t work. Uninstall.”
That’s about it here.
It was faster to produce candidate vaccines. There are also some production benefits because it doesn't involve replicating a virus in eggs.
https://www.nytimes.com/interactive/2020/science/coronavirus...
Your mileage may vary but beware anonymous data.
However, it does concern me to a great deal about all of this, and it reflects my previous worries. My biggest concern is that from the article, these mRNA strands appear to have not only degraded but formed into new "species". What if the mRNA causes the body to produce prions that leads to something like Mad Cow Disease? The fact that Moderna isn't saying anything is very disconcerting.
suppose we grabbed a molecule and then cut it in half, do this many times so you have a collection of first halfs, and second halfs. Each of these is a species of ribonucleic acid. It may sound sinister but its just tech jargon.
i know what was written, however that makes sensationalist and alarmist connotations when the meaning of species is defined by popular conceptions
you are wrong, this submission is speaking about molecular species.
also the prion concern is not valid, prions are a specific protien sequence and do not arise out of mRNA sequences of determined function.
Would you not be more worried about all that lipid nanoparticle in your body?
"They" are so even more "tight lipped" about the nanoparticle wrappers that you do not even question it.
Your body is designed to encounter viral RNA.
How is your body designed to deal with a boatload of nano-sized lipids?
Of course the details of drug approval are not "discussed in the open" because a) trade secrets b) the public doesn't know how sausages are made and can (and do) make a mountain out of a molehill
mRNA instability is probably not such a big deal. Sure you want a high number because that's going to cause the immune reaction, if you have a lower number it's potentially less targets. But having imperfect mRNA strands are not a big deal.
The vaccine does not have to be 100% "perfect", it has to be safer than the virus. I know where to take my chances.
from an official US HHS report https://www.hhs.gov/sites/default/files/2020-annual-report.p...
" OGA coordinated with other U.S. government agencies to strengthen diplomatic ties and offer technical and humanitarian assistance to dissuade countries in the region from accepting aid from these ill intentioned states. Examples include using OGA’s Health Attaché office to persuade Brazil to reject the Russian COVID-19 vaccine,"
That is, the age groups most at-risk from the virus (ages 70+, with comorbidities) are also going to live the shortest, and so suffer from fewer side-effects as well as not reproducing.
So why aren't the rollouts focused on vaccinating the elderly first? By the time this is done the kinks will be ironed out.
> Group 1 – Border and MIQ workers and the people they live with
> Group 2 – Frontline workers and people living in high-risk settings
> Group 3 – People at higher risk of serious outcomes or illness
> Group 4 – General population
https://www.health.govt.nz/our-work/diseases-and-conditions/...