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Comment by isoprophlex | Hacker News Reader

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.

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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.

Edit: I'm wrong here.

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.

Yeah, you are right. It's that the vaccine spikes don't stick the way they are intended to, so they are moving around the body like the virus.

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.

You're right, thanks

Can I have an ELI5 of the TLDR?

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.

which is an interesting example of where a "proven technology" can be less safe than the "new technology"

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.

Thanks. In that case, why doesn't the virus itself cause thrombatic side effects?

Thank you for summarizing this for us, I was hoping to get a good summary of the article!

You're welcome! This is very exciting research, it amazes me how quickly we're able to test hypotheses when we put our mind to it.

Note that this is a preprint awaiting actual publication in a journal... but surely itll pass review.

This is why you don't skip the animal trials.

Why do you say that?

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.

If I've found the right ones, they're not due for Phase 3 completion until 2023:

https://clinicaltrials.gov/ct2/show/NCT04516746

https://clinicaltrials.gov/ct2/show/NCT04505722

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.

Nothing to do with animal testing.

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.

https://www.fda.gov/news-events/press-announcements/coronavi...

https://www.fda.gov/vaccines-blood-biologics/vaccines/emerge...

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.

Link?

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.

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