SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE2
ahajournals.org
ahajournals.org
And, as to the first question that came to my mind, from the paper: "Collectively, our results suggest that the S protein-exerted EC damage overrides the decreased virus infectivity. This conclusion suggests that vaccination-generated antibody and/or exogenous antibody against S protein not only protects the host from SARS-CoV-2 infectivity but also inhibits S protein-imposed endothelial injury and ultimately decrease cardiovascular complication-associated mortality in COVID-19 patients."
It’s horrifically painful. There is no sympathy from anyone since you look normal.
https://www.amazon.com/Herbal-Antivirals-Remedies-Resistant-...
Here is the direct quote from the book, published in 2013:
"Once receptors on these cells are compromised there is enhanced vascular permeability, increased lung edema, neutrophil accumulation, and worsened lung function. In essence, once the virus begins attaching to ACE-2, ACE-2 function begins to be destroyed. ACE-2 function also tends to be less dynamic as people grow older, hence the more negative the effects of SARS infection on the elderly. [...] ACE (in contrast with ACE-2) inhibitors increase the presence of ACE-2 and help protect the lungs from injury."
The author does not look like a medical professional either.
https://www.tctmd.com/news/continue-ace-inhibitorsarbs-covid...
Oh, okay, yeah, here https://www.wired.com/2013/05/h5n1-h1n1-reassortment/
The point is how should we change our recommendations? Are older people or others with certain medical conditions more susceptible to damage?
I don't see how shrugging off this new information is reasonable or scientific.
https://www.sciencedirect.com/science/article/pii/S240545772...
Vitamin D levels had a significant difference between the case and control groups (p = 0.008). Serum calcium and serum zinc levels also had statistically significant differences between the two groups (p < 0.001).
Didn’t it take us thousands of years to realize lead was poisonous?
does 'forever' modify 'produced' or 'should be safe'? if the former, what produces a small amount of the spike protein forever (continuing, not just a small amount one time)?
Downregulation of ACE-2 causes damage, not the spike protein. The spike protein itself causes downregulation, but not enough to cause damage.
The wild virus causes this protein to be produced without check.
It wouldn't just be the mRNA vaccines, anyway. The viral vector ones, as well as the inactivated virus, and the spike protein unit extract ones, all involve getting some of the spike protein either made in the cells, or introduce it directly.
The vaccine has to be orders of magnitude safer than the virus, because (essentially) everyone will get the vaccine, but only some will get the disease. E.g. it might be harmful to vaccinate people in New Zealand and Australia at this point, because for now they cannot get the virus.
What these papers (there are 3 independent ones showing very similar results, all coming out in the last month) show is that the vaccine outcome (specific proteins) that were assumed to be inert and only prime the immune system against the virus, are actually active and damaging. That's a big difference -- and the question of whether it makes sense to vaccinate needs to rely on actual science, not "it's a vaccine so must be good and safe" ideology. It also depends on specific attributes (e.g. age, obesity, etc.)
There's an Israeli study showing myocarditis at a rate of 1:20,000 for the 16-30 age bracket, with 1:100,000 overall (all pfizer)[0] ; the US Army stats are 1:250,000 (for a mix of JNJ,Pfizer.Moderna) but I didn't find age distribution - and these are exceptionally lean and fit individuals, compared to the general population.[1]
That's just myocarditis ; it it related to what's described in this paper? I don't know. Are there any other issues? I don't know. And generally speaking, no one else does either. But because everyone gets vaccinated, we require exceptional proofs of safety. Or at least, did before 2020.
[0] https://www.timesofisrael.com/israel-said-probing-link-betwe...
[1] https://www.military.com/daily-news/2021/04/26/pentagon-trac...
New influenza vaccines (using cell lines) were approved after use in 15,000 people, ~10 years ago: https://www.fiercepharma.com/vaccines/novartis-receives-fda-...
Are you overestimating the safety testing done on other vaccines?
Of course these are the first widely used vaccines for corona viruses and use new technologies to boot, so there's a lot more to it, but I wonder how you've gone about assessing previous safety proofs.
Genetic/DNA vaccines are new.
> A multinational, randomized, observer-blinded, placebo-controlled trial was performed to assess clinical efficacy and safety of Flucelvax during the 2007- 2008 influenza season in adults aged 18 to 49 years in the US, Finland and Poland3.
They took ~4 years to approve it, sounds like they were more cautious for Flucelvax.
The are several important differences: (1) it took 4 years of data, not 6 months of data like Pfizer, (2) using mature, well known technology.
Now, let's compare to a flu vaccine approved with an EUA after 6 months, shall we?
https://www.bmj.com/content/362/bmj.k3948
https://www.sciencemag.org/news/2015/07/why-pandemic-flu-sho...
(Both articles describe the same vaccine, pandemrix)
It caused narcolepsy, a few hundred cases of it. That's a debilitating, life changing disease; by all estimates I know, much worse than the flu it was supposed to prevent. It's not the only case (though there aren't maney - 1976 flu vaccine causing guillan-barre, dengvax worsening dengue, israeli anthrax vaccine causing harm, probably a couple more I'm unaware of; the vast majority of vaccines -- all that I'm aware of that got full approval rather than an EUA - have a 1:1,000,000 or better adverse event profile).
And it isn't even perfectly clear why. The science article says it's likely because there's a similarity between some viral protein and some brain protein -- but that's not clear that's the reason. According to the BMJ article, basically the same vaccine but with a different adjuvant caused none of the issues.
How long did it take to figure this out? Approximately one year of data.
I urge you to read the BMJ article - it eerily describes exactly what's happening now, 11 years ago - some of the names (e.g. Fauci) haven't changed; some have.
> Are you overestimating the safety testing done on other vaccines?
I don't think I am. That's why we have VAERS and a European equivalent. You might notice that a lot of the touted efficiency and safety data is coming from Israel. Well, Israel has no VAERS equivalent, hardly tracks any adverse events for this vaccine (likely on purpose), and decreed that vaccinated people are not to be PCR tested unless they show obvious COVID symptoms, whereas unvaccinated are required to have negative test from the last 48 hours for many activities -- which means the data will show it's working even if it doesn't. Israeli data is rubbish, other data is hardly available. (I currently live in Israel and track this; It's been politicised in Israel to the point that no data coming out of Israel is trustworthy)
So, regardless of safety of other vaccines, we have very little reliable data about the new guys.
> but I wonder how you've gone about assessing previous safety proofs.
By waiting enough time to get data accumulated.
You know why we ddin't have any corona virus vaccine before 2020? It's not for lack of trying. They all failed at various stages, all of which were skipped for the SARS-Cov-2 vaccines.
You can't run a trial if there aren't any people getting infected.
By waiting enough time to get data accumulated.
This isn't a mechanistic explanation of how you've arrived at a stronger level of comfort with earlier safety trials, unless your evaluation criteria is literally just that they took longer.
Corona viruses have been with us for a few thousand (millions?) of years. It is estimated 25% or so of colds are caused by corona viruses. And not surprisingly, they can also cause really, really bad outcomes in the sick and elderly -- in fact, there is some speculation that before they became endemic, they were as virulent as sars-cov-2.
And there definitely have been attempts; not as focused, of course, but nevertheless over many years. The most focused attempts were at SARS-Cov-1 and MERS - and both burned out quickly - but also all failed spectacularly at the animal testing stage.
> This isn't a mechanistic explanation of how you've arrived at a stronger level of comfort with earlier safety trials, unless your evaluation criteria is literally just that they took longer.
(a) animal testing (skipped entirely in this case, which would have shown perhaps that targeting the spike protein may be an issue, and
(b) yes, more time. some signals take time to surface - do read the pandermix papers I linked to. Whatever is happening now is just too close for comfort, and I sincerely hope it will end better.
What more can you ask for, when I show you a horrible experiment from 2009, which matches in almost every possible way except we're now using now technology? With articles from science and the BMJ? Is there anything that can satisfy your request for reasonable doubt?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449230/
I was just asking to understand your reasoning, I wasn't asking you to convince me it was correct, and I'm not trying to convince you it isn't correct.
I don't have it handy now, but for at least one SARS-Cov-1 vaccine candidate everything seemed fine, and good immediate antibody response (as in this paper), but another challenge 3 months later had an ADE response with worse outcomes than a naive infection. IIRC it was done in felines, not in primates.
While in this animal trial they only waited 4 weeks after the second vaccination and challenged, the challenge you mention that was done only 3 months later, this is a small example of a mini long term follow up. They havent done that at all.. They skipped it, just to do the follow up in.. humans, so yes humans are still being trialed with the vaccines. When the next wave comes in the winter, more than 3 months from today, 7 months ahead, in October, it will be a catastrophe caused by ADE.
However, their metric was IIRC "within 3 days of first or second dose"; so 6 days worth of myocarditis compared to your full year number, so a factor of 60 (assuming uniform distribution over the year) to put on same scale.
You're under the impression that either the vaccine must be perfectly safe and/or that the disease is perfectly safe for young people. Both of which are false.
It doesn't have to be perfectly safe; but it has to be significantly safer if you get it, than the disease if you get it -- which is, in fact, the case for all regularly administered vaccines (MMR, polio, tetanus, etc.), and comes with a warning and explanation for those that aren't (our pediatrician made sure we understand the rotavirus vaccine before we gave it to our child (we did) especially because it's safety profile, while still good, is not as good as the MMR and polio ones.
MIS-C is a big discussion that I don't have enough time for, but according to https://www.cidrap.umn.edu/news-perspective/2021/04/new-find..., incidence in the US is 1:50,000. Acute myocarditis often goes away with no damage but not always. MIS-C does too.
And it's not even clear yet if any vaccine will stop MIS-C, so -- no, it's not an entirely acceptable risk.
https://www.cdc.gov/mmwr/volumes/69/wr/mm6932e3.htm?s_cid=mm...
1-in-3 hospitalizations require admittance to the ICU.
The study you cite is total incidence.
But something doesn't compute;
1:12,500 COVID incidence vs. 1:50,000 total incidence means 1 in 4 kids in the US has confirmed covid, despite less than 10% of the US population being verified (32.4M as of this second).
If we extrapolate the 1:12,500 number to the whole population (assuming 10% of the kids are confirmed), it's 1:125,000 for MIS-C in disease, vs. 1:20,000 myocarditis with vaccine. I'm not sure it's valid extrapolation (and I suspect your data, from July, is very outdated), either way -- it is not possible, based on this data, to claim that it is clearly beneficial to vaccinate children.
The data I'm familiar with DOES show that at age > 50 there are clear benefits. But, especially with respect to things like age, obesity and other attributes, it is very far from "one size fits all".
Current total incidence is the wrong metric to use since tht will increase over time. Not using vaccines would mean 3x or so more infections before some level of herd immunity was reached.
It would also give the virus another 3x the number of die rolls towards mutating as well, with pressure to increase transmissibility which should come with an increase in virulence.
And my 1-in-12,500 numbers were before the virus started to mutate to increase transmissibility/virulence. Those numbers will probably drop.
Regardless, if I take your numbers, assuming 33% had the virus, we’re talking about very similar toys incidence at saturation (the 1:20,000 - 1:10,000 range, the error bars are huge), so it is far from obvious that the existing vaccines are safer than the disease.
It is true for all approved vaccines I’m familiar with; but you can’t claim that for any of the Sarscov2 vaccines based on available data.
What I’m really surprised is that somehow the default mindset changed from “we have to establish safety to use” to “we have to establish non-safety to not use”. Am really puzzled by that.
After one year of Covid (and its mutations) that baseline simply doesn't exist (any more). Instead we are in a no-win situation:
(a) We keep lockdowns/non-pharmacological measures and border closures,
(b) We let Covid spread slowly,
(c) We vaccinate.
Each scenario has associated cost. Now back to your point:
> But because everyone gets vaccinated, we require exceptional proofs of safety.
Safety is neither binary (exceptional/not exceptional) nor absolute and always relative to Covid. Each and every vaccine up to now is orders of magnitude safer than Covid for the vast majority of people (YMMV!).
Not an expert, but what's even more interesting is that among the already very few severe side effects, even fewer are due to the 'vaccine ingredients' (e.g. allergic reactions incl. blood clots) and many are conjectured to be due to the 'SARS-Cov-2 ingredients' (e.g. myocarditis). Heuristically speaking you can choose between Covid or a very very very mild version of Covid.
> Each scenario has associated cost.
There are other scenarios, e.g. https://www.ox.ac.uk/news/2021-02-09-common-asthma-treatment... shows a cheap widely available steroid inhaler has comparable efficiency to vaccines in the KPIs studied by the Pfizer trial. I'm not saying it should be used instead of a vaccine; but it's also not true that your list is close to exhaustive. We keep finding out new stuff. In the first 2-3 months, the intubation+ventilation regime was counterproductive; it took a while to realize, but now we know that. We also know (e.g. from Florida and Texas) that the NPI are much less effective than they were assumed to be.
> Each and every vaccine up to now is orders of magnitude safer than Covid for the vast majority of people (YMMV!).
That's ... not been shown. The Israeli study I linked to above (a report of it) says this assertion might be wrong for Pfizer for the sizable group of 16-30 ; The British think that's not true for AZ under age 30 ; many countries in the EU think that's not true for AZ under the age of 50 ; Norway thinks that's not true for frail elderly.
And basically, we only have short term safety data (pfizer: less than a year for 20K people, less than 6 months for the rest), so even if it is true that "every one will eventually get it", it does NOT follow that it makes sense to vaccinate everyone right now -- if it takes 20 years until "everyone eventually gets it", and severe side effects appear 2 years later, then, no, it doesn't make sense.
I linked a BMJ+Science article that showed for a similarly EUAd vaccine, "Pandemrix" in 2009 that it took over a year to figure out that it was causing narcolepsy and worse than the flu it was supposed to stop. It's not just a theoretic possibility - it happened in a very similar setting just 11 years ago, and the causes are NOT perfectly understood to the point that you can guarantee it won't happen again.
> many are conjectured to be due to the 'SARS-Cov-2 ingredients' (e.g. myocarditis). Heuristically speaking you can choose between Covid or a very very very mild version of Covid.
You could be right, but that's not at all clear. This paper from Nature Immunology https://www.nature.com/articles/s41590-020-00808-x.pdf shows that 80% of unexposed people have a T-cell response to SARS-Cov-2 - that is, they have cross-immunity.
It could be that for those 80%, that response would be enough to stop the virus before it can get systemic traction, whereas the vaccine is essentially guaranteed to generate systemic effect. I asked an immunologist, who said he doesn't know the answer and does not believe anyone does without measuring.
That is a good point, I should have defined the category more broadly as 'pharmacological interventions,' of which vaccines make up the biggest and best-studied subcategory (to date).
> That's ... not been shown. The Israeli study I linked to above (a report of it) says this assertion might be wrong for Pfizer for the sizable group of 16-30 ; The British think that's not true for AZ under age 30 ; many countries in the EU think that's not true for AZ under the age of 50 ; Norway thinks that's not true for frail elderly.
Yes and no. Yes, E.g. for AZ there will be a threshold (say 30) at where Covid risk equals vaccine risk. At that point, both risks are very small, to the point that it's more dangerous to drive to the appointment by car. No, when EMA says no AZ under 50 (in Germany it's 60) that's because for that age group we have other vaccines available. Still, even for a 40 year old female it is safer to get AZ than Covid. For that reason current vaccines are safer for most people but not all. Even when they are not safer than Covid, data suggests they are still very safe.
> And basically, we only have short term safety data (pfizer: less than a year for 20K people, less than 6 months for the rest) [...]
I believe you do know that Pfizer/Biontech, Moderna, AZ all started in 04/2020, so we have data for 12m+. As a comparison safety data for Covid is only 6m older.
> I linked a BMJ+Science article that showed for a similarly EUAd vaccine, "Pandemrix" in 2009 that it took over a year to figure out that it was causing narcolepsy and worse than the flu it was supposed to stop.
Yes, Pandemrix is still remembered, especially in Northern Euope, and one reason why regulators are have been super careful, to the point where it didn't make sense to halt vaccination campaigns, see e.g. AZ blood clots. In general we expect side effects of vaccines to have an onset shortly after vaccination, and that has been also true for Pandemrix. However to detect two rare events, say narcolepsy and 5x narcolepsy, you need a lot of data. In the context of H1N1 and narcolepsy, this paper is super interesting [1] https://med.stanford.edu/content/dam/sm/narcolepsy/documents...
> It could be that for those 80%, that response would be enough to stop the virus before it can get systemic traction, [...]
That's not the conclusion of the paper and hopeful speculation. If you mean by 'systemic reaction' the replication of the virus in the host, it's demonstrably false.
I totally get the concern about 'unknown unknowns' but looking at the safety data you are currently engaging in lifestyle choices or are taking medication that are way riskier than current Covid vaccines.
We have data for 12m, but only for a very small population (22k in Pfizer, less in others IIRC). You are unlikely to see a 1:20,000 general population risk (as indicated by the Israeli study) in a 22k "volunteer, must be quite healthy" experiment. Unsurprisingly, there are no deaths in the pfizer trial - neither vaccine nor placebo arm (and no severe disease past day 73 in the placebo arm) That's the 12m data we have.
No, we have 6m real world data for the vaccine, and 18m real world data for the virus. That's .. quite a difference.
> However to detect two rare events, say narcolepsy and 5x narcolepsy, you need a lot of data.
Indeed, which is why I am puzzled -- given that you are very much aware of the details -- that you can keep claiming that "the vaccine is less dangerous than the virus". You have proof from just 11 years ago where it took over a year of real world use to figure otherwise. What makes you think this time is different?
> That's not the conclusion of the paper and hopeful speculation
True. Also, the long term safety of covid vaccines is not a conclusion of any research and is hopeful speculation. And yet, people get no challenge for assuming that, despite counterexamples like Pandemrix.
> you are currently engaging in lifestyle choices or are taking medication that are way riskier than current Covid vaccines.
While that's true, that's also true for my subjective risk from COVID19 (and that's also true for the vast majority of 20-40 year olds). Would you consider that a good reason to ignore covid completely, and not take any precautions? If so, then - why do you care about the vaccine?
If it isn't a good reason -- and I don't think it's a good reason to ignore covid -- then ... why is the same argument not applicable to the covid vaccines safety?
Given that there are vast differences in outcomes in different age groups to the virus, surely that depends on the age group you are targeting. Pushing the vaccine onto children, who are at practically no risk seems morally wrong to me.
Unless the effect observed is due to the antigen the vaccine produces then you wouldn’t expect to see the same behavior in vaccinated humans as they saw experimentally with a full virus, even if some part or the full assembly of the spike is a cause for cellular damage.
https://en.wikipedia.org/wiki/Pfizer%E2%80%93BioNTech_COVID-...
From that link "...two proline substitutions (K986P and V987P, designated "2P") that cause the spike to adopt a prefusion-stabilized conformation reducing the membrane fusion ability, increasing expression and stimulating neutralizing antibodies..."
It's a modified version of the spike protein designed as an antibody target, not to identically replicate the spike protein function.
The load from an mRNA vaccine is miniscule compared to severe, or moderate covid.
A little bit of spike trains your body to identify it and neutralize it.
A whole lot of spike is toxic to your organs and damages them.
To downregulate ACE2 you need a whole lot of receptor activation and a lot of ligands floating around in your system binding to it to cause that. The dose of spike protein matters.
the vaccine causes a small volume of stationary cells in the muscle mass of the shoulder to express the S protien on the surface, staying in place but providing signal to the immune system
[adndm] keep in mind the virus replicates, inside you, the vaccine doesnt, and the vaccine stays where you put it, it doesnt spread out everywhere that has a receptor
something to keep in mind is the fuzz of biological systems. molecular processes can have more than one outcome but there is a general bias toward an overall stability, so when a vaccine is produced, there is a certain amount of fuzz to it in the form of particles that dont assemble correctly or ar otherwise non desireable, processing the vaccine keeps these characters to a minimum.
the same thing happens to the virus, the fuzz portion being in someway unable to replicate or enter a cell, just out of the way the fuzzy dice roll.
so its hard to pin down a number of minimally effective dose for either case, however virus amplifies past the original dose, and spreads to mutiple locations, signaling any molecular system that can be bound to, in this case vast preference being given to ACE-2, resulting in perturbation of the RAS system and the now stereotypic covid symptoms
so viral particles amplify over time, and over a spatial distribution, vaccine particles stay in site and dont replicate and dont migrate to interact with other cells in the tissue or throughout the body.
That being said, other people on this thread have provided reasonable mechanistic explanations as to why the vaccines would not have this effect, but I will also add we have _empirical_ evidence that the vaccine does not impair endothelial function (or at least it is extremely rare) because we have millions of people who have received the vaccine without impaired endothelial function.
Have an autoimmune, and I get most of the rare side effects of medications.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793296/
The data presented in our work, although very heterogeneous in the manner of collecting and investigating samples, have proved to be extremely consistent in witnessing a deficiency of zinc in serum and plasma of patients compared to controls.
So the study indicates that the Spike Protein binds to ACE2 that is found in the membranes of cells located in the lungs, arteries, heart, kidney, and intestines, and down regulates them to the point where it damages your mitochondria in those organs. So according to the research they did, it's not just the virus that can hurt you but the mechanism (Spike Protein) the virus uses to attach to your cells and replicate that can cause this damage.
It is likely that the vaccine itself which holds the mRNA and not the actual Spike Protein or Virus (just the instructions on how to make the Spike Protein) is administered in a intramuscular area of the body (Shoulder Area), never able to live long enough (mRNA dies off quickly) to enter these areas where ACE2 is found (Heart, Lungs, Kidneys, etc). The muscle tissue/cells in the upper arm create some Spike Protein and your immune system basically say WTF is that and kills it long before it can ever reach these organs or areas of the body.
The real Virus typically enters the body through the nose and mouth and heads directly into the sinuses and can spread very quickly to lungs and then move on from there into other organs. If you're someone who is one of the folks (Metabolic Disease, severe autoimmune dysfunction) who might be susceptible to what this study suggests, the vaccine is the way to go since it might give you a better chance to avoid the negative outcome from the Spike Protein affecting ACE2 and then damaging the mitochondria in your Organs cells.
We know to where it typically tends to go now, "the muscle tissue at the site of injection, the lymphatic tissue downstream in your armpit on that side, your spleen, and (for the first day or two) your liver. " [0]
[0]https://blogs.sciencemag.org/pipeline/archives/2021/01/21/mr...
https://twitter.com/manorlaboratory/status/13887170085444198... https://twitter.com/manorlaboratory/status/13887291512893153...
i’m going to give a full response asap. but quickly for the record:
1) the (relatively) small amount of spike protein produced by the mRNA vaccine would not be nearly enough to do any damage
2) i happily got the mRNA vaccine, FWIW
3) i encourage everyone to get it
a couple prelim responses to anti-vaxxers misrepresenting these findings (here: https://twitter.com/manorlaboratory/status/1388717008544419843?s=21). tl;dr: mRNA vaccine is waaaaay safer than COVID19 and everyone should get it - I did and everyone in my family did as well! Our paper just shows this disease really sucks.The rate of zinc deficiency in India is near 50%!
https://covid19criticalcare.com/covid-19-protocols/i-mask-pl...
Plus, they’re giving zinc to people already sick. Why not check people for zinc deficiency and supply them with the zinc they need? I know why, it’s because we don’t believe in preventative care in this country.