Understanding mRNA Covid-19 vaccines
cdc.gov
cdc.gov
as soon as the cell expresses S protien the immune system may then tag it and take a sample then produce a great many antibodies for the price of a small number of cells death relative to the large number of antibodies
In other words, is there a worry of MRNA causing auto-immune reaction/disease due to those proteins getting expressed by host's own healthy cells?
the mRNA of concern will not modify your DNA sequence, the expression of the S protien occurs untill the mRNA is destroyed by the cell, or the cell itself is destroyed taken apart and compared to self antigens, the foriegn antigen is expressed by MHC cells and PresenteD in a context of this is a hostile thing [a wanted poster]
this all occurs in a system of interdependent cell types and thier interactions.
your question addresses the crux of immunology, and needs a lot more attention than would be constructive here.
put on your reading cap and check this out:
keep in mind this is not proven but is a promising angle, CRSPR as made popular is a hijacked mechanism used to edit DNA sequences. normally this mechanism is used in prokaryotic organisms as an immune system. there are tags in the prokaryotes DNA that are used to match with foriegn DNA and signal it for destruction.
this type of arrangement MAY, possibly exist in eukaryotes as well and may be the basis of self/nonself recognition.
i have yet to talk to anyone else in professional context, this is inference on my part but it the best answer i can suggest for now.
you would want to look at antigen presentation and antibody production mechanisms, in deep detail .
Disclaimer: All I know about this comes from Cells at Work/Hataraku Saibou.
So if I understand you correctly, the self-recognition system is something built-in and doesn't change in response to foreign antigens? Or in other words, it's only the recognition of foreign molecules that will change, but this shouldn't affect the production (or culling) of T-cells that are super-sensitive to host's own self-antigens?
PS. And thank you and thanks to others for answering newbie questions on this thread! :)
I think the medical guidance has been pretty clear that you should not get the vaccine in this case. There are a lot of people who care more about their own safety than yours who may try to change your mind. Don't listen to them; don't get your medical advice on the internet. Find an expert.
the molecular level of the mechanism, beyond the cellular level is detail that needs to be elucidated.
> So if I understand you correctly, the self-recognition system is something built-in
Yes. before immune cells are released and "primed" they go through a selection process where the receptors they have for (unknown) antigens are tested against a vast array of proteins the body normally produces, if they bind, they are killed off. Sometimes this doesn't work and if they are activated and bind their (self-)antigen when the immune system is activated (i.e. during an infection) they can attack uninfected cells. Which as a one off event is not problematic, the problem comes from the fact that those immune cells stick around when they contact their antigen, and if it is produced by the body this is a lot, and continue to kill healthy cells and cause inflammation.
> and doesn't change in response to foreign antigens?
By the time the immune cells bind to foreign agents they have already gone through the selection process.
Necessarily a vaccine will produce an immune response (or otherwise it won't have the intended effect), this could cause an autoimmune response because the atuoresponsive cells, presumably, have their antigen around.
> but this shouldn't affect the production (or culling) of T-cells that are super-sensitive to host's own self-antigens?
new ones, no. In fact if you're not a child, you aren't producing many new (unique) T-cells at all. Old ones however may proliferate if their antigen is present and an immune response is triggered (to the vaccine or the virus).
If you want real advice, don't take it from some random on the internet with only a minor in biomed, talk to your doctor or immunologist.
Firstly they only express it as long as the mRNA remains intact. mRNA are degraded naturally so there is a finite time window as the mRNA is not reverse transcribed into DNA and reintegrated into the genome.
> what are the chances that it will also learn to react to other proteins expressed by those cells,
T (and B cells? I can't remember) cells undergo a selection process in the thymus that select against cells with receptors that bind to self proteins, that is proteins made normally by the body. Sometimes this fails and you get autoimmune disorders. Chances are very slim and no more than any other antiviral vaccine.
Why not? Just because it doesn't match up, or is there a deeper reason?
eukaryotes use splicing mechanisms that copy/delete/replicate DNA from one locus to another, this is more reliable as mRNA are unstable and become damaged quickly. cytoplasmic mRNA is not of fidelity and does not reverse compile into the dna sourcecode, or it would produce massive errors and corrupt the DNA.
Reverse transcription only happens when a reverse transcriptase (found in retro-viruses, e.g. HIV-1, HIV-2, Hepatitis B Virus etc) does that and the RNA is the direct viral genome or a transcript of the viral DNA (for DNA viruses). They have special marker sequences at either end to facilitate this (search for terminal repeats)
SARS-CoV-2 is not a retrovirus.
The CDC and other sources argue the vaccine is safe because it doesn't alter your DNA, but I have a vivid imagination and can think of a thousand other ways something might go wrong. Having my DNA altered was never one of my concerns.
what you would get is some false starts, and segment of protien if that at all.
https://en.wikipedia.org/wiki/MHC_class_I#Effect_of_viruses
I don't honestly understand how the immune system decides which protein fragments are okay to develop a response to, but the point is that that is already part of the normal immune response pathway that learns new antigens every day; after the protein fragment shows up on the cell surface, the rest of the process is similar to the response to an attenuated-virus vaccine or a natural infection.
keep in mind there is no proof yet that this is how it works but it is a promissing direction to look into.
I'm no expert either, but I don't see a difference here between virus infected cells and mRNA "infected" cells. So cells primed with mRNA simply produce less virus parts than those with the real virus?
the vaccine is not the whole mRNA, its only the part that codes for immunogenic protien [SARS-2 S] that is exported to the cell membrane
this is not a constituative expression and the cell expressing the foriegn protien is often destroyed later in the process but not always as the vaccine mRNA is edited out of the cytoplasm not replaced by genetic expression and the novel protien goes into turnover mode.
There are also other delivery pathways for mRNA vaccines.
The virus is not functional because the mRNA vaccine only contains one little component of the virus, the spike protein.
You can see a quick comparison chart of the most important vaccine methods in this Nature figure: https://media.springernature.com/lw685/springer-static/image...
...no? This is not gene therapy. The effects of receiving a mRNA vaccine will, apart from training the immune system (which was the whole point), be next to nothing.
Your body is continually being bombarded with random foreign DNA and RNA. That's just how life on Earth works. Yes, introducing a big pile of it at once is not normal... but it's a difference of degree, not something completely new.
If anything, problems are more likely to derive from the lipid bubbles used (at least by Moderna) to package and transport the mRNA.
Noob here, could you expand on that?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583697/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624045/
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edit: Here is more specific information on lipid nanoparticles in RNA vaccines, which explains that RNA vaccines that involve lipid nanoparticles tend to cause a local inflammatory effect, i.e. shoulder soreness.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963972/#sec3-v...
It is absolutely not anything like merging a patch into the master branch.
The safety profile in the 0-2 month timeframe is very easy to understand: they tested it, so they have actual data. But it seems for longer than 2 or 3 months you would need to make an argument based on animal trials or just biological reasoning. But I can't find anyone talking about it at all.
But I don't think they're unconcerned. I think it's a combination of lack of decades-long longitudinal studies, and also that previous phase I / II studies haven't throw up significant red flags.
Do you know why nobody did not conduct phase III before? Is it because of safety concerns or lack of necessity since concerned disease disappeared?
(mRNA would be a good candidate for a flu vaccines because they are fast to produce, which in theory reduces the amount of guessing needed to make the "right" flu vaccine for the year, but of course a) flu vaccines already are a thing even if sometimes wrong and b) a flu vaccine isn't given as high priority overall)
By 2 months all traces of vaccine are long gone and you're just left with an immune system trained to fight COVID (just like millions of people have already had happen naturally). So, while everybody has their eyes open, nobody can really explain the mechanism where something might happen.
Well there are some limited circumstances, but I don’t think they justify not going forward with the vaccine. For instance there is a possibility in some individuals that the mRNA itself (not just the spike protein) as well as the lipid encasing it to protect it and transport it into the cell can cause an immune response. It’s theoretically possible that in some individuals that could result in auto immune responses to other forms of messenger RNA in their cells. [1]
1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906799/
From the article
“A possible concern could be that some mRNA-based vaccine platforms induce potent type I interferon responses, which have been associated not only with inflammation but also potentially with autoimmunity”
Given the many billions of vaccines given of various types, it is about as close to certain as we get in this world to not expecting long term side effects ever.
The reason they aren't concerned about it is for good reason, not because they "haven't looked into it". You have to look at relative risk.
This decision to lift the total ban on this vaccine was probably the easiest decision the FDA ever had to make. This one isn't even a question.
Now they just have to lift the ban on the rest. The standard for EUA is supposed to be "net expected benefit", which they are not following. They are currently only approving EUA when they hit "no conceivable downside", which is a too high standard.
That is not true: https://www.cdc.gov/vaccines/vpd-vac/rotavirus/vac-rotashiel...
It was approved August 1998 and removed from market October 1999 - more than a year later.
Edit: Oh, I see what you are saying - the intussusception happened within 2 weeks of receiving the vaccine.
But that's not really comforting, if it took more than a year to understand that it was linked to the vaccination.
They say: >COVID-19 mRNA vaccines give instructions for our cells to make a harmless piece of what is called the “spike protein.” The spike protein is found on the surface of the virus that causes COVID-19.
So from what I understand the vaccine itself does not contain the spike protein but is simply RNA that is injected into the cell and then the cell goes through its usual process to translates* the RNA to amino acids which then gets churned into protein (the spike protein)?
My first question is how did they make the RNA? Is it the exact same RNA as in the coronavirus or is it artificially generated by them? Does it do the exact same thing that the RNA in coronavirus does and is the spike protein the exact same spike protein found on the surface of the coronavirus or is it different (even if subtly so?)
Can anything go wrong at any point in this process (can the body misuse the RNA, or the spike protein, or anything else) and if so what?
*edited
I am not qualified to answer whether the spike protein is identical to the one in the virus, but from what I understand it is very close. The protein just doesn't have the virus attached. It's like having a factory manufacturing car door handles but no cars.
Things could go wrong, mostly because some folks may have allergic reactions, autoimmune flare ups, or the increased immune response can cause side effects like Bell's palsy. That said, mRNA breaks down quickly on its own, and the spike proteins will be cleaned up quickly. The odds of a serious complication are very, very, very, very low from the studies performed so far. (Expect some flu like symptoms, however, as your body fights the cells with the modified RNA.)
I'm a total layperson here, just synthesizing what I've read.
This mechanism was once explored as a means of performing gene therapy in human beings (a couple of decades past). It was abandoned because of its utter failure to produce lasting genetic effects.
That's a big plus here: we have a well-explored platform for having the cells transiently produce a protein we want the immune system exposed to, but which we already know is useless at producing lasting effects. The only lasting effect here will be in the memory of the immune system, not in the cells affected by the shot.
if not enough is known about the spike protien it is possible, but not greatly probable that an undesireable biochemical process can be initiated but not likely.
if you know how the protien acts biochemically it may also be possible to guarantee a synthetic that is an antigen , but does not induce adverse pathology
Obviously this will be the first wide spread use of a vaccine using a mechanism viruses have used for millions of years. So although care, caution, and respect are clearly justified, I’d just like to see a little more public education on how viruses work in the first place.
It’s easy for the public to hear “the government is programming your cells” and not even understand the basics of how cells or viruses work in the first place.
Here's a 5 minute video explaining mRNA vaccines in laymen's terms (Cliff-Notes style)
https://www.youtube.com/watch?v=the81FQoAUI
Here's a longer, more technical, 43 minute video explaining them and the Moderna/Pfizer/BioNTech/Astrazeneca clinical trial processes in more detail. The biochem part starts at 12:30.
the limitation is an understanding of the virus+host interaction at the level of molecular structure and function.
when you have the amino acid sequence of a protien that triggers the immune system you can work backward and derive an mRNA that would be responsible for coding the protien.
there are multiple layers of complexity in getting from stage 1 to end product but this is a quick simple layout.
DNA virus has some extra tricks compared to RNA virus but the core concept is the same for both.
"Immune compromise" is generally used as a blanket term, but in many people there are specific immune deficiencies, which may or may not factor into the pathway being targeted here. For instance, natalizumab screws with immune cells' translocation across membranes, and shouldn't play a role in responding to a vaccine (I mean, if it wasn't off the market anyway).
If it's a general immune dysfunction (cancer, diabetes), they will see some benefit, but it will be much reduced - specifically because both responding to the vaccine, and responding to the virus post-vaccination, require the activity of the immune system. What this means precisely will vary with the degree and nature of the immune dysfunction: some folks might see some antibody response, and benefit from repeat dosing. Others might fail to seroconvert altogether, in which case it is what it is.
I was thinking that maybe because Covid is an RNA virus, there would be a shortcut to getting the mRNA sequence for creating the spike protein. The scientists could peek at the RNA in the actual virus, recognize the spike protein, and put that in the vaccine. Whereas with a DNA virus, it would require extra work.
But from your answer, it sounds like that's not what they do? Or, maybe they could do that but it's not any easier than working backwards from the amino acid sequence.
This stuff is all very interesting!
a DNA virus must be understood somewhat to find the reading frame for the protien you need, this is the case for RNA virus as well however RNA virus are limited in size due to the instability of RNA, this means less kruft to wade through until you find the FOO
Are they using mRNA because it's easier to manufacture? Or is the protein too instable?
the liposomal capsule holding the mRNA has been engineered to deliver the mRNA to the cell and fuse with it delivering the mRNA
confoundingly the mRNA is fragile thus the ultracold dryice freezer required for holding.
the protien is stable on its own, but will be destroyed by exocytic proteases unless shielded by insertion into a membrane
This approach is like sneaking in blueprints to a factory (cell) that makes (proteins using mRNA) whatever it has blueprints for, and gets inspectors that come around occasionally (immune surveillance), or very frequently under active infection, looking for contraband.
When the body start producing this foreign proteins in the presence of something to trigger the immune system (called an adjuvant which all vaccines use to make the body recognise as bad and not harmless/irrelevant) the immune system starts producing a response against that.
> adjuvent [sic] is not neccesary[sic] for immune response,
Completely false. Unless the immune system has been exposed to something similar before (e.g. SARS/MERS n.b. made up example I have no idea if the spikes of SARS or MERS are molecularly similar enough), no adjuvant means situation normal for the immune system. If there is nothing to signal to the immune system that this new antigen is bad then it will treat it as neutral suppressing any vaccine response, which is worse that if the vaccine had not been delivered at all.
>is nessecary[sic] for spreading out the antigen producing character among more doses
the point of booster shots is to ensure that antibodies are maintained at sufficient levels to fight off a real infection. If a response has been established, i guess adjuvants are not as necessary? (did biomed, but not a vaccine researcher) I have no idea if they are included or not for boosters.
> rather than using a concentration of mRNA that in itself produces enough protien[sic] to induce immune response
A high concentration won't do shit if the immune system doesn't have anything to activate it, it will just see a high concentration of irrelevant new, i.e. foreign protein.
This is Completely false.
Natural immunity does not require adjuvent.
spreading out a scarce valuable resource by use of adjuvent is a standard practice.
ANY complex not recognized by the MHC will elicit an invader response, the immediate vigor of this response is attenuated by inclusion of adjuvent in the final formulation of the vaccine. we would all die 100% of the time if adjuvent was required to mount immune response, to infection.
> we would all die 100% of the time if adjuvent was required to mount immune response, to infection.
Indeed, but it is required for a vaccine to function properly.
without adjuvent many vaccines would need much greater concentration of the antigen producing component.
by inducing an attenuated response, using an adjuvent, you can manufacture many more doses of the vaccine using less mRNA in each dose.
the substances you are mentioning are features of live pathogens and are being mimicked by adjuvents.
It is true that if you have a strong adjuvant, you could get away with smaller doses of the antigen, which is good for pandemic vaccines.
Source: Charles Janeway, "Approaching the asymptote? Evolution and revolution in immunology," http://symposium.cshlp.org/content/54/1.long
P.S. I wrote a COVID adjuvant grant this past spring, and my mother studies immunological tolerance. So if you disagree can you at least share some sources?
you are wrong, and its right in front of you.
please tell me about KNO3
please tell me about priming and boosting.
please tell me about innate humoral response, and cell mediated response.
i see you are still a student.
once again vaccines are not obligated to adjuvents
adjuvents increase the response to a signal allowing a weaker signal to evoke a response of threshold level.
the economic and practical bounds incurred by the expense of the immunogenic product are offset by thus exploiting, the biological property of amplification we can spread out the materials to make many more doses of vaccine requireing fewer "boost" dosages.
the big angle to work is the lack of cytoplasmic Vir-mRNA of immunogenic character. the current S protien production system is a get it shipping now product, with more work we can produce a sequence that stimulates cytoplasmic processes also involved in the induction of primary immune response.
the current sequence doesnt do that.
have a look here and see where this is heading :
https://pubmed.ncbi.nlm.nih.gov/27252702/
Interferon production at scale is tedious to say the least, it is superior to induce in vivo interferon dynamics, along with immunogenic antigen translation.
Whereas the virus encodes the whole spike, the capsid protein and whatever else the virus needs to replicate like promoter sequences and an origin of replication. It is much larger and is replicate.
Basically it skips all the viral machinery and just codes for a small piece that identifies the virus to the immune system.
It's one thing to use a viral vector to reprogram some number of cells. Due to the Emergency Use Authorization, much of the safety testing has been skipped.
you can see timelines here: https://www.bbc.com/news/health-55056016
tldr: nothing skipped; however it was compressed.
Seems safe enough. Hopefully not famous last words...
And much of the safety testing hasn’t been skipped. The vaccine went through full phase 2/3 trials. The post trial surveillance phase was shortened, but it’s still ongoing.
No, it wouldn't. The goal posts would immediately move.
> BNT162b2 is a nucleoside modified mRNA (modRNA) vaccine encoding an optimized full-length version of the SARS-CoV-2 spike (S) protein...
which appears to be entirely public (along with the rest of the SARS-CoV-2 genome):
The vaccine contains the mRNA sequence for the protein, so cells produce it, triggering an immune response.
The "nucleotide modified" bit just means they replace some nucleotides with nucleotide isomers like pseudouridine (https://en.wikipedia.org/wiki/Pseudouridine) to keep the vaccine itself from being attacked. The sequence remains the same.