Long Term Side Effects of mRNA Vaccines Unlikely, Part 3

Now we are moving on to consider possible long-term side effects from the genetic payload itself, the mRNA inside the lipid nanoparticle.

Purity of the genetic payload

The first question to ask about the safety of the genetic payload is, how sure can we be sure that the payload is what is intended and not defective or mixed with dangerous impurities?  Some concerns people have had in the past about vaccines include mercury impurities or worries about protein remnants from chicken eggs in which some vaccines are grown.  So it's worth looking at the manufacturing process for mRNA.  (A lot of the information from this section I got from these two videos: here, and here.  They are long watches but pretty informative.)

The manufacturing process

All living beings create messenger RNA from DNA as part of the regular life of the cell.  In the nucleus of the cell, you have DNA, free floating genetic "building block" material (the four basic molecules from which all RNA is built, the "nucleotides"), and an enzyme (called "RNA polymerase") that reads (transcribes) the DNA and builds mRNA from the nucleotides based on what it reads.

The manufacturing process mimics that setup.  First, you create a custom strand of DNA (your "template") that contains the genetic instructions for the protein you want.  Then you put that in a tub along with a soup of nucleotides and add a bunch of those enzymes (RNA polymerase) and some salts.  The enzymes will do their thing, read your DNA and convert all the nucleotides around them into the RNA you want.

The product of this is a tub full of some template DNA, some enzymes, some leftover nucleotides, and a bunch of RNA, some of it complete and some of it failed or partial.  The major challenge is then to strain and/or chemically separate the complete RNA from all the other stuff in the tub.  You then quality-control the result to ensure you have achieved sufficient purity of the final product.  Most of the manufacturing progress in this area has to do with clever ways of getting higher yields from the straining / purification part of the process.

Commoditization

A very important character of this process is that it relies entirely on commercial, off-the-shelf equipment and ingredients.  Creating small custom pieces of DNA is routinely done nowadays via various processes and any big genetics lab can do it.  You can buy both nucleotides and RNA polymerase online if you want to: here's a site where you can buy nucleotides and  here's a site where you can buy RNA polymerase.  Equipment for doing RNA transcription, including the filtering, are commercially available.  Hardware and software for doing the purity checks are industry standard.

This has very important safety implications, because it means that the manufacturing process for mRNA is not new, even though the specific mRNA for the vaccines is new.  Ways to guarantee sufficient purities of the end product have already been worked out by the industry.  Safety problems that can come about because of surprises in a new manufacturing process are therefore eliminated. 

This was a major time saver for the mRNA vaccine approval process as well.  Moderna, for example, when asked by the FDA about their manufacturing process, was able to say "it's mRNA in lipid nanoparticles: the same equipment and process as they did for Patirisan, which you already fully reviewed and approved".  This got them a quick "thumbs up" from the FDA on the manufacturing front and saved a lot of time.

Chemical vs. biological

Another important part of this manufacturing process is that it is entirely chemical.  It relies on no living organisms, nor on any cells from living organisms.  This means that you can theoretically crank out product much faster than vaccines that rely on growth cycles of living cells in "bioreactors".  It also eliminates a whole class of potential health problems with proteins from host organisms getting into the vaccine.

In conclusion, we can give the manufacturing process a "pass" in terms of innate safety.  It is tried-and-true in a way in which the specifics of the genetic payload itself is not, and it is not any more likely to have weird or new contaminants in it than any previous genetic therapeutic has been.  Furthermore, its chemical nature precludes a whole class of potential contamination to which older vaccines might have been susceptible.  

So now let's move on to considering the mRNA itself, and what possible long-term safety consequences it might have.  Theoretically, we can consider the mRNA in three stages: before it enters the cell, after it enters the cell, and the protein that is generated from it by the cell.

mRNA in the intercellular region

While the mRNA is packages in a lipid nanosphere to keep it from interacting with the body before it gets into a cell, what if some of the mRNA is unintentionally released into the intercellular region?  You can assume that at least a certain amount of this will happen, because nothing is perfect and some nanoparticles *will* break down before being absorbed by cells as designed.

I originally had a much larger argument planned for this section with multiple ways of showing that random mRNA fragments in the body aren't a problem, bringing in things like how the body handles natural cell replication failures and cellular disintegration being a normal occurrence.  Those arguments are all quite valid, but I think a simpler, common-sense argument is good enough: we can know that mRNA fragments aren't a problem in the intercellular region because we've been trying to get mRNA to do useful things for us for decades and we've found that they're so fragile that we *need* to use lipid nanospheres to get them to do anything.  The challenge of getting mRNA to survive the intercellular region has been described in this article: 

The complexity of the problem is enormous. Naked RNA or DNA molecules are rapidly degraded in biological fluids, do not accumulate in target tissues following systemic administration, and cannot penetrate into target cells even if they get to the target tissue. Further, the immune system is exquisitely designed to recognize and destroy vectors containing genetic information

Even using lipid nanoparticles, the mRNA vaccines have to be treated very carefully or the mRNA can be degraded just by the temperature.  It might not actually need the deep freezing that the vaccine as a whole needs (I think that's more due to the lipid nanoparticles than the mRNA), but nonetheless, it's not super-sturdy stuff.

There is only danger to the mRNA strands from the intercellular region, not the other way round, and this is true even on a minutes-to-hours time scale, let alone in the long-term.

mRNA in the cell

Some people have been very nervous about the vaccines because they hear it contains mRNA, which the think will modify the DNA in their cells, which they associate I think with comic-book-style mutations?  I'm not going to talk about this concern much, since other people are debunking it ably.  Just the fact that mRNA vaccines are injecting genetic material into your cells is not a rational cause for fear, any more than the fact that the common cold does the same sort of thing is a rational cause for fear.  I talk about this sort of irrational fear a bit in an earlier post, so I'm not going to say anything more about it now.

The spike protein

So, now for the end-product of the mRNA once it is produced by the cells: the spike protein.  Could it cause some long-term issues?  Let's run it through the same mechanisms we laid out in the previous post:

• Material accumulation: no.  We know from PCR tests of Covid-19 infected individuals (which are extremely sensitive and can detect even fragments of individual viral particles) that the body eventually eliminates all the spike particles from the system.  And this is for people who have system-wide infections, some of them lasting months, with the virus replicating all throughout the body and pumping out spike-covered viruses the whole time.  Once the infection is beaten, it only takes a matter of days or at most weeks before all of the particles are cleared.  A two-time shot in the arm will also be completely cleared.
• Persistence by self-replicating colonies: impossible.
• Damage to non-regenerative tissue: no.  All the same arguments that applied to lipid nanoparticles apply to the protein as well.
• Cumulative effect: no.  Same arguments apply.
• Interaction with adaptive or "learning" body mechanisms: no.  Again, the same arguments apply.

That again leaves the immunological response, which *is* a valid manner in which the spike protein could cause a long-term effect.  So now we are going to deal with that question.

Immunological response

Lipid nanoparticles

I said I would return to the immunological response to lipid nanoparticles in the previous post.  Here I will point out that the immunological response to foreign objects in the body relies on detection that those objects are foreign, and depends solely on the surface of the object in question.  The body is not able to probe into an object for foreign DNA, it must touch the surface of the thing.

For lipid nanoparticles, the surface of the particle is the PEG coating.  This is why the nanoparticles are coated in PEG in the first place, because it reduces immunogenic response.  Because of this, the surface of mRNA vaccines should look identical to all of the older liposome injections which were also coated in PEG, from the standpoint of the body's immune response.

This is not to say that there won't be a reaction--there will be some reaction.  However, what the immune system will be reacting to is exactly the same thing it reacts to in much older medicines: a tiny round particle coated in PEG.  We should therefore expect that the long-term possible side effects of the immune response to the lipid nanoparticles to be no different than the long-term side effects of the immune response to those older liposomes--which is to say, nothing.

The spike protein

The spike protein, on the other hand, is a new protein and we do not have long-term data on the immune reaction to it.  One concern that has been raised is, suppose the spike protein is similar in some ways to good, human proteins elsewhere in the body.  When the immune system develops a memory of how to neutralize the spike protein, couldn't it sometimes accidentally generate an antibody that attacks these human proteins as well?  In other words, couldn't the vaccine cause some sort of auto-immune condition to develop?

The answer to this is, possibly.  Auto-immune disorders of various kinds are certainly possible rare side-effects of all vaccines.  Now, I do not personally know (and I'm not sure if scientists do either) whether the mechanism which triggers an auto-immune disorder is what I have just described: bad antibody generation because of *similarity* between the antigen and some human protein.  It's possible that what happens is more of a simple mistake: the immune system gets excited by the presence of an invader, and then during the course of the immune system arousal some over-excited antigen presenting cell grabs a human protein of some sort and presents it to a T-cell.  But whatever the mechanism, we do know that this sort of thing does happen some times.

The long term?

However, knowing that this sort of thing could possibly happen isn't enough.  We know that this doesn't happen at any meaningful frequency in the short-term because of the safety data and adverse side effect tracking.  So for there to be a long-term risk of this, it has to be possible for an auto-immune disorder to arise after a vaccine is given, but not in the first year.

This does not match with how the immune system works.  In order for the immune system to build a long-term memory of some antigen which will trigger the multiplication and release of specific antibodies, it needs those antigen particles to be physically present.  Special cells grab bits of the offending material and present them to other cells, and this is the origin point of the immune "learning" process.  It doesn't proceed if there is no more offending material to present.  If the body's immune system is going to learn some incorrect antibody recipe to an antigen, it has to be while that antigen is present.  And we already said that the spike protein is completely eliminated from the body within days or weeks of the vaccine injection, so there is a short time-span in which this could happen.

Moreover, the nature of the human immune system response is to ramp up antibody production over the course of a few days to a week, keep up the antibodies while it sees that there is still an infection and for a while after that, and then spin down antibody production again to some background level.  We have studies on the timing of this surge and spin down with the new vaccines; here's an important study on this for Moderna.  You can see the antibodies spike shortly after the booster shot of the vaccine (about 5 weeks after the first shot) and begin steadily declining after that.

Since this is the case, the time of maximum danger from antibodies produced by a vaccine is 4-6 weeks after the injection.  If any auto-immune problems are going to be caused by vaccine-generated antibodies, they are for sure going to show up no later than that period.

Vaccine safety timeline

Because issues of auto-immune disorders or other problems stemming from the immunological response are common concerns for all vaccines, this question of timing of possible problems has been considered for a long time.  The history of all failed vaccines has been examined, and on that basis it is accepted among vaccine experts that if there are going to be any long-term side effects from a vaccine, they will manifest within six weeks of administration.  There are no known exceptions to that timeline yet in the entire history of vaccines.  Based on that, the FDA required two full months of safety data from the new vaccines before considering them for emergency use authorization, and this *wasn't* considered an accelerated timeline for approval.  The real reason the approval is considered "emergency use" rather than a full approval is not because of lack of long-term safety data--in fact, the reason is that for full approval, the FDA normally asks for a vaccine to show efficacy for a longer period of time than what we know so far for the Covid vaccines (great interview that talks about this among other things here).  They are more concerned with the effects of the vaccine possibly waning over time than they are about it possibly gaining more negative effects.

Conclusion

The process by which mRNA is mass produced is not new, but rather a known and well controlled procedure which we can trust.  The mRNA itself is a safe material which should not be expected to do anything unless it gets into the cytoplasm of the cell.  The spike proteins generated will cause an immune reaction, and the effects of this immune reaction will fully manifest by at least six weeks after injection.  We therefore have very good knowledge of what this reaction entails.  Rare long-term side effects are possible, but at this point we know that whatever auto-immune reactions do happen to some people are going to be extremely rare, at about the same frequency as they happen with ordinary vaccines that have been with us for decades at the most.