Long Term Side Effects of mRNA Vaccines Unlikely, Part 2

What are the possible long-term side effects of lipid nanoparticles? 

Lipid nanoparticles are not new technology invented for the mRNA vaccines; there is history and safety data for them.  Therefore I will start with what is already known about long-term effects of lipid nanoparticles, and then move on to consider whether the constituent materials of lipid nanoparticles even allow for any sort of long-term side effect.

History of lipid nanoparticles

Liposomes

According to Lipid Nanoparticles: Production, Characterization and Stability by Shah et al., the idea to surround fragile or reactive drugs in a lipid layer in order to target delivery to specific parts of the body was first theorized in the early 20th century (Shah et al., 4).  It was not until 1961 that this concept was first put into practice, with the development of the liposome:  https://en.wikipedia.org/wiki/Liposome.  The liposome was really the first medicinal nanoparticle: it was a lipid sphere containing an aqueous solution in its center in which a desired drug was dissolved.  Its purpose is to either protect a fragile drug from the body until the drug reaches its desired destination OR protect the body from a dangerous drug until the drug reaches some target for destruction (chemotherapy is the biggest use case here).

Since its introduction in the '60s, the liposome has been used for many types of drugs.  It is the most common vehicle used for any sort of targeted drug delivery, and according to this review of the state of liposomes written in 2017, it is used as a drug delivery mechanism in the areas of analgesics, fungal disease medicine, cancer therapy, viral vaccines and something called "photodynamic therapy".

The fundamental ingredients used for lipid-assisted drug delivery have been around for many decades, even if not in exactly the same form as modern lipid nanoparticles used to deliver genetic material. This should put a severe limit on the doubts as to the safety of modern forms. Some people, for example, have raised allergy concerns with the substance called "polyethylene glycol" (PEG) with which the lipid nanoparticles of the mRNA vaccines are coated.  But this coating has been used on liposomes and other injected drugs since the '70s.  This is not to say that there are no allergy concerns with the substance, but what this does mean is that we have ample long-term safety data on PEG and so far no known long-term effects have been found.  It is not a valid cause for concern about long-term side effects.

Lipid Nanoparticles

If that is the case, what is new about lipid nanoparticles, and why were they developed separately from liposomes?  The key thing that needed to be changed was the aqueous center.  As I mentioned before, RNA is a fragile thing.  One of the fragile things about both RNA and DNA is that they are water soluble;  you can't put genetic material in the center of a liposome, because it would just dissolve.

The solid lipid nanoparticle was thus created as a way of delivering fragile material like RNA that you don't want dissolved in water.  Instead of an aqueous center, it bundles up the drug into a solid lipid "matrix".  These are more challenging to manufacture than liposomes, but scientists have been working on them since the mid '80s, the first drugs commercially delivered by them came out in 1993 and they have been "greatly exploited ever since as drug carriers" (Shah et al., 4).

More recently, lipid nanoparticles have become the most popular option for various gene therapy drugs, like the mRNA vaccines.  This has been enabled by evolutions in the design of the lipids used that increase the stability of the particles and reduce the immune reaction to them, while also reducing the particles' "cytotoxicity" (which is the quality of being toxic to cells--an important thing to do if you want to keep the cell to which you deliver the genetic payload to remain intact and functional).  The primary breakthrough here had to do with neutralizing the surface charge of the lipid nanoparticles, which made them neutral with respect to body chemistry and hence non-reactive at the cellular level.

Note that while lipid nanoparticles have tweaked chemistry with respect to older liposomes, the long-term effects of the material should not have changed at all.  Cytotoxicity, which the older lipid formations could exhibit, is a short-term effect of nanoparticles with a particular surface charge.  Over time, all of these lipids are bio-degradable and will eventually be broken down by the body's organic solvents into the same component parts.  Here is a study from 2013 looking at a representative lipid and studying how rapidly it is biodegraded and eliminated from the system (answer: rapidly and safely, with the caveat that the study was on rats, though that shouldn't make a difference here).

Most of the projects using these newer lipid formations are still undergoing trials, but a few have seen full FDA approval.  Patisiran, for example, was FDA approved in 2018, and the first patients dosed with Patisiran and tracked ever since were recruited no later than 2013 (link to clinical trial here).  Here is a link to a list from 2018 of 22 genetic therapies using lipid nanoparticles constructed just like the lipid nanoparticles used for the mRNA vaccines.

Safety conclusion from history

In summary, the medical world has had 50 years of real-world (i.e., patients dosed) experience with lipid drug delivery systems, 20 years of experience more specifically with lipid nanoparticles, and at least 8 years of experience of exactly the type of lipid nanoparticles which are now used in the mRNA vaccines.  No long-term side effects resulting from lipid nanoparticles have ever been described.  Short-term side effects from older lipid formulations included some cytotoxicity, but newer formulations have substantially removed that side-effect, thus enabling a lot of gene therapy options which were not possible in the past.

Possible mechanisms for long-term side effects

Let's now spend some time thinking about how a medicine might have long-term side effects.  It's theoretically possible that lipid nanoparticles have long-term side effects that have been missed by scientists and doctors, so I'd like to go over the different mechanisms by which drugs can have long-term side effects.  Let's look at a number of real-life examples and see which ones might apply to lipid nanoparticles

Accumulation of material

Example: Lead poisoning.  Lead poisoning causes long-term side effects because lead is a material which the body can only eliminate very slowly.  Small amounts therefore accumulate inside the body and over time become enough to interfere with various biological processes.

Accumulation of material in the body which cannot be easily eliminated has been identified as a concern for some types of nanoparticles, namely gold nanoparticles.  However, lipid nanoparticles cannot possibly act in the same way.  They are all biodegradable.  They have different lifespans in the body depending on their exact composition, but none of them can last long enough to be a long-term concern.  After receiving a lipid nanoparticle injection, no more particles will be left in the body in a matter of days or weeks, let alone months or years.

Persistence by self-replicating colonies

Example: Chicken pox.  The chicken pox virus is able to cause Shingles many years after an initial infection because the virus replicates throughout the body and manages to establish dormant colonies in the nervous system.  At some point, through mechanisms which are unclear, these dormant colonies can re-awaken spread through neuronal tissues.

Lipid nanoparticle obviously cannot cause long-term side effects in this way.

Damage to non-regenerative tissue

Examples: Lyme Disease, Covid-19.  Lyme disease is a bacteria that spreads throughout your body.  If not caught quickly enough, it spreads through your nervous system as well and damages nerve tissue.  Nerve tissue doesn't really regenerate, so the side-effects of Lyme disease can be permanent.

Some cases of Covid-19 have also shown to cause some neuronal symptoms, but we don't yet know if it can cause permanent damage to nerve tissue in the way Lyme disease can.  However, we *do* know it can cause scarring to heart tissue.  Almost all bodily tissues regenerate to some degree or another, but some organs regenerate at a much slower rate than others do.  Cardiac tissue regenerates so slowly that it essentially doesn't regenerate at all, so scarring of the heart is a problem you can expect to affect you for the rest of your life.

If a drug were to cause tissue damage to one of these slowly-regenerating organs, it could cause problems in the long term when that organ is under more stress but not be obvious right at the time.

Which organs do we worry about here?  Primarily, these would be: heart, lung, brain and nervous system, and eyes (retinal cells do not regenerate).  There are other cell types which take a fairly long time to regenerate (from 8-10 years for some muscles and intestinal cells, for example), but they do regenerate--and we are looking for long-term effects that would not yet have shown up after the 8 or so years these specific lipid nanoparticles have been administered to test subjects, so we can discount any organs that would naturally self-heal in that time period.

So, can the lipid nanoparticles injected for these vaccines substantially damage the heart, lung, brain or nervous system, or the eyes?  I think the answer to this is pretty clearly, "no".  The course of lipid nanoparticles through the body is well understood.  Here is a study that looked at the safety of lipid nanoparticles delivering a particular genetic payload on rats and monkeys.  They dissected all of the major organs, looking for any evidence of toxicity or organ damage.  The only organ they found to be affected by the lipid nanoparticles directly was the liver, where there was some slight oxidative stress.  Oxidative stress is what damages your liver when you drink alcohol; it's reversible because the liver self-regenerates quickly, and you have to have quite a lot of it all at once to give yourself permanent liver damage.

More specifically in the case of the mRNA vaccines, the course of the vaccine through the body is very predictable.  It's injected into the upper arm muscle, where it's initially trapped by the regular matrix of muscle tissue.  It slowly drains into the nearby lymph nodes, and what is not metabolized at a cellular level is disposed of by the normal waste system: i.e., filtered out by the kidney and liver and then excreted.  So we can eliminate damage to vital organs as a possible way of causing long-term side effects for lipid nanoparticles.

Cumulative effect

Example: carcinogens.  Some substances have a deleterious effect if they are used for a very long period of time.  For example, some materials appear to slightly promote the mutation of human cells, thus increasing the chance that a dangerous mutation will come about in the form of cancer.  In every case of material of this sort that I am aware of, however, a long period of time of exposure to the material is necessary to statistically increase the chance of cancer.  Birth control, for example, may well increase the chance of breast cancer, but that is something that is taken day-in and day-out, constantly, for many years.  Likewise, smoking is something that is done habitually and often, usually over the course of many years.

The mRNA vaccines are given in two doses only.  The lipid nanoparticles exist within the body for a small number of days, twice in your lifetime, and then that's it.  Thus they are not susceptible to this form of unexpected long-term side effect, where each use increases the odds of some negative outcome by some tiny amount, which grows over the course of cumulative uses to be a significant risk.

Interaction with adaptive or "learning" body mechanisms

Example: addictive drugs (oxycodone, et al.).  Certain mechanisms in the body adapt to different circumstances and can thus "learn" a behavior at some biological level.  Once they learn a certain behavior, this behavior can become very difficult to unlearn, thus becoming a long-term side effect.  Pleasure receptors in the brain can become accustomed to the euphoria of a drug-induced high, making it difficult to find pleasure in any normal activity again.  Any strong, mind-altering chemical has the capability to have this sort of side-effect, as the mind is the pre-eminent learning organ.

The endocrine system can probably also be counted as a potential source for long-term side effects of this sort.  While the endocrine system isn't a "learning" system per se, it is a complex interrelation of hormones which is designed to be adaptive to various situations.  It's possible an imbalance among the interrelation of hormones here might cause some long-running, self-perpetuating problem--though I have not actually been able to come up with a real-life example of this sort of thing being the *source* of long term issues yet.

Lipid nanoparticles can't really cause issues with either of these systems, however.  With both brain-driven processes and endocrine processes, drugs that can cause serious side-effects through interaction with them are very chemically specific.  Pain and pleasure receptors require very specific chemicals to activate; hormones stimulate bodily functions using very specific chemical signatures.  Microscopic balls of lipid are not going to interact with any of these systems in the specific ways necessary to trigger them.  And even if they did, I'm not aware of any dangerous interaction with these volatile systems that is not immediately obvious.  You can become addicted to a painkiller because of the power of its effects on your brain and nervous system, but likewise because of that power, you can't become addicted without noticing it.  If there is a long-term side-effect to lipid nanoparticles, however, it has to be something that happens without anyone initially noticing it.  So we can eliminate brain and endocrine problems as possibilities.

There remains, however, one "learning" body mechanism which *can* interact with lipid nanoparticles, and that is:

The immune system

Now we have arrived at the only way in which I think it is legitimately possible that lipid nanoparticles can have a long-term side effect on the human body.  While lipid nanoparticles are intentionally designed and manufactured in such a way as to have as little interaction with the human immune system as possible, and it is know that they are relatively effective at hiding from the immune system in order to be able to deliver their genetic payload to cells, nevertheless we also know that they aren't 100% effective at this.  There is some slight immune reaction purely to the lipid nanoparticles when injected into the body.

And this makes complete sense: it is the job of the immune system to find and eliminate foreign microscopic particles, and lipid nanoparticles are certainly that.  Furthermore, anything that the immune system reacts to, carries with it the danger of a long-term side effect because the immune system has a memory system: for certain pathogens, it learns about the pathogen and makes specific antibodies which it releases to counteract that pathogen, and it can retain this memory for life.

The immune system, therefore, is a mechanism by which any vaccine--including one based on lipid nanoparticles--could plausibly cause a long-term side effect.

Is it likely, however, that lipid nanoparticles do sometimes cause such a long-term side effect?  I'm actually going to leave that question till the next part, because the immune response is a factor for both the lipid nanoparticle and the genetic payload, and it's a very important thing to consider.  So for just right now, I'm going to leave this question open.

Conclusion on plausible mechanisms for long-term side effects

The conclusion, after considering all mechanisms that I can think of which could create a long-term side effect in any way at all, is that the only *real* possibility here is some interaction with the immune system.  No other plausible mechanism exists by which microscopic bundles of biodegradable, chemically inert material which are broken down and eliminated from the body quickly could cause any sort of long-term problem, which was not also immediately evident in the short term.