A Look-Ahead at the State of Immunity Over the Next Few Months

How is vaccine production going to look by April?

Using current rates of vaccine delivery and expected increases that have been reported, my back-of-the-envelope math estimates that ~150 million U.S. residents will have received at least one shot of the Covid vaccine by the end of March.  Meanwhile, if surveys are to be believed, only about 2/3rds of American citizens actually *really* want the vaccine, and about 1/3 are either unsure or decidedly against it.  This means only about 145 million Americans are both eligible to get the vaccine *and* really want to get it.

Vaccine production will still be ramping up, however.  Pfizer, Moderna, and Johnson & Johnson will all still be increasing production and delivery at that time.  Early April is also the earliest time at which Novavax could also see FDA approval, which would increase the pool of available vaccines still more.  This means that at the beginning of April, pretty much all Americans that *want* the vaccine will already be vaccinated, *and* the supply will continue to go up.  So early April will mark the transition into the "vaccine glut" phase, at least for the U.S., where everyone who wants a vaccine is going to be able to get one with relative ease.  This is when the job of convincing more people to take the vaccine is going to be much more important.

What does this mean for immunity and reduction of spread of the virus?

We now know that even one shot of the mRNA vaccines starts conferring pretty good immunity after 3 weeks.  So in early April, we're going to have ~130 million people with good immunity from vaccines (subtracting off the people who were immunized at the tail end of March).  Further, the most vulnerable populations should have a much higher rate of immunity, and also a lot of people who are more prone to being serious spreaders should also have a much higher rate of immunity.  This should be devastating to the death rates for Covid, and really bad for its spreading capability as well.

In addition to immunity from the vaccines, we'll also have a fair amount of immunity from people having been infected and recovered.  Right now, there have been about 30 million known cases of Covid in the U.S., counting past and present.  The unknown asymptomatic cases are, as you would expect, unknown, but a decent estimate for the size of that population is double the size of the known cases.  Now, you can't just add those people into the total number of people with immunity from vaccines, because all lot of the people who get the vaccine may well have been unknown asymptomatic carriers from before as well.  However, it is the case that the asymptomatic unknowns are more likely to be young and healthy, and thus less likely to have already been vaccinated by the end of March.  So I think it's reasonable to add, say, 40 million people to the total number of people with some immunity to Covid by the beginning of April.

This means we'll have roughly 52% of the population with some immunity to Covid by the beginning of April, with that number rapidly increasing due to vaccines already given in late March and new vaccines given as well.  What is that going to do to Covid spread?

Estimates for Covid R0 vary, but I like the number 3 as a reasonable estimate.  This would be the reproductive rate *without* any social distancing measures--the "life as normal" reproductive rate.  In the naïve, "perfect mixing", epidemiology scenarios, you modify the R0 by the percent of population with immunity in order to get the current effective reproductive rate.  So, 50% immunity would drop an R0 of 3 down to an R of 1.5.  This still gives you spread and growth if you abandon all social distancing and masking measures, but it's not such a huge rate.  This is in the same ballpark as the seasonal flu.

Caveats

But there are some additional caveats we can put on these numbers.  First, I expect regulations enforcing masking will still be in effect in most places throughout all of March and into April.  These should continue to cut down on Covid transmissibility, and if you start with an R of 1.5, you only need an extra 33% reduction in transmissibility to keep the virus decreasing rather than increasing.  Second, Covid does not spread in the "perfect-mixing, simplified" style.  It seems to have a more asymmetrical style of spread than does the seasonal flu, relying more on super-spreader events than the flu does.  This *should* tend to mean that those people who are more likely to get and spread Covid will have already gotten the disease, recovered, and developed immunity earlier rather than later.  So those 40 million people we already added into the "some immunity" pool will more important to halting the spread of the disease than remaining people who have not yet had the disease.  The fact that we have been vaccinating with an eye to the more dangerous transmission scenarios (medical staff, prison inmates, etc.) should work in the same way.  How *exactly* this factor will influence Covid spread is difficult to quantify, but I think it is an important factor.  Third and finally, in early April winter will be mostly over.  At this point, it's pretty clear I think that there is a seasonal aspect to Covid and that it has reduced transmissibility outside of winter weather.  Again it is hard to quantify exactly what effect this will have, but again I suspect that it will be substantial.

Conclusion

With all of these considerations in place, I think we can foresee April being a very tough month to be Covid in the United States.  As I said, you only need an extra 33% protection against transmission to put a pandemic into subsidence if the R0 is 3-ish and you have 50% herd immunity, and I think the "extra factors" I mentioned will probably have at least that effect.  If I'm right, that means that it should be possible to remove all social restrictions in the U.S. in early April *and* still see infection numbers continue to decrease.  It's likely public authorities will proceed with more caution than this, and that's probably a good thing.  If it were up to me, when we get to this point, I'd remove all restrictions except requirements to wear masks in public indoor locations (being an easy restriction to live with that doesn't damage the economy) and aggressively continue a public vaccination campaign with the goal of getting to 80% vaccination rate (probably the best we can do considering the amount of vaccine hesitation).

The major factor that could throw a wrench in the spokes of this happy prediction is the spread of newer Covid variants.  What we really need to know to know how bad a factor this could be, is how much the newer variants escape the natural immunization from the original variant and the immunization derived from the vaccine.  That is the most critical new information I am looking for right now; I know there are trials and experiments looking for this information now and I am eagerly awaiting better information coming out of these.  For now, I'm retaining a cautious but hopeful optimism.

Long Term Side Effects of mRNA Vaccines Unlikely, Conclusion

Conclusion: A Different Category of Possibility

Having gone through all ways that I could think of mRNA vaccines could possibly cause long-term complications without those complications arising fairly soon after administration, I could not find any.  I couldn't even think of a mechanism by which such a long-term complication could happen.

This is not the same thing as a proof that such a thing couldn't happen.  "I thought about it very hard and I couldn't think of a way it could happen" isn't a proof--maybe you just don't know enough to think about the right things!  No one could claim to know enough about the human body and the immune system to be able to understand absolutely everything any therapeutic could do.

But that's why the title of this series of posts was "Long Term Side Effects of mRNA Vaccines Unlikely": unlikely, not impossible.  "Unlikely" is the limit of what we can prove at this point.

What I think this series does prove is that the risk of such a long-term complication lies in the realm of the true "unknown unknowns".  Especially considering how such a long-term complication has never before come up from a new vaccine, it would be a risk from out of left field--something truly new and unforeseeable.  

I think this is an important result that should have consequences on our own decision making.  One way of dealing with risks is appropriate if there are known possibilities of something bad happening, but if all you have is doubts that you know enough about some thing--even after all the experts have done everything they can to understand every possible risk about it--then it is not appropriate to consider this thing a risk in the same way.  The risk exists in a different category of possibility.

What I mean here might become more clear when you compare the risk of the new vaccines against some other things.

Comparative risk

Compared to Covid-19

Compared to the risks associated with getting the new vaccines, Covid-19 has many risks of long-term consequences.  There are flat-out "knowns": permanent lung damage and heart tissue scarring are the two most likely long-term consequence that we know about, but there are a whole host of other things that are known to happen to sufferers of severe Covid as well.  Then there are "known unknowns", such as the possibility of heart tissue damage even from mild cases, and the potential for nerve tissue damage (given that we see Covid has neurological side effects which may or may not involve permanent damage to nerve tissue based on what we know so far).

Then there are the "unknown unknowns".  And here, Covid has all of the same potential to cause issues that the vaccine does.  For the vaccine, by far the most likely class of problems from which some unknown long-term complication could come is auto-immune issues.  But everything that I identified as a potential for causing problems from the vaccine, the virus also does.  

Suppose there were some antibody that the immune system generates in response to the spike protein from the vaccine that ultimately causes some sort of long-term problem.  Well, not only does an actual infection from the virus also produce that spike protein, it 

1. produces the whole virus as well (giving the immune systems more features to react to and hence more chances to produce some hypothetical dangerous antibody), 
2. it produces them throughout the body in many more types of tissue as it spreads around (thus multiplying the number of possible interactions between the foreign invader and different types of human cells and exponentially increasing the chance of a human cell getting targeted by the immune system), and 
3. it produces them for far longer than the few days that the vaccine exists in the human body.  This length of time in which the immune system is in a heightened "battle mode" thus also increases the chance which I mentioned for some over-zealous member of the immune system to trigger an immunity against the wrong thing.

Some people have been nonchalant about the risks of catching Covid-19, but very hesitant to take the vaccine.  This makes no sense whatsoever.  Not only does catching Covid-19 carry with it all of the same risk of the unknown that the vaccine does, it has whole classes of risk--of things both known and unknown--which the vaccine does not.  I can understand the desire to avoid both things, but to consider the virus a relatively safe known compared to the unknown risk of the vaccine is pure ignorance or irrationality.

Compared to other vaccines

Most of what I have talked about in these series of posts applies similarly to a lot of other vaccines.  But not all, and it would be worth discussing those ways in which mRNA vaccines are likely to be safer than the more traditional types of vaccines.  This would be a good topic for a dedicated post, in fact.

The only specific thing I'm going to mention here is how the most common type of traditional vaccine works, which is by taking the actual virus and neutralizing it in some way, then injecting the deactivated virus into the body, thus eliciting the immune response.  Whatever way the virus is neutralized, it involves serious damage to the viral particles--by necessity, because "neutralize" is another way of saying "destroy the basic functioning capacity of the virus".

What this means is that a traditional vaccine involves the injection of randomly damaged microscopic material into your body: at the cellular level, billions of individually mangled viruses, possibly with weird broken structures and possibly with randomly scrambled RNA from radiation.  Normally this turns out OK, but there have been instances in the past where the damage to the virus itself has been suspected of causing the antibodies generated in response to them to be defective, and even possibly dangerous (read up on a failed RSV vaccine from the '60s for this, though the "damaged virus" theory is currently out of favor).

It has to be admitted that mRNA vaccines have a much cleaner, more predictable path towards generating immunity, at least in theory.  It has always been the theory that mRNA vaccines will be inherently safer than older vaccines due to the very targeted and controlled antigen that they generate and the very precise way in which this antigen is produced.

Up until recently, this idea has been just theory, but I think it is worth understanding that mRNA vaccines have some key theoretical safety advantages to older forms.

Final Conclusion

No one can claim perfect knowledge of the future, but when it comes to the long-term safety of the new vaccines, it is at least a very safe bet that they will turn out to be completely fine.  I did not hesitate to get the vaccine myself, and neither should anyone else.

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.

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.

Long Term Side Effects of mRNA Vaccines Unlikely, Part 1

Some people are concerned about the possible side effects of the new Covid-19 vaccines.  With tens of millions of doses of these vaccines administered, we now have definitive evidence that these vaccines are quite safe--in the short term.  But what about possible long term side effects?

While it's not true that the development of these vaccines was "rushed" (a topic for another post), nevertheless it is true that the first people ever injected with these specific mRNA vaccines were Phase 1 trial participants on March 16th, 2020 (https://www.cidrap.umn.edu/news-perspective/2020/07/hopeful-results-phase-1-moderna-covid-vaccine-trial).  Therefore the longest running data we have on the effects of these vaccines is only about 11 months old only; we can't definitively prove on the that basis that there won't be side effects that only surface after a year or more of taking the vaccine.

However, in the case of the mRNA vaccines, the medicine in question is quite straightforward and specific in its action.  It is a very simple compound of two parts: an RNA genetic payload, surrounded by a lipid nanoparticle sphere.  This simplicity makes it reasonable to attempt to think through all the side effects that the two components of this vaccine might possibly produce.  What do we know about the possible long-term effects of the components of this vaccine?  Can we think of a mechanism by which either might produce some long-term effect?  If what we know about the components of the vaccine tends to rule out long-term side effects, and if we cannot come up with reasonable mechanisms by which the vaccine could possibly cause long-term side effects, we might then conclude that the vaccine is very unlikely to produce long-term side effects.

As it turns out, there are good reasons to predict that no long-term side effects will manifest from these mRNA vaccines, which I will begin presenting now. I plan on breaking this up into four parts: 

1. An overview of how the mRNA vaccines work (compared to the virus against which they inoculate).
2. What are the possible long-term side effects of the lipid nanoparticle.
3. What are the possible long-term side effects of the genetic payload.
4. Summary of possible risks and comparison to risks of infection.

How the mRNA Covid Vaccines Work

It's useful to compare the working of the mRNA vaccines side-by-side with the workings of the coronavirus itself, because in many ways the vaccine is a simplified, mechanical version of the virus.  Both are genetic material (specifically RNA) delivery mechanisms.

Envelope and Payload

Both the Covid virus and the mRNA vaccines are composed of small particles: roughly the same size of about 1/10th the diameter of the typical human cell.  The virus is composed of an outer membrane layer that's studded with spiky protrusions (the "spike protein") and contains a large single strand of RNA inside which holds the genetic instructions for making copies of the complete virus.  

The particles inside the mRNA vaccine are just super-tiny spheres of lipid with a coating (a "surfactant") that keeps the sphere of lipid together.  Instead of containing a single continuous strand of RNA with instructions for making the whole virus, the vaccine particle contains multiple much smaller strands of RNA which are each *part* of the virus RNA--specifically, the part that contains the instructions for making the spike protein (about 13% of the total genetic code of the virus, specifically from about the 21563th nucleobase in the chain to the 25384th, see full genetic sequence of virus here).

That the two structures are very similar is due to a simple fact that both structures have to deal with: RNA, being single-stranded, is much more fragile than double-stranded DNA.  Both particles are aiming to deliver their RNA payload to human cells, but the inter-cellular space in the human body is hostile to the survival of free-floating RNA.  Without a more durable delivery particle, the RNA would disintegrate quickly rather than penetrate into any cells.  So both systems implement an envelope-and-payload structure to get the job done.

Cell Infiltration and Replication

The Covid virus infiltrates the human cell using the spike protein.  This binds to a receptor on the cell surface (the "ACE2" receptor) and allows the virus to open up the cell wall and inject its payload RNA.  This RNA is then taken up by the cell's protein manufacturing process and whole new copies of the virus are created and "bud" out of the infected cell.

Since what is produced in the end here is more fully functional copies of the virus, this process repeats over and over again as more cells are infected and replicate the virus.  The infection spreads throughout the body, able to multiply wherever there are cells that have ACE2 receptors.

Lipid nanoparticles do not require a spike protein.  Instead, they merge with the cell naturally because of compatible chemistry between the lipid particle and the lipid membrane of the cell.  Once inside the cell, the lipid structure dissolves in the higher pH setting and releases the mRNA particles into the protein manufacturing structures of the cell.  The cell then proceeds to manufacture only the spike proteins.

Because only the code for the spike protein is included in the nanoparticle, this process continues only until all of the nanoparticles that were injected into the muscle have either merged with a cell and produced spike proteins, or broken down in the intercellular region.

Immune System Response

In the case of both the virus and the nanoparticles, the immune response is roughly the same.  The spike protein is identified as a foreign invader of the body and the standard immune response is invoked against it.  Importantly, the body also learns how to produce a neutralizing antibody: a protein shaped just right so that it latches on to the spike protein.  Once the body's immune system has learned how to do that, whenever it senses that same spike protein again, it will ramp up production of these antibodies.  The viral particles will then pick up these antibodies all over on their spike proteins, which will then no longer able to fit into the cell wall receptacles.  The virus will therefore lose its ability to penetrate cells and reproduce, and thus the infection is halted before it can progress very far.