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.