Messenger RNA-based Vaccines: A Nobel Prize Worthy Invention

This morning, Pfizer and BioNTech announced some very positive results regarding the trial of their messenger RNA-based Coronavirus vaccine.  The efficacy was found to be above 90%, which vastly exceeded expectations.  

The implications are profound, and include a proof point that genetic vaccines (a brand new highly extensible technology) can be very effective.  In addition the medical community will now have a much higher confidence that the human immune system will respond to coronavirus vaccines with some form of lasting immunity.  

Further, the invention of messenger RNA vaccine technology (and genetic vaccine tech in general) will have highly impactful medical uses in the future.  Some applications may include the treatment of diseases where the body can't make a proper version of a particular protein (such as sickle cell anemia among many others).  This invention is perhaps one of the most impactful of the decade.

The Dow is up over 1200 points today as a result of today's news.

So what are messenger RNA-based (m-RNA) vaccines, how do they work and why are they so exciting?  This is what I will discuss in today's blog post.

Let's start with a brief refresher on how the old-style vaccines work.

How Traditional Vaccines Work (in Brief)

Traditional (non-genetic) vaccines are used to stimulate the body's immune system by introducing a weakened (or killed) version of the virus. Other traditional vaccines inject a substance that looks like a subcomponent of a virus (and there are additional forms of traditional vaccines as well).  The general idea is to teach the adaptive immune system of the body what the virus looks like, so when a real virus comes along, the body can react much more quickly to kill it.  

Let's focus in on the traditional subcomponent (or protein) vaccines - the ones where some portion of the virus is injected into muscular tissue to evoke an immune response.  


Figure 1: The Coronavirus

As you can see from Figure 1, the coronavirus is comprised of a spherical structure which is coated with little spikes - these are the so-called spike proteins that help the virus enter a human cell.  Many subcomponent (traditional) vaccines currently under development today target this spike protein because it is the most prominent and distinctive element.  These vaccines are designed to work by basically injecting a piece of this spike protein into human tissue in order to train the immune system to recognize it.  Note that when the actual virus enters the body, the spike protein is very visible while the virus is circulating in the blood and in tissues - this helps considerably in having the immune system's antibodies recognize it. And when they do, they can quickly attach to the virus and render it harmless.

But it turns out that there is a better way than simply injecting the spike protein in order to have it recognized by the immune system.  Genetic coronavirus vaccines, including Pfizer's m-RNA vaccine, basically turn human muscle cells into spike protein-producing factories.

The Central Dogma of Biology: Protein Synthesis

The human body needs a continuing supply of proteins in order to live, and one of the most important bodily functions is the ongoing synthesis of these essential molecules.  Biologists refer to this process of making proteins as the Central Dogma and it works as follows:

Protein Synthesis: Biology's Central Dogma

  • Proteins are molecules that provide the structure, function and regulation of the body's cells, tissues and organs.  They are comprised of a string of amino acids (think of amino acids as building blocks for proteins).
  • DNA carries instructions for creating these proteins.  The instructions will tell the cell what the exact sequence of amino acids needs to be to make a properly functioning protein.
  • In order to execute those DNA-based instructions, a string of m-RNA (messenger RNA) is created using the DNA as a template.  This is called transcription, which happens in the cell's nucleus.  The piece of m-RNA that is created by the transcription process now contains a copy of the instructions for creating the protein.
  • The m-RNA (the instructions) then migrates to the cytoplasm of the cell (outside the nucleus but still inside the cell) and is read and translated into a complete protein by ribosomes.  This is called, oddly enough, translation.  
    • In this process, the m-RNA instructions are executed by the ribosome by gathering up various amino acids and assembling them in the correct sequence.  
    • You can think of a ribosome as a kind of a protein assembly factory, where a string of m-RNA provides the instructions for the assembly, a bunch of amino acids is the raw material, and a protein is the finished product.  
    • (Note that the details of how this happens are very interesting - and involve yet another form of RNA called transfer RNA - but this is beyond the scope of this post.)
  • The resulting now-connected string of amino acids, which constitutes a complete protein, then folds itself up into whatever configuration is required for it to function properly.  
  • The protein then goes on to perform its cellular duties, whatever that may be.

Genetic Vaccines

A genetic vaccine, such as the m-RNA based Pfizer formulation, works by hijacking the body's protein synthesis pathway (described in the box above).  

In Pfizer's case, a string of m-RNA that encodes for the entire coronavirus spike protein is injected directly into muscle tissue.  The muscle cells promptly uptake the m-RNA which, once in the cell, migrates to its ribosomes.  The ribosomes in turn, start churning out copies of the coronavirus spike protein.  This happens just as if these m-RNA based instructions were issued by the body's own cell.

These newly-made spike proteins then start circulating through the bloodstream (and are presented to T cells - see my blog post on the human immune system for details). The spike proteins are harmless by themselves but are recognized by the human immune system as foreign to the body.  The adaptive immune system starts activating a response that is specific to those spike proteins.

After a couple of weeks (and a second "booster" shot), the human body's immune system is now trained to recognize and attack any entity that contains or looks like the spike protein.

Advantages and Disadvantages

One key advantage to genetic vaccines is that they can be modified quickly and easily.  Any mutations that the virus undergoes can impact the efficacy of vaccines - but genetic vaccines can have their sequences quickly updated to match any new mutated versions of the virus that are observed. This is a significant strength.  

In addition, this technology has uses far beyond vaccines.  Many genetic diseases result from a missing or mutated section of DNA that has been inherited - the result is a non functioning (or missing) protein.  A good example is sickle cell anemia - in which the hemoglobin protein has been altered so it can't carry oxygen molecules efficiently. Sometime in the future, it may be possible to inject m-RNA molecules that code for instructions to make properly functioning hemoglobin molecules.  There are many other examples.

But, there are disadvantages.  m-RNA molecules degrade quite quickly at room temperature and must be transported and stored at -80º C.  This so-called cold chain for supplying the vaccine is very expensive and will inhibit distribution.  

Summary

The Pfizer interim results announced today portend an end to the Coronavirus epidemic.  There is every reason to believe that the Moderna vaccine, which is very similar, will achieve equivalent results.  We await the final results of the trial, which are expected next month.  I would expect an FDA emergency use authorization (EUA) to be issued perhaps as early as the end of December, with full authorization following in January or February.  Perhaps 25M people could be treated (50M vaccine doses) under the EUA.  Pfizer has stated they can supply as much as 1.3B doses in 2021, treating 650M people.  Maybe life will return to normal in the summer of 2021.  We can only hope.

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