mRNA Covid-19 Vaccines

Approximately one year after the first outbreak of Covid-19 in Wuhan, China late in 2019, two vaccines were approved for emergency use in the United States and vaccinations began.  They were the Pfizer-BioNTech and the Moderna vaccines.  My wife and I received our second doses of the Moderna vaccine on March 15, 2021. These vaccines are reputed to use a radically new vaccine technology called mRNA (messenger RiboNucleic Acid) technology.  I did some reading to get an idea of how this new technology works and how it compares to other and older technologies.  This is a summary of what I learned.

First, a little general information. All living organisms on earth carry the blueprint for their structure in the form of DNA (deoxyribonucleic acid) code.  DNA is a long molecule that looks rather like a long twisted ladder (a double helix).  Each step of this ladder is a “base pair”, two nucleobases (small clumps of strongly bound atoms) one at each side of the ladder with a hydrogen bond connecting across between them. There are only four different types of such clumps found in DNA and there are rules about which of such nucleobases can match up across from each other to produce a step of the ladder.  Differences in organisms are reflected in corresponding differences in the sequence of base pairs along this ladder.  Most DNA in a cell is confined to the nucleus of the cell.

DNA expresses itself (determines the characteristics of the cell it resides in) by producing RNA which can pass out of the nucleus into the cell proper.  RNA is a long molecule rather like a piece of one side of the DNA ladder with the nucleobases unpaired, hanging out from the side. This lack of pairing (stuff hanging out rather loosely) makes the RNA less stable and more reactive than DNA.  There are again four types of nucleobases found on RNA strands; three are identical to those found on DNA and one type of nucleobase which is different.  Once outside the nucleus these strands of RNA, called messenger RNA (mRNA), find a structure elsewhere in the cell called a ribosome.  Ribosomes contain another kind of RNA called ribosomal RNA (rRNA). Ribosomes function as protein factories. Proteins are among the most common structural and functional molecules making up a cell.  In the cell outside the nucleus there is also a third kind of RNA, called transfer RNA (tRNA), whose job it is to bring the building blocks of proteins, amino acids, to the ribosomes.  While all three types of RNA are required to produce a protein, it is the mRNA which describes the particular protein which will actually be produced.  The proteins which are produced in the ribosome containing rRNA, with raw material supplied by the tRNA according to the plan supplied by the mRNA, become parts of the cell in which they are produced.  Therefore, it is the mRNA which determines the characteristics of the cell. If you would like to better visualize a comparison of an RNA strand to a DNA strand go look at this Figure. https://mappingignorance.org/app/uploads/2013/04/RNA_I_Figure2.png

Now a quick word about vaccines.  When a pathogen, be it bacterium or virus, gets into an organism (for example a human being) its goal is to live and reproduce, in general, at the expense of that organism.  Successful organisms, in order to preserve themselves, have evolved mechanisms to detect, attack and destroy such pathogens.  These mechanisms make up an organism’s immune response.  The problem is that it takes a certain amount of time for this immune system to detect the intruder, develop an appropriate response, and scale the response up to a level where it can overpower the invading pathogen.  On the other hand, in the absence of constraints, a pathogen will reproduce exponential, 2, 4, 8, 16, 32, 64, 128, 256, 512, 1024, etc. up to levels where the organism is overwhelmed, severely damaged and eventually killed.  Therefore, a race occurs in which the immune system is trying to detect and scale up an appropriate response before the exponential growth of the pathogen seriously harms or kills the organism.  The function of a vaccine is to give the immune system a head start in this race.  The vaccine presents the immune system with something that looks like the pathogen so that it can launch into its detect, develop and scaleup response without facing the actual pathogen.  Later, if it does face the pathogen, it need only continue the scaleup phase of the response and so can quickly destroy the pathogens while there are still relatively few of them in the organism.  The trick is to figure out how to trigger an appropriate immune system response without actually introducing the dangerous pathogen.  Four earlier strategies which have been used with success are:  1) Find an innocuous virus or bacterium which will stimulate an immune response which is also effective against the target pathogen. For example, introduce cowpox to vaccinate against smallpox.  2) Introduce the dead pathogen to stimulate an immune response that is effective against the same pathogen when live.  For example, the Salk vaccine introduces a dead polio virus to stimulate a response also effective against the live virus.   3)  Introduce an attenuated version of a pathogen, perhaps damaged so it cannot reproduce, to stimulate an immune response to the fully functional healthy version of the pathogen.  For example, the yellow fever vaccine introduces an attenuated yellow fever virus. 4) Use an innocuous virus loaded with some extra DNA from the target pathogen to trigger an immune response which will also be effective against the target pathogen alone.  This is rather like strategy 1 above but the innocuous virus is being engineered by genetic manipulation.  This is called a viral vector approach.  A common cold like virus is frequently used as the vector.  This technique was used to develop an Ebola vaccine.

Covid-19 was detected in Wuhan China in late 2019.  Chinese scientists were able to isolate and genetically sequence the causal virus.  This means they were able to produce an ordered list of all the approximately 30,000 base pairs (ladder steps) along the length of its DNA molecule, its genome.  On January 10, 2020 they posted this sequence on a preprint server making it available to the entire world.  Two relatively new pharmaceutical startups, Moderna (US) and BioNtech (Germany) were able to take this sequence and determine the subsequence of DNA base pairs which describe the protein which makes up the spikes on the outside of the virus.  They then determine what mRNA molecule would be produced by that DNA in order to instruct the creation, in a ribosome, of that protein.  Since mRNA molecules are relatively delicate and highly susceptible to attack, to get them into target cells within the patient, it was necessary that they be modified to conceal their identity from the immune system while leaving them capable of functioning properly when they reach a ribosome within a cell.  Much of this work was facilitated by technology licensed from the University of Pennsylvania, whose researchers have been active in this area for the past 10 to 20 years. BioNtech jointed with Pfizer (US) to mass produce and distribute its version of the vaccine.

These mRNA vaccines work as follows.  The camouflaged mRNA (describing only the protein in the virus’s spikes) is injected into the muscle of the patient’s arm.  When this mRNA encounters individual cells in the muscle, it passes through their cell membranes, and finds ribosomes within the cell. Only a relatively small fraction of the cells in the immediate area of the injection are so invaded.  The mRNA then instructs these ribosomes to create the protein found in the virus’s spikes.  The ribosomes, being equal opportunity protein factories, comply and produce the protein.  The protein is then released from the ribosomes and integrates into the structure of the patient’s cells, trying to produce virus like spikes on them.  When the patient’s immune system encounters cells with this abnormal protein, it identifies them as invaders and launches an immune response.  The immune response is targeted specifically at the foreign protein and ramps up until that protein has been destroyed.  The immune system is left with a heightened sensitivity to the presence of the abnormal protein, a supply of already produced antibodies capable of destroying it, and the capacity to immediately produce many more such antibodies.  If actual viruses with that protein in their spikes appear, they can be very rapidly destroyed, preventing their exponential growth to any significant level.

The actual development of the mRNA vaccine only took a couple of months but the many levels of testing to verify that it was both effective against the virus and that it was not harmful to humans took the better part of a year.  The vaccine could be produced based on the published DNA sequencing, but efficacy and safety could only be proven by trials in an environment in which the virus was actually active. 

A test which says that a vaccine is 95% effective is one in which you start with two equal groups of people. One is injected with the vaccine, the other with a placebo.  They are subjected to the same risk of infection until the placebo group develops 100 cases of Covid-19 while the vaccinated group develops only 5 cases. The assumption is that the other 95 cases which did not occur in the vaccinated group were prevented by the vaccine, therefore it is 95% effective.  Statistically, one would like to have larger numbers, perhaps 1000 cases in the placebo group and 50 in the vaccinated group, so that one can put small error bars on the 95% effectiveness number.

Other Covid-19 vaccines now in common use are:

            Johnson & Johnson – US – Viral vector vaccine

            AstraZeneca – UK – Viral vector vaccine

Sputnik V – Russia – Viral vector vaccine

CoronaVac – China – Dead virus vaccine

As someone with significant scientific experience, thought admittedly not in virology, I would make the following observations comparing mRNA vaccines (like Pfizer and Moderna) to these other vaccines.  The other vaccines involve injecting other complete foreign organisms into the patient’s body.  To the extent that these organisms are not as dead, or as attenuated, or as innocuous as intended, they represent a risk in themselves.  Reliable procedures and quality controls should guarantee their safety, but in this regard the mRNA vaccines are more inherently safe.  In the vector-based vaccines, the presence of the vector, with its substantial range of additional alien proteins, there is the possibility of distracting and defusing the patient’s immune response. In the mRNA vaccine, the only alien protein presented to the immune system is that of the target pathogen. However, the dead and attenuated virus vaccines do have some advantages.  In the case of both the mRNA and viral vector vaccines, the immune response is directed at one particular protein from the pathogen rather than at the pathogen in general with all of its other alien proteins.  If the pathogen happens to undergo a variation in the single target protein, the effectiveness of the vaccine may then fail for that variant and one could be back to zero.   While for a dead or attenuated pathogen vaccine, the immune system would be familiar with, and prepared to deal with, other proteins within the pathogen, thereby retaining much of its efficacy despite a variation in any single protein.