mRNA Vaccines

To understand how mRNA vaccines work, we must first have a basic understanding of cells and genetics.  Zzzzzzz.  Wait!  Before you go to sleep, we’re going to make this really short and really simple.  Cells are bags of jelly—jellybeans, so to speak—and in those jellybeans is a kernel called a nucleus.  DNA lives in the nucleus, and like the cell’s hard drive, DNA stores and preserves the cell’s genetic code.  Genetic code is a series of nitrogen bases strung together to form nucleic acid.  There are only four possible bases, so just like computer code is a series of 1’s and 0’s, genetic code is a series of A’s, T’s, G’s, and C’s, each letter standing for a different nitrogen base.  DNA is arranged in two complimentary stands—the famous double helix of Watson and Crick—to create code redundancy like mirrored hard drives that protect your data in case of a crash.

When the genetic code needs to be accessed, a specific portion of the DNA untwists, exposing a segment of code which is copied onto a new strand of messenger RNA (mRNA).  Unlike DNA, RNA is only a single strand of nucleic acid and much less stable.  The mRNA floats into the cell jelly, the cytoplasm, where ribosomes attach and move along the strand, coupling together amino acids as they go.  Every sequence of three bases on the mRNA, known as a codon, codes for a specific amino acid.  For example, GCA codes for alanine, CAA codes for glutamine, and so on.  There are 20 different amino acids, each with its own codon or codons (some have more than one).   Put together according to the sequence of bases on the mRNA, the amino acid chains become a protein.  Out of the trillions of possible amino acid combinations, the proteins formed by your genetic code define the shape of your nose, the length of your bones, the complexion of your skin and everything else that makes you you.  Once the right number of proteins have been made, the mRNA disintegrates into the cytoplasm of the cell.  The process starts again in the nucleus, and a new protein is created as called for by the cell.

What if mRNA could be injected directly into cytoplasm without first being created in the nucleus?  Then the cell’s machinery could create a protein that wasn’t part of the cell’s genetic code.  That’s exactly the hypothesis behind mRNA vaccines.  After the vaccine delivers mRNA into the cytoplasm of muscle cells in the arm, those cells begin forming the protein coded by the mRNA in the vaccine—in the case of COVID vaccines, one of the spike proteins known to exist on the SARS-CoV-2 viral capsule—and those proteins make their way to the surface of the cell where the immune system forms antibodies which are memorized by the body for future use.  How cool is that!

Various companies have been working on mRNA vaccines for over a decade, but none made it to production until the pandemic demanded rapid vaccine development.  Although never been used on a large scale before, mRNA vaccine technology is appealing for several reasons:

1. Molecular sequencing systems makes creation of mRNA almost as easy as writing a computer script.  
2. Once sequenced, mRNA can be mass produced easily and cheaply.  
3. There is no danger from viable pathogens in the vaccine production.  
4. There are no infectious agents or toxins injected into the vaccine recipient.  
5. Once the delivery system is perfected, vaccinations for many different pathogens can be created by simply altering the mRNA sequence, making it possible for vaccines to respond quickly to emerging viral variants. 

Before we anoint mRNA vaccines as our pandemic savior, we should first listen to voices urging caution about this new technology.  For example, in a recent New England Journal of Medicine publication, Dr. Mariana Castells and Dr. Elizabeth Phillips note that the incidence of anaphylaxis, a serious, sometimes fatal allergic reaction, associated with the Pfizer SARS-CoV-2 mRNA vaccine is “10 times as high as the incidence reported with all previous vaccines, at approximately 1 in 100,000, as compared 1 in 1,000,000.”  Why?  And moreover, what are our expectations of vaccination?  Do vaccines prevent COVID or simply reduce COVID complications?  How long will immunity last?  Who should NOT get the vaccine?  Answers to these and other questions are not readily apparent, not because of a failure of diligence, but because there has simply not been enough time to collect, compile and analyze the data that will eventually yield answers. 

The Center for Evidence Based Practice at the University of Pennsylvania recently published a review of the adverse effects of mRNA vaccines.  Among their findings are the following:

1. There are no specific guidelines for use of messenger RNA (mRNA) vaccines or contraindications to mRNA vaccines. 
2. No large trials of any mRNA vaccine have been completed yet. 
3. The only evidence on safety of mRNA vaccines comes from small phase I and phase II trials of SARS-CoV-2 vaccines, with follow-up typically less than two months. 
4. Systemic adverse events such as fatigue, muscle aches, headache, and chills are common 
5. The rate and severity of adverse events appears to be higher for the second dose of vaccine than for the first. 
6. Higher vaccine doses appear to increase the rate and severity of adverse events.
7. Larger trials of SARS-CoV-2 vaccines are in progress, with results expected in mid-2021.
8. There is not sufficient evidence to support any conclusions on the comparative safety of different mRNA vaccines. 
9. Direct evidence on the comparative safety of mRNA vaccines and other vaccines is lacking. 

Clearly, mRNA vaccines offer an attractive, promising alternative to other vaccine technology, especially when a new vaccine is needed quickly.  However, it is a new technology associated with risks of the unknown.  Many unanswered questions remain, demanding a sober examination of the evidence for and against vaccine safety.  Since the risk-to-benefit ratio from taking a COVID vaccine varies individually, I urge individual decisions, not collective ones. The Infectious Diseases Society of America recently published a comprehensive FAQ on vaccine safety which you may find to be a valuable great resource for making an individual decision.  

Although paved with good intentions, the early path of new technologies is frequently littered with unintended consequences.  Next time, I will tell a story of good intentions that ended tragically for many.