There seems to be a lot of confusion about how the new COVID-19 mRNA vaccines from Pfizer and Moderna. The purpose of this article is to give the casual reader a 15 minute (plus or minus an hour) scientific review of the mRNA technology that is the basis of those new vaccines.
There will be several new COVID-19 vaccines that should be available widely in the next few weeks, but none of those will use mRNA vaccine technology. When those become available, I’ll try to write up a similar review of those technologies.
Let’s give this a go.
What are the COVID-19 mRNA vaccines?
The Pfizer and Moderna Therapeutics COVID-19 vaccines are mRNA vaccines that rely upon an mRNA, or messenger RNA, molecule to induce an immune response. So these vaccines are different than traditional ones that deliver an antigen to induce an adaptive immune response – instead, the mRNA vaccines cause cells within the body to temporarily produce the antigen which then causes the immune response.
So, let’s take some time to explain how mRNA works within cells.
In other words, the mRNA sequence usually corresponds directly to the DNA sequence for one gene. These mRNA sequences “carry” that genetic message from the nucleus to a ribosome for translation, where tRNA triplets, which code for one amino acid, attach to the appropriate mRNA triplet, adding one amino acid to a protein chain.
As in DNA, genetic information in mRNA is contained in the sequence of nucleotides, which are arranged into codons consisting of three ribonucleotides each. Each codon codes for a specific amino acid, except the stop codons, which terminate protein synthesis.
Note that the mRNA does nothing to the DNA strand in your genes – it merely reads the sequence for one gene.
Yes, that’s a lot of cell biology, though I took years of courses in cell biology, so trust me when I say I barely touched the surface of this whole process. If you want to take a deep dive into the science of mRNA and mRNA vaccines, my friend Edward Nirenberg wrote two articles that will satisfy your desires – they really make it clear how this all works and doesn’t work.
When an mRNA strand exits the nucleus and enters the cytoplasm, it attaches to ribosomes, and this is where protein synthesis progresses. The ribosome reads the base sequence of the mRNA, three bases at a time. Each three-base triplet, called a codon, specifies a particular amino acid, except for a few with regulatory functions (e.g., UGA =“Stop!”).
If the first three-base codon is AUG, then a molecule of the amino acid methionine is brought into place. If the next triplet is AAA, that brings in the amino acid lysine. The methionine and lysine molecules are attached together. The next triplet is, say, GCC, and that brings in alanine, which is attached to the lysine. The ribosome has read nine bases, AUGAAAGCC, and compiled a short chain of three amino acids, abbreviated Met-Lys-Ala, or MKA (see amino acid abbreviations here).
The ribosome continues reading all of the mRNA bases until it hits a stop signal—which is also a triplet codon such as UGA—and the now long chain of amino acids falls loose. This chain may be a functional protein immediately, or, more usually, it might undergo some additional post-translational processing by enzymes to become active.
Once the mRNA has created a protein, it is then ripped apart by enzymes in the cell, so that the individual RNA nucleotides can go back to being reused in a whole new mRNA sequence. The cellular machinery of translating DNA into proteins is constantly recirculating itself.
The mRNA vaccine technology relies upon a specific mRNA sequence to kickstart the endogenous production of proteins that are structurally equivalent to the viral antigens. The mRNA sequences in the vaccine enter the cell (with a carrier protein), heads to the ribosomes to create the SARS-CoV-2 antigens. These antigens will depart the cell and will trigger the body’s adaptive immune system to produce antibodies effective against the actual target, in this case, the S-protein or spike on the SARS-CoV-2 virus.
These COVID-19 mRNA vaccines induce the production of anti-SARS-CoV-2 virus-neutralizing antibodies, which provide short-term protection by binding to the spike proteins, preventing them from entering our cells. It also induces memory B and memory T cells which provide long-term immune responses to COVID-19.
One more thing – the antigens produced by these mRNA sequences are biologically inert. They will induce an immune response, but they will not cause any other biological effect including becoming pathogenic.
So, let’s summarize. The mRNA vaccines make use of the cell’s ribosome to create the S-protein of the SARS-CoV-2 virus. That antigen induces short- and long-term immune system responses that will attack the virus plus “remember” that antigen allowing the immune system to quickly attack the virus if it shows up again in the future.
Someone used this analogy to describe how mRNA works. Let’s say you have a book that represents the genetic code (lots of people describe our genetic code as the official manual of our individual person). You then scan that book in a copy machine, and now you have a bunch of papers that are an image of the original book. The copy does not change the original book. It can’t.
The mRNA in these COVID-19 vaccines cannot be injected directly into the body. Those mRNA molecules would be broken down quickly and could not enter the cells to produce the S-protein antigen. So, the mRNA fragments are encapsulated within lipid nanoparticles.
Lipid nanoparticles are small spherical particles harboring a diameter ranging from 1-100 nm made of lipids. For those not familiar with cell biology, our cells (and any living cells, from an Archaea to a human cell) are separated from the outside by the presence of a cell membrane made of two layers of phospholipids.
These phospholipids harbor overall the same structure (see below) – two chains of fatty acids (made of carbon and hydrogen atoms) “tails” that look like a hairpin, and a hydrophilic “head” that is made of a polar molecule (glycerol, ceramide, and other similar molecules). This is what a regular phospholipid in your cell membrane looks like:
If you have been preparing salad dressing with vegetable oil and vinegar, you likely notice that the oil droplet would aggregate together into one big slick, whereas you will notice a clear interface between the vinegar and the oil slick. This is because the lipids present in the vegetable oil will align their hydrophobic tails inside the droplet and expose their hydrophilic head outside to interact with the water molecules of the vinegar.
This is what we call “micelles”. If you work hard enough, you can create structures called “liposomes” that are able to capture water and solutes within the oil slick, separating from the rest of the water of the vinegar by having a lipid layer.
These structures look very similar to what we would see with cell membranes: a sack of water trapped inside a grease globule. Because of the lipophilic nature of the cell membrane, if you have a small molecule that is also lipophilic, it can easily cross the membrane and enter the cell very easily.
In case you’re interested, the Moderna vaccine, these lipids that are included in the vaccine are – (SM-102, 1,2-dimyristoyl-rac-glycero3-methoxypolyethylene glycol-2000 [PEG2000-DMG], cholesterol, and 1,2-distearoyl-snglycero-3-phosphocholine [DSPC]).
For the Pfizer vaccine, these lipids are – (4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide, 1,2-distearoyl-snglycero-3-phosphocholine, and cholesterol.
Yes, these sound like “chemicals,” let’s be clear that all lipids in all organisms are “chemicals.” As an example, here is the name for simple cholesterol circulating in your blood – (3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol. It sounds complicated, but any organic chemist could draw the structure from that formula.
I know that these vaccines rely on a complex technology that is substantially different than what is used in nearly every vaccine that came before this pandemic. I know that it’s scary to hear about new technology, especially when it feels like you need a Ph.D. to comprehend how they work. That’s the purpose of this article – it gives links to information that should help you understand how these COVID-19 mRNA vaccines work.
There are advantages to this technology that may become more apparent in the upcoming months:
- Once the virus is sequenced, as the SARS-CoV-2 virus was in February 2020, it is much easier to isolate the DNA or RNA sequence that codes for the most antigenic parts of the virus, in this case, the S-protein. With that information, it’s easy to develop the mRNA sequence and put it into a vaccine. That’s why Moderna and Pfizer were available first.
- If the virus mutates to a form that makes the vaccine less effective, it’s much easier to produce a new vaccine that has mRNA that codes for the new mutated antigens. Older technology vaccines would require a much more laborious process to produce a new vaccine, much like we do with the seasonal flu.
- It’s much easier to produce vaccines that induce an immune response against the viral antigens.
In February and March 2021, we should have three new vaccines to discuss, but for the time being, at least in the USA, the COVID-19 mRNA vaccines are our only choices. The vaccines are very safe and very effective (at least in the short-term), so they are also excellent choices for vaccination against COVID-19.