What are mRNA vaccines?
Building intuition about this new technology.
It’s 2021, and after hundreds of years of mostly the same old vaccines (some archeological evidence suggests that the first inoculations were developed in ancient China or India) we’ve seen a fundamental shift in vaccine technology. It’s matched by a recent explosive growth in our knowledge of biology. Since the discovery of the structure of DNA in 1953, we’ve rapidly acquired new knowledge about the inner workings of cells. This new knowledge has driven progress in many areas of medicine, including vaccines.
What is mRNA?
RNA is “ribonucleic acid”, it’s one of the main ways that genetic information is encoded, with DNA (deoxyribonucleic acid) being the other. mRNA stands for “messenger RNA”. But in order to unpack that, we’ve gotta talk about what RNA is, why this RNA is called a “messenger”, and look at DNA transcription within the cell.
A brief refresher
Luckily, we don’t need much beyond high school biology to gain an intuitive understanding of how mRNA vaccine technology works. Let’s start with the “central dogma of molecular biology” which states that:
DNA makes RNA and RNA makes proteins.
This tells us that genetic information flows from DNA to RNA and then into proteins. Proteins drive essential operations in the cells, like repairing damaged DNA, orchestrating cell death, and transporting molecules across the cell membrane. Generally, they carry out all of the processes of life.
Transcription and translation
Transcription describes the process by which DNA is copied into mRNA. During transcription, DNA unravels at the location it is going to be read from, and then the RNA polymerase enzyme handles reading the DNA and transcribing it into RNA. This RNA strand, called the primary transcript, carries the same information as the strand of DNA it was copied from. In human and animal cells and in other eukaryotes, the primary transcript has to undergo some processing before it is ready to be translated. During this processing step, special caps are added to the ends of the RNA and sometimes pieces of it may be spliced out.
Translation is the method of going from mRNA to building a protein. Once the processing step has been completed, a messenger RNA (mRNA) molecule is ready to be used for building the protein it encodes for.
Interpreting the genetic code
When translation happens, the sequence of bases (called nucleotides) in the mRNA (U, A, G, G, C, U, etc.), gets converted into an amino acid chain called a polypeptide. A polypeptide is effectively an unfinished protein. The nucleotides in the mRNA are read in groups of three (triplets). These triplets are called codons.
Translation happens in powerful molecular machines called ribosomes, which are responsible for building polypeptides. Once a ribosome has grabbed an mRNA strand and read a “start” codon, it continues down the mRNA, reading it in triplets, until it finds the “stop” codon. As it goes along, it builds up a polypeptide chain.
However, the ribosome can’t match amino acids to their corresponding codons by itself. For this, it relies on transfer RNA (tRNA). tRNA floats around the cell, holding an amino acid on one end with the matching nucleotides for that amino acid on the other end.
When a tRNA exactly matches the codon currently being read, it binds onto that codon and delivers the amino acid to the ribosome. The amino acid is then added onto the polypeptide chain. Translation is over when the ribosome reaches a stop codon and it releases the chain.
The polypeptide chain then folds up into a protein, and voila! We’ve gone from DNA to RNA all the way to protein.
To summarize, mRNA had the essential role of transcribing the information about what protein to build and then translating it into amino acids. Without mRNA, the process would fail, and if something could manipulate the DNA or mRNA in a cell, then it could trick that cell into making proteins it’s not normally supposed to.
Viruses
One organism that excels at tricking cells into manufacturing proteins they’re not supposed to is a virus. In fact, infecting other cells and using their molecular machinery to generate copies of themselves is the only way viruses can reproduce. For this and other reasons, viruses aren't living things.
Virus anatomy
The anatomy of a virus changes depending on if it is a bacteriophage (a virus which infects bacteria) or an animal virus. Animal viruses are the relevant kind here, since they infect humans, so we will look at those.
The spikes refer to spike proteins, which enables the virus to latch on to animal cells. The envelope refers simply to the container which holds the capsid, if it has one, and the genetic material in the core. Not all viruses have capsids, but for those that do, it is a secondary protein shell which encloses the genetic material. The nucleic acid core can be DNA or RNA and is the genetic material that hijacks the machinery of the cell. The DNA/RNA the virus carries will be inserted into the host cell’s DNA so that when that cell reproduces, the viral genome is expressed.
Real quick, let’s run through how a virus gets inside our cells:
The spike proteins let it latch onto the surface of our cells.
The virus inserts its nucleic acid package (DNA or RNA) into the cell.
This viral genetic material gets inserted into the cell’s DNA.
When the cell reproduces, the viral DNA is expressed and the cell begins making copies of the virus.
We’ve got a high-level overview of what viruses do, now let’s look at vaccines.
What are vaccines?
Vaccines are medications which serve to inoculate you against a particular infective disease. They are typically administered via injection and often, but not always, contain a weakened or killed disease-causing microorganism. Alternatively, the vaccine may contain a toxin or surface protein from the microorganism we are inoculating against.
How do vaccines work?
When a vaccine is administered, the microorganisms within it stimulate your immune system and cause it to start producing antibodies. Antibodies are identifier proteins used by your immune system to identify and neutralize bacteria and viruses. Antibody production is a normal part of what happens when you get sick. Once you’ve been fully vaccinated, your immune system has antibodies that it can use to quickly identify and destroy that particular disease the next time it enters your body. Vaccines let you develop immunity to a disease without actually getting sick!
Until recently, vaccines only ever contained deactivated or weakened microorganisms or their parts. The mRNA vaccines by Moderna and BioNTech/Pfizer are some of the first vaccines to ever contain something that is not an inert or weakened part of a microorganism.
How are mRNA vaccines different?
Where other vaccines carry an inert microorganism or a part of it, mRNA vaccines carry mRNA from the microorganism they are designed to vaccinate against. Much of the pioneering work in the science behind mRNA vaccines was done by Katalin Kariko. Specifically, these kinds of vaccines work against retroviruses, that is, the kind of viruses that carry mRNA as the genetic material which infects the host cell. The COVID-19 virus and HIV are both examples of retroviruses.
The COVID vaccines from Moderna and BioNTech/Pfizer both contain the mRNA code (in BioNTech's case, the code is modified) from the COVID-19 virus that encodes for the spike proteins on the outside of the virus. This mRNA then gets into our cells and gets expressed, thereby tricking our cells into using the protein production pipeline we outlined above to manufacture only the spike proteins, not the entire virus! Then, as the spike proteins are released into our bloodstream, our immune system responds and develops antibodies to identify and neutralize the proteins. Now, when our bodies come into contact with a full COVID virus, our immune systems can quickly and effectively mount a response and destroy the virus, even though it’s only seen the spike proteins! If you want to read more about the genetic content of the BioNTech virus, check out this excellent blog post.
mRNA vaccines are the future
These kinds of vaccines have incredible therapeutic potential, including the ability to vaccinate against some cancers. As the technology matures, production pipelines for these vaccines will get more and more streamlined, and engineers will work to solve many of the logistical challenges that currently exist around transporting and storing the Moderna and BioNTech/Pfizer vaccines. mRNA vaccines will enable us to respond even more rapidly to the next pandemic, since you can build the vaccine out of a piece of the virus’s own genetic material. All in all, I’m very excited about the potential for mRNA vaccine technology.
What are your thought on mRNA vaccines? Are you excited about them too, or perhaps nervous? Or did you notice something wrong in the article and you want to fact-check me? Whatever it is, please share your thoughts in the comments below.