mRNA Vaccines – New Technique, Same Immune Response

Recently there has been a lot of attention on two of the newest immunizations developed to aid in the fight against COVID-19, the illness caused by the coronavirus (also known as SARS-CoV-2). These vaccines employ a relatively new technique of using messenger ribonucleic acid, or mRNA, to help our immune system create immunity against SARS-CoV-2. 

To better understand this type of immunization, let’s take a look at the cellular biology behind it, and see how it works to give you an immune response against SARS-CoV-2. These explanations rely on some fairly advanced cellular biology concepts, but we’ll try to keep it as straightforward as possible. For an even more detailed look at this topic, check out Edward Nirenberg’s excellent discussion of this topic, which we’ve linked in the footnotes at the end of the article.(1) 

What is mRNA?

mRNA is a type of RNA that contains instructions from the DNA in your genome.(2) DNA lives in the nucleus of a cell, and RNA is created by cellular machinery that reads the DNA, turns it into RNA and ships it outside of the nucleus into the cell’s workshop, a compartment called the cytosol.

Once it’s on the cell’s workbench, the other molecular machines read the RNA and turn it into a protein. After the protein is created the mRNA is degraded and digested by a clean-up crew of enzymes, so its components can be recycled. 

So, the basic flow of genetic information inside your cells looks like this:

DNA → RNA → Protein

This is the core concept for all of cellular biology.

How does SARS-CoV-2 infect cells?

Like most viruses,  SARS-CoV-2  attaches to the outside of a cell using a structure called a spike protein. The spike protein attaches to a receptor, allowing it to grab onto the outside of a cell, and then injects viral RNA instructions inside. Your cells follow the instructions in the viral RNA to make viral proteins, which then combine to create more viruses, which attach to new cells. SARS-CoV-2 is made of 29 proteins, and the virus cleverly uses our own cellular machinery to make more copies of these proteins. Your immune system eventually catches on and makes antibodies that attack the virus, but this process takes time and while the immune system is gearing up, the virus is replicating unchecked and you end up with the illness known as COVID-19.

How does the COVID-19 mRNA vaccine work?

The vaccines made by both Moderna and Pfizer use this mRNA technique. Messenger RNA (mRNA) contains instructions for the machinery inside your cells to create protein. What if we could give the cell some sets of instructions that made just one part of the virus, to help the immune system get a head start on creating protective antibodies? That’s how mRNA vaccines work! 

In the vaccine there are mRNA instructions for that spike protein we discussed earlier, which gives your cells directions for how to make the exact same spike protein the SARS-CoV-2 uses to attach to cells. Your body recognizes the spike protein as foreign and begins to make antibodies for it. If you make antibodies against the spike protein, they block the spikes and make it so the virus has a hard time infecting you. And it does it in the exact same way the virus would, if you were infected.

There’s no way for vaccine mRNA to be integrated into DNA. In fact, humans don’t actively make the machinery (an enzyme called reverse transcriptase) to do it. Even if the mRNA could somehow get into the nucleus — which it doesn’t — and be turned back into DNA — which it can’t —  it wouldn’t just be integrated into the genome.

Let’s look at this process in a little more detail:

mRNA is a really fragile molecule. This makes sense – the cell only needs these instructions for a brief period of time before they’re taken apart and recycled. That’s why both of the mRNA vaccines need to be kept cold until right before being administered. One of the mRNA vaccines needs to be kept very cold: -80 degrees C. This keeps the mRNA stable until the immunization can be administered. 

Another thing to be aware of is that our cellular machines are pretty picky when it comes to mRNA. They have quality-control procedures to make sure that mistakes in the translation from DNA to mRNA are caught. This quality control ensures that the message stays the same and you are not playing the molecular biology equivalent of the “Telephone” game every time a protein is made.

So how do we get a fragile set of mRNA instructions into a cell where it can make a protein? By using lipids (fats). The mRNA molecules are placed inside a cholesterol envelope that the cells are able to absorb. This happens locally, right where the injection is placed; the mRNA isn’t circulating throughout the body.

Once inside, the mRNA molecules interact with the cellular machinery and make some spike proteins, after which the mRNA is destroyed by the cell’s cleanup crew. Your immune system detects the foreign spike protein and does what it does best – activates and begins to make antibodies. But instead of millions of cells getting infected with SARS-CoV-2 and making all 29 viral proteins, a relatively small number of cells near the injection site make just one protein, which means a lot less overall immune stimulation.

Remember, mRNA is in the working area of the cell called the cytosol, and never goes into the nucleus where the DNA is stored. There’s no way for vaccine mRNA to be integrated into DNA. In fact, humans don’t actively make the machinery (an enzyme called reverse transcriptase) to do it. Even if the mRNA could somehow get into the nucleus — which it doesn’t — and be turned back into DNA — which it can’t —  it wouldn’t just be integrated into the genome. We would not have lasted very long as an organism if our genome just took up random new genes every time we came in contact with a virus. We have surveillance mechanisms, kind of like a spell-checker program, that monitor for mistakes and remove them.

One good way to imagine an mRNA vaccine is to think of a fortune cookie:

1. The cookie is brought to your table (immunization placed). 
2. The slip of paper (mRNA) is inside the cookie (a lipid layer to protect it). 
3. You open the cookie (mRNA goes into a cell) and read the fortune. The letters spell out a message (a protein is made from mRNA instructions). 
4. The message (spike protein) tells you some useful information (your immune system is able to make antibodies to the spike protein and train itself to defend against the SARS-CoV-2 virus.) 
5. After you’ve read the message you throw it away (mRNA is quickly degraded via enzymes within the cell). 
6. You don’t eat the paper (mRNA does not integrate into the genome). 
7. If you opened the cookie and the message you read was nonsense, you’d just ignore it (mRNA is subject to quality control mechanisms in the cell – garbage RNA is not translated and gets marked for rapid destruction).

So while using mRNA in vaccines is a new technique, it is effectively doing the same thing that all other immunizations do: using a tiny dose of a naturally-occurring foreign protein or sugar (called an antigen) to teach your body how to fight an illness using the strength of your natural immune system. 

Because the mRNA is a set of instructions to build the antigen, we can rely on our bodies to produce this protein rather than waiting for the antigen to be produced by the virus in a lab. This means we can make more of the vaccine, easier, faster, and safer because all that needs to be in the immunization is mRNA instructions (there are no preservatives in the mRNA vaccines).

Those are the basics of mRNA and how it is used in vaccines. NDs For Vaccines will have more articles on the COVID-19 immunizations soon as more information becomes available. Next we’ll dive into what is known about the benefits and risks of the COVID-19 vaccines, so check back soon.

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Footnotes and Resources

1. https://www.deplatformdisease.com/blog/mrna-vaccines-and-covid-19 
2. https://www.genome.gov/genetics-glossary/RNA-Ribonucleic-Acid

Images:

1. Animal cell image by Kelvinsong – Own work, CC0, https://commons.wikimedia.org/w/index.php?curid=22952603
2. Coronavirus image By CDC/ Alissa Eckert, MS; Dan Higgins, MAM – https://phil.cdc.gov/Details.aspx?pid=23312 This media comes from the Centers for Disease Control and Prevention’s Public Health Image Library (PHIL), with identification number #23312.