How do Moderna and Pfizer's mRNA vaccine work?

This post had strong contributions from Lawrence Chiou, a graduate student in Biophysics at Stanford.

• Both the Moderna and Pfizer Covid vaccines are mRNA-based vaccines

• mRNA vaccines let your body produce viral proteins (but not the viruses themselves) that teach your immune system to recognize the same proteins in real viruses.

• Experts are excited: mRNA vaccines are potentially safer and easier to produce than traditional ones

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Usually, you develop immunity when your immune system learns to recognize a virus. This can happen if you get infected (like catching a cold). Or, in the case of traditional vaccines, it’s by introducing a sufficiently “weakened virus” into your body. Your body still learns to identify the virus and can develop immunity, without undergoing the strain of an infection.

The challenge with conventional viral vaccines is that it’s hard to find the right process to "cook" the virus so that it's no longer dangerous but not mangled beyond recognition. And in some cases, it’s difficult to find the balance between creating a robust immune response and creating an infection. “Live attenuated” vaccines (like for measles) use a live but weakened virus to work. But if someone (like a leukemia patient) is immunocompromised, they might not even be able to handle that.

This is where mRNA vaccines can shine. If you remember from biology class, messenger RNA (mRNA) shows up when your cells read their DNA to produce proteins.  In that process, the DNA gets “unzipped”, and a long RNA “copy” of the protein’s blueprint is produced. In mRNA vaccines, you’re injected with a lot of mRNA that codes for a specific viral protein (in Covid’s case, the Spike protein).  Your body produces these proteins without making the full virus. Your immune system still learns to recognize the same viral proteins that it would encounter during an infection, without an infection. 

Compared to conventional vaccine development, mRNA has the potential to become a more reproducible way of doing things because mRNA is basically a program with well-defined rules. If a different virus comes along we can just re-jigger it. There'll still be unique challenges to tackle with each virus (like you might need a larger capsule for longer mRNA), but mRNA vaccine is a platform that's more adaptable to solve different viral "problems", whereas conventional vaccine research is closer to "guess and check".

For example, with SARS-CoV-2, Chinese scientists uploaded the complete genetic sequence to the internet back in January. With that information, it was possible for Moderna and others to start work right away. They didn't have to wait for people to collect frozen samples of virus and ship them to the U.S., grow it in a lab, and only then start to experiment.

One downside of mRNA vaccines is stability: mRNA degrades quickly if not kept at low temperatures. A lot of vaccine engineers’ work was probably focused on figuring out where a given RNA molecule was most vulnerable, and which lipids you should wrap the mRNA in to prevent breakdown. Otherwise the mRNA vaccines would have to be shipped and stored under extreme refrigeration. As it is, Moderna’s mRNA vaccine needs to be stored at -20 degrees celsius, which is feasible for medical centers. (In comparison, Pfizer’s needed to be stored at -70 degrees celsius. For reference, the flu vaccine is to be stored between 2 and 8 degrees celsius).

The thing that makes mRNA much safer than "gene therapy" is again, that mRNA is rapidly degraded. There are no permanent, unintended changes to the host cell’s genome. One concern was that the lipid particles used to deliver the mRNA could cause an adverse immune reaction, but no severe reactions were noted in the ongoing Phase 3 trial. 

For additional reading, you can check out:

https://www.nature.com/articles/s41541-020-0159-8

https://massivesci.com/articles/mrna-vaccine-covid19-coronavirus-moderna/

https://www.kaggle.com/c/stanford-covid-vaccine

https://www.the-scientist.com/news-opinion/scientists-scan-for-weaknesses-in-the-sars-cov-2-spike-protein-67404

https://www.hindawi.com/journals/jir/2020/7201752/

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