Understanding COVID Vaccines
This grew out of a facebook reply where someone asked for information about the vaccine. It is long, but they seemed to like it. I hope it is as useful to you as several people there told me it was for them.
I get why this vaccine is a little bit spooky. Even as a well educated technical person, when I first learned about the technology being used last year, it gave me pause. I read a lot about mRNA in general and realized something that put my mind at ease. Maybe it will do the same for you, maybe not. Not knowing your background, here is a little general background on cell biology to help you understand what comes next.
Cell Biology Basics
Your cells keep their DNA in a semipermeable sack in the center of the cell called the nucleus. That DNA contains instructions for all the proteins that your body manufactures*. The DNA is in the nucleus to be protected from damage from all the chemical activity in the rest of the cell. Inside the nucleus, the DNA instructions are transcribed into mRNA copies which can migrate out of the nucleus, attach themselves to protein assembly factories (ribosomes) inside your cells which then produce whatever protein the mRNA instructions direct it to make. These factories are what a virus invader takes over to make copies of itself.
mRNA is not super stable and degrades over a few days, so your cells are constantly replacing it. This has a benefit. It helps cells respond to different conditions. Like if you need to amp up production of some particular protein, or stop making as much of one say, after some healing process completes, the earlier protein manufacturing instructions plans become less common after some time.
mRNA Vaccine Tech Development: a 30 year story
mRNA as a therapeutic to get cells to produce something useful (for instance, a pituitary hormone in a test rat that does not make enough) has been around as an idea since the 90’s and was tested in animals that early. The idea of rapid response vaccines based on them started to percolate in the 2000s. The biggest hurdle has been delivery, because mRNA is pretty fragile outside of cells (and only lasts a few days inside unless it is replaced).
The lipid droplet delivery system was developed in the past 10 years and turned out to be pretty effective. mRNA vaccines for Zika, Ebola and rabies were being tested in animals by the middle of last decade, maybe earlier.
One idea has been to use mRNA vaccines as custom treatments for cancers, coding for protein antigens unique to each patient’s specific malignancy. This could train the body’s own immune system to take out cells making those proteins. There have been numerous clinical trials for this in humans. These approvals were probably compassionate/experimental type things for patients with few other options. This is a key part of the story, because the process of customizing for individuals’ cancer means the infrastructure/know how to quickly customize the mRNA to code for a specific protein and get it into a delivery system, already existed by the time the pandemic started.
The mRNA COVID Vaccines
The idea of the COVID vaccines is to send cells mRNA, that, instead of coding for a body protein or a malignant cell protein, codes for a protein that makes up part of the SARS-CoV-2 virus. The chosen targets are proteins that make up its spikes. When this spike protein-coding mRNA gets taken into your cells, those cells start making copies of spike proteins (mostly only near the injection site). When those proteins start coming out of your cells, your immune system says “Hey, WTF is THAT??” and starts producing antibodies to stick to them and does some other things that prepares it to disable and destroy viruses with those or similar proteins. Your immune system is now trained to see those proteins and has a solution all ready to go to eliminate them when the real thing shows up. Without that practice training from being vaccinated it takes a few to several days for your immune systems to learn to recognize the virus as an invader. During that time, the virus has free reign to reproduce over and over again. With the know-how to make custom mRNA for cancer vaccines already in hand it was quick work to cook up something that would make custom mRNA that codes for a protein unique to this virus.
It is a little spooky to think about some of your cells in the area of the intramuscular injection having their protein factories redirected to produce viral proteins. (I point out the intramuscular injection because it turns out any mRNA-lipid droplet vaccine that makes it into your blood quickly finds its way into your liver where it is completely broken down in about 12 hours). What makes redirecting some of my cells’ protein less spooky for me is knowing this is what viruses do already, except they make our cells produce the full set of proteins to make an entire virus particle.
A virus is made of lots of different proteins and genetic material. Sometimes viral genes are DNA encoded. For this one it is RNA. When a virion (virus particle) attaches to a cell it injects a complete list of RNA protein making instructions so the infected cell starts making complete virus particles. The cell starts making ALL the proteins that make up the virus and others that duplicate the viral RNA, and other helper proteins.
One helper protein is really nasty. The virus has instructions to make a protein that tricks the cell into chopping up any mRNA that does not have a special “for making COVID virus proteins” tag on it. It also shuts the door to the cell’s protein factories once it gets a viral protein plan in side. these two functions shuts down the infected cell’s natural protein production so it focuses nearly entirely on viral proteins. This protein is NOT coded for in the vaccine.
Each infected cell ends up making many copies of the virions, which then start coming out of the cell and floating around in your body looking for new cells to infect. The cycle time for the SARS-CoV-2 virus is something like 6 hours and by the time it has run its course in a single cell in about 2 days, each infected cell produces hundreds of thousands to a million virions!
The mRNA in the vaccine is a short segment of genetic code and can only make a few proteins associated with the spike protein part of the virus. There is no coding in the vaccine for proteins to make more copies of the RNA, no coding for the proteins that make up the bulk of the virus shell (capsid). This means cells that take in the mRNA vaccine cannot make a complete virus. Those instructions were not included. It is like sending a mechanical drawing of a wheel to a factory . That factory will never produce an entire car from that drawing, and it won’t know how to produce new plans for whole cars to send to other factories. The virus is a like a whole car with all the mechanical drawings and assembly instructions in the glove compartment, and instructions on how to make copies of the instructions for new cars. The vaccine does not have the complete set of instructions, or even anywhere close to it. The full virus genome for this virus has about 30,000 bases ( individual letters in the instructions) . The mRNA in the vaccine contains a subset of the 3831 bases that code for the spike protein: not enough to make a whole car!
The mRNA in the vaccine tricks cells into making spike protein for a while, then the mRNA breaks down and spike protein production stops. The spike proteins migrate out of your cells at some level and that is what teaches your immune system how to fight off the virus. This is also why mutations to the spike protein code in a virus can result in antibody evasion. Because the protein is different antibodies your immune system is making for an older version of the protein won’t attach to the mutated spike protein as well. (The immune systems has many layers to it though that I don’t understand. Part of it is adaptive and can recognize variations of the original protein. )
Allergies
The delivery system for the mRNA is lipid droplets and some polyethylene glycol to keep the lipid droplets stable. Polyethylene glycol is in many things we use from toothpaste to sunscreen to shampoo. Most people have no sensitivity to it, but some do. This is why there is a rare allergic reaction for some people when the vaccine is injected into their bodies and why you have to wait around for 15 minutes to see if you have a bad reaction.
How they did it so fast!
The idea behind these vaccines has been around for a long time, and vaccines with the same approach have been tested in animals and even humans for some years. When this crisis came around it was pretty quick work to make the needed mRNA coding changes. Then it was a matter of scaling up production some to have enough for saferty and then large scale efficacy trials in people. Some tens of thousands of folks in the effectiveness trials were injected with the Pfizer-BioNTech vaccine back in June 2020!
Another thing that sped up getting this to the public is the government removed a lot of capital investment risk. Many of these vaccines began the process of production scaling even before efficacy trials were complete and it was known if they worked. Companies would not generally take that risk and that would take place AFTER the test results but with the US Govt footing the bill, they did it in parallel. That is why it was so fast.
References
https://www.nature.com/articles/d41586-021-02039-y How the virus enters a cell and replicates
https://www.nature.com/articles/nrd.2017.243 (Here is a review article from 2018 about the promise of mRNA vaccines. The authors never would have guessed how soon they would be mass produced….)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539923/ (genetics of COVID-19)
https://stanmed.stanford.edu/2020issue2/how-coronavirus-destroys-cells-treatments.html Good laypersons overview of how viruses replicate)
https://www.nature.com/articles/s41579-020-00468-6 (Coronavirus replication)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685332/ (The total number and mass of SARS-CoV-2 virions)
The whole mRNA thing can be a little scary, and months before the trials finished, my brother and I were both a little anxious about that approach. As I learned more about the nuts and bolts biology, my concerns eased.
