A COVID-19 Vaccine Explainer
The fastest vaccine that was ever developed before covid19 took seven years. With covid19, we got to multiple 95% effective vaccines in under a year. How is that possible?
A new class of vaccines that’s based on mRNA. Covid19 is the very first time they will be tried in humans. This fact is, reasonably, freaking a lot of people out. Including me.
To wrap my head around the covid19 vaccine I needed to understand a few concepts:
How did vaccines work before, and what were the shortcomings?
What is an mRNA vaccine and what does it do differently?
From there we can discuss:
The implications of a successful mRNA vaccine
The unknowns and risks of the covid19 vaccines
How Vaccines Work
Your Immune System
Let’s start with how viruses replicate:
Viruses enter our cells using surface proteins (Spike proteins on CoVs) that grab onto our cells like a key entering a lock.
Virus DNA hijacks our cells to create full copies of themselves.
When you get sick and fight off a virus, you do so in two ways: adaptive immunity, and innate immunity.
Adaptive, or learned, immunity - Cells gobble up a virus floating in your blood, chew it up, and present the surface proteins, or antigens, to cells called B-cells. B-cells create antibodies that can “smother” the antigen proteins, making the virus unable to enter any more cells. The antibodies float around your body, and memory B-cells remember how to make those antibodies.
Innate immunity you are born with - Other immune cells, called Killer T-cells attack and destroy any cells that have been infected by a virus, by recognizing changes to the cell surface from the virus breaking out. Memory killer T-cells remember how to attack.
Image from: https://www.historyofvaccines.org/content/how-vaccines-work
The first thing to recognize here is that your body doesn’t respond to the virus per se, rather an antigen protein of the virus. Therefore, your body doesn’t need to be infected by a virus to learn to fight it off, it just has to learn the antigen to build up a response.
The second thing to understand is that antibodies and killer T-cells are great for fighting off an infection…while they stick around. But to become truly immune, you need the memory B cells and memory killer T-cells. Antibodies will fade over time. The memory cells allow you to make new antibodies quickly in the future.
There seems to be a correlation between how sick a virus makes you and the chance that your body will make memory cells. Perhaps this is a way of conserving energy. If a virus is easy enough to fight off that you don’t get very sick, maybe your body decides it’s not worth using up memory to create memory cells.
Vaccines
The goal of a vaccine is to teach your immune system to recognize a virus and learn to fight off that virus, without you having to get sick with the virus. Ideally, vaccines will get your body to make life-long immune memory cells of that response.
The challenge is finding safe ways to teach your immune system without getting you sick.
Vaccines to date have used different methods to present the antigen safely:
Weakened or hobbled versions of a virus (live attenuated viruses)
Dead version (inactivated)
Adding the DNA code for an antigen to a weak virus (subunit)
Live attenuated viruses are great because they tend to trigger the creation of memory cells, but they are not appropriate for people with compromised immune systems who cannot fight off even the weakened version. Inactivated vaccines are safer, but more difficult to make and don’t produce memory cells so you need periodic boosters. Almost all the vaccines you know of are one of these two.
Subunit vaccines is where all the research and promise is. They “infect” our cells with the instructions to make a single antigen protein (instead of a full virus). Our bodies learn to fight the antigen the same way we would learn to if it were attached to a complete virus, but there’s no actual virus involved.
With this feat we remove the risk of accidentally setting off a pandemic, or of hurting immunocompromised people, or of mutating the virus while manufacturing the vaccine. Subunit vaccines can also be way faster to make because you don’t have to grow a virus. Plus, we can potentially pack the ability to make a whole bunch of antigens into a single shot!
The challenge is that your body may not take the antigen-only seriously enough. If it doesn’t take it seriously, your body won’t generate memory cells and long-lasting immunity. Many subunit vaccines today just aren’t potent enough.
To date, subunit vaccines have been DNA based. A string of viral DNA (not the whole virus genome) is added to non-lethal virus. For example, the Oxford–AstraZeneca SARS-CoV-2 vaccine is made from adding SARS-CoV-2 antigen DNA to a virus that affects chimpanzees.
The chimpanzee virus delivers the SARS DNA instructions to the cell to produce the SARS-CoV-2 spike protein. B-cells develop antibodies & hopefully B-cell memory. Killer T-cells can eat the infected cells and hopefully create T-cell memory as well.
The mRNA Vaccine
In the last few years, the next generation of subunit vaccines using mRNA have generated a lot of excitement. In animal studies, they were very safe. Unlike live attenuated and inactivated vaccines, mRNA vaccines seem to induce strong killer T-cell responses, probably because they efficiently get to the antigen protein. mRNA vaccines also seem to create a bigger antibody response with only one or two doses. The strength of these responses generated enough memory cells that mRNA vaccines could be life-long.
mRNA vaccines create this improved response because they are more efficient than DNA subunit vaccines. DNA lives in a cell nucleus. For DNA to make a protein, one gene from the DNA must be copied onto a messenger, or mRNA. The messenger then has to travel out of the nucleus over to the endosome, or protein factories in a cell. There, the mRNA can be used to assemble a protein. After the protein is assembled, the mRNA is trashed. (like a snapchat message)
DNA vs mRNA vaccines from: https://doi.org/10.3389/fimmu.2019.00594
By creating a vaccine out of mRNA instead of DNA, we get to skip the copying and traveling steps. Making mRNA is also fast. You can create a vaccine, the instructions to build a protein, as soon as you sequence a new virus antigen. And because all you are doing is combining chemicals, you can manufacture them at scale, rapidly.
mRNA is meant to be temporary, which means it’s also not very stable. Even though we have understood the power of mRNA vaccines since the 90’s, it took until the last 10 yers for scientists to find a way to make mRNA strands stable and able to break into human cells. Once they figured this chemistry out, they finally had all the keys. To me, mRNA is one of the most exciting things to happen in medicine in a long time.
The Implications of an mRNA vaccine
The flu kills a lot of people every year. And the flu vaccine, despite our best efforts, is less than 60% effective. Worst of all, the antibodies from the flu vaccine are gone in 90 days, though flu season is 6 months long. The flu vaccine is not useless, but it’s not our strongest work.
Using DNA-subunit vaccines, we were able to improve on the inactivated vaccines that had to be grown in eggs. We were also able to create a purified vaccine that protects against multiple flu strains. DNA-subunit flu vaccines were safer, but still not more effective.
mRNA could be so much better. Instead of chasing the flu surface proteins that constantly mutate, we could target other antigens on the flu that don’t tend to mutate and create a universal flu vaccine. An mRNA flu vaccine that triggered antibody and T-cell memory could give us life-long protection so we wouldn’t need a yearly shot!
We are seeing this magic play out right now. Pfizer and Moderna’s mRNA vaccines for SARS-CoV2 were developed, manufactured, and started in human trials in less than 2 months from when the virus was sequenced. Both companies have publicized 95% efficacy that has already outlasted the 90 days of the flu vaccine.
And there’s no reason to stop with SARS-CoV-2. If this vaccine is successful, we already have what we need (genetic sequences) to develop a super effective vaccine to perhaps any virus we have encountered, or will encounter! That’s insane.
My guess is that assuming the mRNA Covid-19 vaccines are successful, we may even re-work existing vaccines (polio, measles) to be mRNA.
The Risks of an mRNA vaccine
The SARS-CoV-2 mRNA vaccines are the first ever mRNA vaccines. So far, with 30,000 people given a shot, very few issues have been noted. Though we won’t have long term data for a long time, with other vaccines, negative reactions tend to happen within a couple of weeks, and we are well past that bar.
However, with all things, usually the greatest danger is in the unknown unknowns. Could an mRNA vaccine hurt us in a way we haven’t even thought to look for?
I’m fascinated by the idea that we could vaccinate against anything using mRNA. But what happens if we give people immunity to everything? It’s not natural for a human to encounter 100 different deadly viruses in their life, which is the only way they would naturally learn 100 different virus-fighting strategies. Do our bodies have a limit on the number of killer T-cells or antibodies we can handle floating around? Is that why our immune systems are choosy about creating memory cells?
And what about the effects of teaching the body to mount a very strong response to a single protein? Right now we are in the midst of an incredible rise in immune dysfunction and autoimmune diseases. These diseases happen when immune cells, like antibodies, attack either harmless things (pollen, peanuts) or our own cells. Could the protein targets created by mRNA vaccines cause more misidentification mistakes? Could the antigen we choose look too much like a natural protein in our bodies and cause autoimmune disease?
Lastly, viruses are a natural part of our personal ecosystems, along with bacteria and fungi. Human coronaviruses are everywhere all the time, constantly adding to our ecosystems. Would a “universal” CoV vaccine mess up our viromes? What are the implications of that?
No one has answers to any of these questions, because we won’t know until we create a universal vaccine and see what happens. Even today, the Pfizer and Moderna studies were done in healthy adults, so we don’t know the implications of vaccinating toddlers with plastic immune systems, children, or people with various immune dysfunctions. As those folks get vaccinated, we will eventually learn.
But the hope is real. And we can create adaptive strategies to deal with almost any possible downsides, like only vaccinating enough people to snuff out a pandemic.
Conclusion
I was freaked out about mRNA vaccines until I understood better what they really are. Now I’m cautious but excited. I’m definitely not trying to suggest that anyone get or not get this new class of vaccines.
As with all things, we can only make good decisions once we understand what the new treatment is and how it works. It’s possible that mRNA vaccines will be the safest ever vaccines and reduce adverse events while increasing compliance. I hope that’s true.
For now, I feel better thinking through what I want to know about the vaccine data and being able to decide if it’s for me and my family more deeply than simple statements like “vaccines save lives.”
Please let me know if you didn't understand something or if you feel I misrepresented any concepts.
