The layman’s guide to how the Pfizer and Moderna vaccines work

The layman’s guide to how the Pfizer and Moderna vaccines work

Every article I have read about how the Pfizer and Moderna vaccines work is either too high-level to be very informative or a peer-reviewed academic article that requires a doctorate in genetics to understand. As someone who spends many of my waking hours helping management consultants and other experts explain complex business concepts in simple terms, I couldn’t help but sit down to produce an article to fill that gap. Since both COVID-19 and the vaccines rely on messenger RNA, I begin by explaining what mRNA is and how it works. My goal is to explain these processes for anyone with high school biology and a vague understanding of DNA because that was my starting point.

Let’s start with mRNA

All day long, every cell in your body builds proteins to use in the cell or outside of it. These proteins are the essential building blocks of life. The family of proteins called myosins, for example, enables your muscles to contract. Each cell is told which proteins to build by long molecules called messenger RNA, or mRNA, produced in the cell’s nucleus. These are transcribed from the DNA that resides in every nucleus and contains your complete genome.

On the one hand, this process is not very complicated. DNA consists of just four different bases, chemical structures that each contain about 15 atoms inside a double-helix structure that holds it all together. On the other hand, it’s bogglingly complex. Each DNA strand in each cell of your body contains the same sequence of about 2 billion of these four bases, the unique order of which defines you. In each cell, one or more sections of this DNA produce the mRNA for that cell.

Figure 1: mRNA being transcribed from a section of DNA in a cell nucleus[1]

The mRNA molecules pass from the nucleus into the body of the cell, where structures called ribosomes use them as instructions for building proteins in a process called translation. mRNA molecules also consist of just four different bases and average about 2,000 bases in length. Again, the order is critical; it defines the protein that will be made.

The proteins produced by the ribosomes can be large and complicated molecules, but they are constructed from just 20 different amino acids in the sequence defined by the mRNA. The combination of each successive three bases in the mRNA tells the ribosome which amino acid comes next.

Figure 2: Each group of three bases specifies the next amino acid in the protein[2]

This means that just a few components—four bases in each strand of DNA and RNA and 20 amino acids—give rise to infinite possibilities. Even though humans share 99.9% of their DNA, there’s no chance that anyone dead, living, or yet to be born will be genetically identical to you.

After translation, the mRNA breaks down and gets expelled from the cell, and the protein goes on to do its job.

How the Covid-19 virus uses mRNA

Figure 3: The spike is one of six elements of a coronavirus

The COVID-19 coronavirus, SARS-CoV-2, hijacks the human body’s mRNA translation process to replicate itself. Once breathed in, it attaches itself to cells in the respiratory system, from the nose to the lungs. The infamous spikes latch onto the membrane of a cell, the virion dissolves the membrane, and then mRNA molecules contained inside it pass into the cell. These mRNA molecules contain instructions for making more SARS-CoV-2 virions, and the human ribosomes unwittingly read them and manufacture more. The newly minted virions migrate outside the cell where they might encounter the body’s immune system or another cell, which they hijack to make more virions.

Figure 4: The SARS-CoV-2 virus tells human cells to make more copies of itself

Think about that for a second. The SARS-CoV-2 virus doesn’t replicate by splitting in two like a bacterium but breaks into your cells and tells them to make copies. It keeps going until your immune system overcomes it, or it overcomes you. If you have a strong immune system, it might knock the virus down before it can gain hold and you might only suffer the mild symptoms of a common cold, such as headache and mild fever, or none at all. If your immune system is not as strong, the coronavirus can replicate until it overwhelms it. Then your immune system might go into a deadly cytokine storm, sending millions of cells to fight the infection in the lungs and causing massive amounts of damage in the process.

The breakthrough of mRNA vaccines

The Pfizer and Moderna vaccines are the first to make use of our mRNA processes. Earlier generations of vaccines used other techniques. Polio vaccines, for instance, rely on inactivated or weakened versions of the virus to provoke a response from the body’s immune system. But mRNA vaccines use SARS-CoV-2’s own mRNA trick against it.

Developing mRNA drugs, not just vaccines, has been a goal for 20 years. The first human genome was sequenced in 2000 and took a year to complete. Today you can have yours sequenced by 23AndMe for $150 and get the results in a few days. Once we have a genome and know which parts relate to which proteins, we can design and create the mRNA to build any of those proteins.

The biggest challenge for mRNA therapies has been how to get it into a cell without the body destroying it as a presumed invader first. COVID-19 has a sophisticated way of getting its mRNA into cells. The spike has a binding area at the top (in green) that unfolds to latch onto the cell membrane. Then it dissolves the membrane so that the mRNA can pass from inside the virion to the cell without ever being directly exposed to the body’s immune system.

Figure 5: The SARS-CoV-2 spike

Two recent breakthroughs have allowed biotech developers to protect mRNA until it enters the cells. First, nano-lipid technology developed in the 1990s allows mRNA to be encapsulated in tiny oil particles that protect it until the particles stick to a cell and the mRNA can pass through the membrane. Second, Katalin Karikó, a board member of BioNTech (Pfizer’s partner), figured out six years ago that if you slightly modify one of the bases in mRNA, you can trick the body into not attacking it as an interloper without impeding its function in protein building. She and a colleague discovered this after ten years of not getting grants because mRNA therapies were considered too fringe and being demoted at Stanford for not getting grants. She’s now in the running for a Nobel Prize.

The Pfizer mRNA Vaccine

China published the genome of the SARS-CoV-2 virus on January 11, 2020. Using that Chinese data, BioNTech took a few days to produce mRNA for five different parts of the virus, including the spike. They had their vaccines in preclinical animal studies within a couple of weeks. In the history of vaccine development, a time-to-product this short is unprecedented. Pre-COVID, vaccine development often took 10 to 15 years.

But once developed, it still took several months to put the vaccine they opted for (the spike) through in-human trials, starting with Phase 1 (safety and efficacy), Phase 2 (dosage), and Phase 3 (comparative outcomes in a double-blinded trial with 70,000 participants), which is the longest. Then more time to scale up production and make them.

When the vaccine is injected into an arm, the nano lipid particles attach to cells, and the mRNA passes through the membrane into the cell. That cell then builds coronavirus spikes which pass outside, prompting the immune system to create antibodies to attack invaders with those spikes in the future. Some cells are able to present the spikes on the outside in such a way that the body’s T and B cells can build longer-term immunity too. That’s one reason the mRNA vaccines are so effective and are likely to confer immunity for an extended period.

Figure 5: The vaccine prompts the cells to produce spikes and present them to the immune system

Safety of mRNA vaccines

Each mRNA molecule can produce more than one spike protein. How many is determined by the structure of the tail of the molecule which gets a little shorter each time it’s used.  When the tail is too short, the cell stops using it and breaks it down into its constituent chemicals, as it does with every other mRNA molecule. Eventually, the protein spikes, which are harmless, are also broken down. So there is nothing left to hurt you.

Short-term side effects such as headaches and fatigue are common and the consequence of the immune system being kicked into action by the vaccine. Serious side effects of any vaccine are rare and usually happen in the first eight weeks.[3] The J&J and AstraZeneca COVID vaccines have produced serious side effects. But they use a different technology—a modified form of another virus to provoke the immune system—and appear to have caused problems in a very small number of people. No serious side effects have been reported for either mRNA vaccine in the 400 million doses administered by the end of May 2021. The short- and long-term effects of COVID, on the other hand, are common and often fatal.

[1] http://hyperphysics.phy-astr.gsu.edu/hbase/Organic/transcription.html

[2] http://glencoe.mheducation.com/sites/0078778085/student_view0/unit3/chapter10/standardized_test_practice.html

[3] https://www.chop.edu/news/long-term-side-effects-covid-19-vaccine

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