How the New mRNA Vaccines Work

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Our nation’s response to the Covid-19 pandemic has involved so many failures that it’s hard to count them. We failed to curtail travel from China when we could. We failed to set up robust procedures for testing, tracing and quarantining. We failed to foresee the need for tests and PPE and so failed to maintain adequate supplies. We failed in our messaging about masks, trying to restrict them at first to medical personnel and giving the false impression that they don’t work or are unnecessary. We failed to mandate masks and social distancing when we could have limited the disease to small, containable outbreaks. We failed to have any coherent national policy and messaging; in many cases individual states failed to have consistent policies and messaging.

In general, while fighting a horribly contagious pandemic, we Americans acted like a herd of 328 million cats. We strayed like the sheep in Handel’s Messiah: “every one to his own way.”

But in one respect only, our response to the pandemic has been spectacular: the new vaccines. Not only did we roll out safe and effective vaccines in record time. We and the Germans developed a whole new vaccine technology that offers exciting new vistas for preventative medicine. In the long run, the new vaccines promise to be as important in fighting contagious disease as Alexander Fleming’s discovery of the very first antibiotic, penicillin, in 1928.

I write, of course, about the two new so-called “mRNA” vaccines—the two-shot regimens offered by Moderna and Pfizer. This essay explains in some detail how they work and why they are so spectacular.

Vaccines themselves are nothing new. Although occasionally controversial, vaccines for smallpox have been around since the 1700s. Not surprisingly, smallpox was the first terrible contagious disease to have been wholly eradicated by vaccination.

To non-doctors and the uneducated, vaccines are counterintuitive. They protect you against a disease by giving something like the agent that causes the disease. They’re a bit like taking “the hair of the dog that bit you” to cure a hangover, but in reverse. You take the hair of the dog before being exposed to the disease agent. It protects you by provoking your body to arouse and “train” its natural defenses—antibodies, T-cells and B-cells—to recognize and fight the invader if it ever comes for real.

This counterintuitive aspect of vaccines makes them ripe for misinformation and demagoguery. How can giving you the same agent that causes the disease protect you?

But it does. As usual, the devil is the in details, here in the words “something like.” Obviously you can’t just be inoculated with the live, whole, active disease agent itself, or else you would get the disease. So the virus that causes disease must be modified in some way.

The smallpox vaccine developed by the British doctor Edward Jenner used the bug for the similar disease cowpox, which was much less dangerous. Later vaccines used viruses modified, inactivated or “killed” in the laboratory. These vaccines work because the body’s immune system can recognize and train itself to respond to certain proteins in the virus, even through the virus itself is “inactivated” from reproducing, or “killed.” (Viruses aren’t really alive like bacteria, so the word “killed” is technically inapt as applied to them.)

This was the state of art of vaccine technology for about two centuries, from the late 1700s until the late 1900s. Then it was all pretty much ad hoc experimental science, trial and error. Research doctors would find and isolate the disease agent, modify it in various ways, and see whether its use as a vaccine would provoke an effective immune response. There was no reliable general method or approach because no one understood the molecular basis of infection and immunity.

All that began to change with the discovery of DNA, or deoxyribonucleic acid. This long molecule, twisted in a double helix, is the repository of heredity and the basis of life. Three men and one woman discovered its double-helix physical structure, which makes it work. The men (Watson, Crick and Wilkins) got the Nobel Prize in 1962; the woman (Rosalind Franklin) did not because she had died by the time of the award, and Nobels must have live recipients.

It took decades for this monumental discovery of the structure of DNA to ripen into the whole field of study now known as “molecular biology.” It also took the contemporaneous development of whole fields of unrelated technology, such as computers, electron microscopes and X-ray crystallography. For DNA is no simple molecule like those you study in high-school or college inorganic chemistry. The human genome, for example, has 3.2 billion base pairs, each of which comprises two amino acids. There is no way that the human mind could conceive of such complex molecules, let alone handle them in detail, without the aid of digital computers that can store gigabytes of data in reliable memories.

Today, we have automated machines, called “sequencers,” that can “read” samples of DNA. We have enzymes that can cut specified sections out of the long molecules. We have a technique—polymerase chain reaction or PCR (the subject of yet another Nobel Prize)—that can amplify small samples of sections, or of whole DNA, for testing and sequencing. We even have a technique, called CRISPR-Cas/9—to edit DNA by inserting partial sequences in designated places.

This is just the briefest review of a whole series of tremendous advances in science and technology that made the Moderna and Pfizer mRNA vaccines possible. They could never have been developed without all the intermediate steps: the understanding of DNA, the use of electron microscopes, and the development of sequencers, PCR, and CRISPR-Cas/9.

Each of these steps, in itself, was a monumental discovery. Together, they represented half a century of the most sustained and miraculous advance of science and technology in human history. They now make it possible to “design” vaccines the way you would design a car or computer, rather than by finding what works by blind experimentation with patients, through repetitive trial and error.

To see how this is possible, we need to consider one more piece of the puzzle. DNA itself is more like a library, a catalog of information, than working parts of a molecular machine like a human cell. Proteins are the basic building blocks of working cells, and hence of our bodies. But how does the information in the DNA “library” get translated into the myriad proteins the make our bodies work?

The answer is an intermediate “blueprint” in another molecule, ribonucleic acid, or RNA. RNA serves as a template for building proteins in a cellular organelle called a “ribosome.” A specialized “messenger” RNA, or mRNA, molecule translates the blueprint in the corresponding part of the huge DNA molecule into a smaller blueprint for a particular protein. Then the ribosome uses the mRNA blueprint to construct the protein itself.

With this complex but necessary background, we can now understand how the Moderna and Pfizer mRNA vaccines work. They are the first-ever “designer” vaccines, designed and built at the molecular level to provoke an immune response to a particular protein—and only that protein—in a virus.

The protein that the designers chose for their immune target is the so-called “spike” protein of the coronavirus that causes Covid-19, namely SARS-CoV-2. This is the protein that cartoons of the virus depict as a spike sticking out of a spherical body, looking like the protruding trigger of an old-fashioned explosive sea mine.

Why is that choice so important? The “spike” protein is the means by which all known coronaviruses first enter a human cell. It’s the key to the molecular lock that lets the virus inside the cell to do its damage. Without access to a human cell’s inner machinery, the virus can’t replicate. It can’t reproduce and multiply, so it can’t cause disease. Without the spike protein entry key, the virus is just a random piece of useless junk in the bloodstream and lymphatic fluids, susceptible to elimination in urine or feces.

The Moderna and Pfizer vaccines are just bits of mRNA that code for the spike protein. They are not the spike protein itself. Instead, they instruct the ribosomes in human cells to make the spike protein, which the human immune system then recognizes as “foreign.” Over a couple of weeks, the immune system exposed to the spike protein trains itself to produce antibodies, T-cells and B-cells to attach to, neutralize and eliminate the spike protein and anything associated with it, such as the SARS-CoV-2 virus.

An additional complexity was getting the mRNA that codes for the spike protein safely inside human cells. For this, the vaccine designers had to use lipid nanoparticles containing the mRNA—essentially nanoparticles of a special fat to shield the mRNA until it can get inside the human cell and do its work. These nanoparticles took decades to develop; they require the low-temperature storage for which the mRNA vaccines are notorious.

These technical features of the mRNA vaccines underlie the reasons they are so spectacular. They did not require the usual years or decades of trial and error to develop. Instead, the mRNA vaccines were designed from the ground up, using the modern tools of molecular biology that can sequence (“read”), clip and synthesize arbitrary sequences of amino acids. The designers simply took the spike protein, read it, synthesized an mRNA sequence to code for it, synthesized the mRNA in quantity, inserted each molecule in a lipid nanoparticle, and made the result cold enough to keep everything stable until the shot in the arm. The whole thing was purpose-built at the molecular level.

The mRNA vaccines work by getting human cells themselves to manufacture the spike protein. Then the immune system recognizes it as foreign and trains itself to fight the virus. So far, every variant of the SARS-CoV-2 virus has the same spike protein, so the vaccines are effective against all known variants.

But here’s the most important point. The mRNA vaccines work by immunizing your body against the virus’ spike protein only. They do not contain (or code for) any other part of the virus. So there is no possible way—chemically, biologically or even theoretically—that the mRNA vaccines can make you sick with Covid-19. Unlike so-called “traditional” vaccines, which use a whole but inactivated virus, or parts of a virus, the mRNA vaccines do not contain or code for any part the viral machinery for self-replication, which causes disease.

Thus, if any symptoms of Covid-19 appear after a person receives an mRNA vaccine, there are only two logical possibilities. First, the patient may have been infected before being vaccinated, or shortly afterward but before the vaccine’s immunity kicked in. Second, for some reason the vaccine was not effective in that particular patient: even the unprecedented effectiveness of 95% allows some 5% of patients to get the disease after being vaccinated. There is absolutely no physical way that the vaccine itself could cause the disease or its respiratory symptoms.

In theory, the presence of the mRNA and/or spike protein in the body might cause some sort of adverse reaction, particularly in the long run. But that hasn’t yet been observed, either in the tens of thousands of patients in clinical trials or in the tens of millions of vaccinated patients in the US and around the world.

Nor is this kind of theoretical long-term effect at all likely. Pfizer’s recent data on waning of the antibody response some six months after the second shot suggest that the internal production of the spike protein is waning also. Otherwise, the antibody level would remain high, or there might even be some immune-system overreaction due to the long-term presence of the self-generated spike protein in the body.

The fact that none of these things has been observed suggests what one would expect. In the normal course of waste removal, both the self-generated spike protein and the artificial mRNA that codes for it are eliminated from the body over time. To maintain the high level of immune response, they have to be replenished, when and if desired, by a new injection, i.e., a “booster shot.”

The mRNA vaccines’ operation is thus extremely simple. It is limited to producing one molecule only, the spike protein. So it should be easy to test for residuals of the mRNA and/or spike protein in tissue, blood and lymph fluids, and to correlate their probable decay with decay in immune function. Since the vaccine contains no other part of the virus, and nothing else but the lipid nanoparticles, the risk of unintended consequences is far less than in other vaccines, which often include unknown or unintended parts of the virus. This indeed may be the source of the rare occurrences of blood clots with the Johnson and Johnson vaccine.

At the end of the day, the Moderna and Pfizer mRNA vaccines are the result of half a century of spectacular progress in medicine, molecular biology and related technology. The way that they work—targeting the specific spike protein and nothing else—makes unintended consequences unlikely, even in theory. More important, it makes “designer” vaccines, developed at unprecedented speed in response to new and evolving pathogens, practically possible. As the New York Times just reported, Dr. Fauci is pushing for federal money—a mere few billion dollars—to create vaccines against known deadly pathogens that might evolve to become more contagious.

As for me, I don’t just talk the talk; I also walk the walk. I had my second dose of the Moderna vaccine in February. From the very beginning, I wanted an mRNA vaccine because I understand how they work. (I chose Moderna over Pfizer only because Moderna’s cold-storage requirements were less severe.) As soon as a booster of either is available I will take one.

But here’s the most important point. The mRNA vaccines work by immunizing your body against the virus’ spike protein only. They do not contain (or code for) any other part of the virus. So there is no possible way—chemically, biologically or even theoretically—that the mRNA vaccines can make you sick with Covid-19. Unlike so-called “traditional” vaccines, which use a whole but inactivated virus, or unknown parts of a virus, the mRNA vaccines do not contain or code for any part the viral machinery for self-replication, which causes disease.

As for the future, I will seek out mRNA vaccines for any new or evolving pathogen (including new Covid variants) that arises during my lifetime. Not only is mRNA vaccine technology the wave of the future. It promises astoundingly rapid development of effective vaccines, precisely targeted at the weak point of any new virus that nature or our fellow man may throw at us. What could be more intelligent medicine, and what could have fewer unintended consequences, especially as compared to vaccines designed by trial and error?

ERRATUM: An earlier version of this post reported that smallpox is making a small comeback in the US due to vaccine refuseniks. That was wrong: smallpox is still eradicated; only measles is making a comeback. I regret the error and thank JMcDonald, whose comment on the DailyKos version of this post corrected it.

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