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The First COVID-19 Vaccines: What’s mRNA Got To Do With It?

Most of us have an intuitive understanding of how a vaccine works: show the immune system a bit of a pathogen, or something mimicking it, and trick it into responding as if natural infection is happening. The COVID-19 pandemic ushered in a flood of vaccine options.

When I was writing “How the various COVID vaccines work,” which ran here at DNA Science on September 10, I had to keep reviewing summary charts to remember who was doing what. Vaccine technology has gone beyond live, weakened, or killed virus, even past the once-groundbreaking subunit vaccines that present parts of a pathogen, like the hepatitis B surface antigen or pertussis toxin. Now we have DNA and RNA vaccines too, delivered in different ways.

The first two vaccines against COVID-19, Tozinameran (the Pfizer/BioNTech vaccine) and mRNA-1273, Moderna’s still unchristened candidate on the brink of emergency use authorization, are mRNA. And that’s confusing people, based, perhaps, on when they took high school biology (more on that coming). So here’s a brief consideration of mRNA and how it can alert the immune system to fight SARS-CoV-2.

First, some things that the new vaccines are not and cannot do:
• They aren’t viruses.
• They aren’t “natural” – they’re synthesized.
• They can’t enter a nucleus of a human cell and mutate our DNA. Even if they did, they’d encode the viral spike protein – as a vaccine does.
• They aren’t derived from human embryos or fetuses.

A Brief Biology Lesson

Proteins lie behind traits, directly or indirectly. Clotting factors stop bleeding. Keratin forms hair and skin, collagen the body’s glue, and hormones carry messages. Most of the enzyme types that propel metabolism fast enough for life are proteins (a few are RNA). Proteins pepper viral surfaces, like the trios of spikes from which the coronaviruses take their name and use to bind and invade our cells.

Genes consist of a sequence of DNA building blocks that form a code that tells cells how to make specific proteins, which are built of amino acids. Francis Crick described it in Nature in 1961. In translating the code from gene to protein, a cell transcribes the information into an intermediate form, to preserve the DNA database. That’s messenger RNA, aka mRNA.

A cell makes mRNA for a simple reason: it can’t use up its DNA and stay alive. Like a lone volume of a book in an old-fashioned library that someone takes out and never returns, DNA is precious. Copies ensure that the information persists, even if the original book or instructions vanish, and passes to the next cell generation during division.

Familiarity with mRNA Depends on Age

Some of the deer-in-the-headlights response to mRNA as a vaccine may come from members of the media who don’t ordinarily report science, and oversimplify. CNN, for example, called RNA “a component of DNA.” No. Both are nucleic acids. (RNA differs from DNA in one of the four building blocks, RNA is single-stranded, and it’s much shorter than DNA.)

When I began lecturing in an adult ed program, about 20 years ago, a gentleman took me aside during the break. “Ricki, when these folks were in school, we didn’t know about DNA.” That came in 1953 with Watson and Crick’s famous paper.

Figuring out how genes encode proteins took longer, with experiments to crack the genetic code – assigning RNA triplets to one of the 20 amino acids of proteins – starting in 1959. “Genetic code” traditionally refers to that correspondence, and it is universal to all life and viruses. (See In Search of the Human Genetic Code).) More modern usage equates DNA, RNA, or genetic code with computer code; RNA or DNA sequence is more accurate.

I learned about DNA, RNA, and protein – the “central dogma” of molecular biology – in AP biology, then in college circa 1972. But the DNA-RNA-protein mantra has since migrated down to general high school biology, and I wrote about it in a middle school textbook. I imagine many people forgot the details as soon as the final exam was over, unless they took biology again in college. It’s like my not knowing much about history.

But the central dogma is, well, central in high school biology. I worked on the New York State Science Learning Standards in 2016, which boil a very complex idea down: “Construct an explanation based on evidence for how the structure of DNA determines the structure of proteins, which carry out the essential functions of life through systems of specialized cells.”

Modified mRNAs as Vaccines
An mRNA vaccine encodes a protein unique to a pathogen – like a virus’s spike. The two first COVID vaccines are gulped into cells and freed outside the nuclei, where the machinery that normally translates mRNAs into proteins goes to work. Soon, the cells release viral spike proteins – but not viruses – and cells of the immune system – dendritic cells and macrophages – sound the alarm. Within a few days, T cells activate B cells to crank out antibodies. Immunity has begun.

An mRNA vaccine can elicit a more powerful immune response than any other kind, but modifications improve on nature. A “modRNA” vaccine can evade the tiny bubbles of innate immune system proteins that can trigger potentially deadly overproduction of cytokines, and also avoid being chewed up by enzymes (ribonucleases).

The modified RNA – something as simple as latching a methyl group (CH3) onto one of the four base types – alters the encoded protein in subtle ways, modifying the twists and turns of the amino acid chain to fashion a topography that both shields the modRNA from the RNA-eaters, but allows production of spikes to proceed full speed ahead.

Additional modifications to parts of the mRNA that cap both ends further stabilize the molecules and boost spike protein output. And two amino acids – prolines – inserted at a key part in the sequence stabilize the spike protein in the three-dimensional shape that it naturally assumes just before it binds to the human ACE-2 receptors on cells.

The shots in arms happening all over the world right now represent decades of research.

A Brief History of mRNA Vaccines

Published reports of efforts to make mRNA vaccines go back to 1990 in mice and 1992 in rats. Much credit is now belatedly being given to Katalin Karikó, who sought grant funding to develop RNA-based vaccines starting in the mid-1980s. Her patent with co-worker Drew Weissman from the University of Pennsylvania, who is now with Pfizer partner BioNTech, was issued in 2006.

Tweaked, synthesized, modRNAs have been developed against Zika virus, influenza, cytomegalovirus, and two less familiar ones. So the stage was set when, on January 10, Chinese researchers published the first genome sequence of the new enemy, SARS-CoV-2.

The modRNA vaccines encode the 1273 amino acids that make up the viral spike protein – hence Moderna’s “mRNA-1273.” (See COVID-19 Vaccine Will Close in on the Spikes,” posted here at DNA Science February 20, my third COVID article; this one is #56).

I Failed at Finding the Recipes

I’ve read many articles and patents in search of the distinctions between the two mRNA vaccines. Here’s Moderna’s and here’s Pfizer’s.

Both vaccines encode spike protein with the added prolines. Both are delivered in lipid (fat) concoctions. Even those are similar. They consist of cholesterol, phosphocholine, polyethylene glycol, and the fourth is proprietary, a positively-charged special sauce. But the “lipid nanoparticle” is just the carrier, melting into the cell membrane and shielding the RNA for a time inside the cell.

Both vaccines are engineered to be more visible to the immune system – but is that due to the prolines, or an additional, proprietary tweak? Probably the latter, because something unique must distinguish the patents, and explain why the vaccines are not interchangeable. You can’t start with Pfizer for shot one and switch to Moderna for shot two, or vice versa.

I read Moderna’s 135-page protocol and patents, and entries for the COVID vaccines listed at ClinicalTrials.gov, which currently number 328. The volume of information is stunningly overwhelming, as is the global effort to take down the minuscule monster that is SARS-CoV-2.

CODA

What I find most astonishing is that these viruses that slip inside our cells and do so much damage, even turning our immune systems against us in the molecular violence of a cytokine storm, can exert so much power because, ultimately, they came from our own genomes. They likely came from jumping genes, which are indeed a thing, discovered in the 1940s. How else could the viral spikes recognize and then swivel and bind to the molecules on our cells and invade?

There’s so much to think about these days.

Discussion
    1. According to the clinical trials, no, and I don’t think it would. But more time has to pass and more data accrue. Great question, and I appreciate your courtesy (compared to some other comments).

    2. Hello, I am very concerned about how many cells will be involved and this killed in this process?! I’m not seeing this information. How is this able to be controlled. So, how is it that this spike protein process doesn’t invade all cells? And how does the process stop?

    3. Cells aren’t killed. The spike protein is foreign to a human body so it alerts the immune system. And the RNA disappears quite quickly. It does it’s job and it’s gone. We have trillions of cells. A few hundred or even thousand being destroyed from a needle – as would be the case in any vaccine that is an injection – would not make a difference.

    4. What if you missed 2nd vaccine, can you get phizer after the 42 days and be okay or more side effects?

    1. SARS-CoV-2 most likely came from a bat virus RaTG13 – the genomes are very much alike in sequence – and perhaps picked up the affinity to our ACE2 receptors in a Malayan pangolin. That evidence, based on the RNA sequences, is more compelling, at least to me, than the idea that a man in a lab came up with it. Several new articles discuss future coronaviruses, percolating into existence right now. As long as humans keep invading the habitats of other types of animals, pathogenic viruses will continue to be spawned and evolve.

  1. I’ve been told by two different doctors that it is, indeed, acceptable to start with one vaccine and finish with another if needed. Is there new science on that?

  2. I’m trying to find out how many, and what type of cells the mRNA affects. Is it every cell in the body, or is there a minimum number of cells that have to grow the partial spike protein in order for the immune response to occur? Thank you for your answer and great article.

    1. I’ve wondered about this too. The spikes alert dendritic cells of the immune system and they spread the message. I’m looking forward to learning more about these very questions.

    1. I noticed you did not receive a response to your question. I would like to understand this as well. What exactly is the “secret sauce” the author mentions above and what exactly makes it proprietary? Can someone explain in detail how luciferace contributes to one or more of the vaccines?

  3. Why is having the vaccine more effective at fighting the disease than actually having the disease itself and recovering? Is it because vaccines are more generic so can cover more mutations? Furthermore do not both generate antibodies which will have the same life expectency?

    1. What a terrific question! The vaccine mRNAs are engineered so that the body makes many distinct antibodies against different parts of the viral spike. So, a natural infection might elicit say 6 types of antibodies, but the vaccine, 18. I’m making these numbers up. But, the vaccines are “optimized.” It’s hard to explain this without giving a biology lecture, but basically for some amino acids, more than one mRNA triplet specifies it. Some work better than others.

  4. Very interesting article.

    I was wondering if pfizer or moderna published their entire mRNA sequence, or if part of their proprietary withheld information is actually a sequence of mRNA or even a protein?

    1. I didn’t come across the sequence anywhere. I did look through the patents for Moderna and Pfizer in search of how the mRNAs differ but never figured it out.

  5. Have you recieved the vaccine? Which brand did you get? What were your side-effects?
    Thanks for answering our questions.

    1. Pfizer. Mild side effects first time, none the second. In fact, I felt great after the second. I think I may have had mild COVID in August, which might explain my response to the first but not the second dose.

  6. You suggest that RNA is not a component of DNA as quoted… “CNN, for example, called RNA “a component of DNA.” No. Both are nucleic acids. (RNA differs from DNA in one of the four building blocks, RNA is single-stranded, and it’s much shorter than DNA.)

    I cant see how that makes sense since RNA is derived from DNA as a copy of a particular DNA segment carrying specific codons for what ever protein needs to be synthesized. You cannot have RNA without the DNA. Both are nucleic acids yes, but you must have DNA to make the RNA.

    Also, humans have developed antibodies naturally against the COVD virus. Has there been any research into the natural RNA sequences that synthesize proteins that the body can produce naturally without introducing viral segments?

    1. Yes RNA in a cell is derived from DNA, with the characteristics unique to RNA – single-stranded, uracil instead of thymine, ribose instead of deoxyribose. But mRNA scan be made synthetically, and that is the case for the vaccines.

    1. No. The preclinical research that underlies development of any drug or vaccine may have at some point used the human embryonic stem cell lines that President Bush approved years ago. When people discover this they tend to panic that the COVID vaccines entailed destroying fetuses. Not so.

    1. A lab. The mRNA in the vaccines is synthetic. That means biochemists make it. It is a nucleic acid molecule. The chemists also tweak it in certain ways to elicit a more diverse set of antibodies than natural immunity. Federally-approved human embryonic stem cells have been used in preclinical research since the late 1990s, I forget the year, when President Bush approved a handful of cell lines. So, if you take any therapeutic drugs, there’s a good chance they were developed following preclinical use that uses these cells. Plus the exact cells are taken from cell culture outside of anyone’s body. There’s a great deal of misinformation about hES cells.

  7. What stops the DNA from continuing to make spike proteins? Your body would have a chronic battle? Could the “programmed” DNA have behave much like a cancer cell, a cell gone rogue… “Chronic spike protein syndrome”

    1. DNA isn’t involved. That step is skipped. The mRNA that is the vaccine stays in the cytoplasm, where it is translated into protein, as would happen for any transcript. Eventually that mRNA is used up – it doesn’t get into the nucleus and bind to DNA and change it, as many people fear.

  8. I received this spam on Facebook from someone who thinks it’s all a big GOV plot. could you please address the crazy amount of inaccuracy of this? ( the On messenger RNA-based vaccines ” I wondered if anyone ever wondered how the Spike protein, once produced, escapes from the cell, since the receptors it binds to are all found in the outer membrane. After months of studying the protein synthesis mechanism, its three-dimensional structure, the cleavage sites, the RdRp, the polymerase that transforms ssRNA into dsRNA … I became convinced that the only way out was to cause cellular apoptosis (suicide). And I had confirmation from an American study that, starting from the same observation, it obtained the same result. So: mRNA enters a cell (I imagine there will be millions of copies of mRNA in a vaccine, otherwise it would have no effect), and colonizes a cell (millions, therefore). Thanks to the synthetic phospholipid “shell” (the one that causes anaphylactic shock) that surrounds it and fuses with the cell membrane, the mRNA molecule penetrates the cytoplasm. The single helix, before being destroyed by the lysosomes, is transformed into dsRNA, which, thanks to the RdRp, will produce other mRNA molecules that will be transcribed in Spike. The Spike protein is foreign to the cell and, therefore, is attacked by lysosomes and broken down and its parts are exposed on the membrane, where they activate the complement system and call up the macrophages that destroy the cell, releasing the surviving Spike proteins into the circulation. But also by sending pieces of cell into circulation, even membrane proteins. The granulocytes phagocytes and expose them, activating the cytokine cascade that causes inflammation and which, moreover, calls the B lymphocytes to produce antibodies. Meanwhile, the vaccinated individual had: anaphylactic shock (if allergic), cell lysis with tissue damage, inflammation with fever, tremors, fatigue. Once the antibodies are produced, they target both the Spike and, in some cases, the membrane proteins of that cell type (the infected one), causing it to be recognized as an “enemy” and causing an autoimmune reaction that will destroy it in the within a few months or years. If it is the PNS or the CNS that is affected, the damages are those recorded in these two months, as well as if it affects lung, heart, kidney tissue, etc. But there is also a second way in which the cell is induced to commit suicide: the presence of dsRNA activates the production of interferon which, when released, attracts killer T lymphocytes, which attack the cell and destroy it. However, these also have the ability to memorize what they destroy and, therefore, if they attack membrane proteins, they also cause tissue destruction and autoimmunity.) wow, so sorry you had to read through this but this guy spams a lot of older marginally educated people…

    1. This is quite a mix of steps, and I’m not sure which are accurate and which aren’t. I don’t know that lysosomes have a recognition function akin to that of antibodies and would attack spikes. I also don’t know if there is a ds mRNA stage. Why would that be necessary? Can anyone else comment on which parts of this are accurate and white aren’t?

  9. Very informative article! I have one question though which I can’t seem to find any info on, and that is:
    Are there any particular types of cells in our body that the mRNA vaccines specifically target to serve as factories for the spike protein?

    1. Great question and I love the spelling of your name! The mRNA gets into dendritic cells, which signal other components of the immune response, but they also get into muscle cells, sometimes, near the injection site and that explains some of the discomfort. I’ve been wondering about other cell types too — haven’t found the answer.

    2. Hi Dr. Lewis,

      My understanding is that mRNA transcribed from the same gene can translate into different proteins depending on the type of cell in which the translation is occurring. If this is correct than Ricke Gibbs’s question points to a significant issue – can the mRNA in the Covid vaccines be translated into unexpected proteins in certain cells of the body and thus cause unexpected results down the road.

      Looks like there is not an answer to this yet. Is there anything you might add or point me to to research more information along this direction?

      Many thanks!

    3. You bring up a good point. From what I know the mRNA of the vaccine is chewed up pretty quickly, within a day. So I don’t think an errant protein part could be made in sufficient load and in enough cells to exert an effect on the phenotype. But yes, the same transcript can be translated as different subsets in different cell types.

  10. Is there evidence the COVID-19 vaccines cause a flare in persons with inflammatory arthritis, specifically HLA B27 positive spondyloarthritis? Is there an increased risk of a cytokine storm? My question is specific to persons NOT on immune suppressing drugs, but being treated with NSAIDs.

  11. Pardon my ignorance. What is the source of the mRNA used in the vaccines? Is it from the Sars-2 virus itself that is cultivated and stored for vaccine use? Is the mRNA then extracted from the Sars-2 virus, contained in the lipid nanoparticle, and then used in the vaccines? If the mRNA is from the virus, how are the labs able to cultivate such a huge quantity of the virus, and therefore the mRNa, and therefore the vaccines? Many thanks

  12. Do they know that the immune response from the vaccine won’t trigger long COVID symptoms? If so, how do they know, and is this something they will be monitoring?

  13. I’ve had live cell therapy from sheep embryo and am concerned about having the vaccine.
    Your thoughts are appreciated..

    1. What type of cells did you have put into your body, and how? I’m unfamiliar with a sheep embryo cell therapy, but I can’t imagine how a bit of synthetic mRNA would interact with that.

  14. Pardon my ignorance. What is the source of the mRNA used in the vaccines? Is it from the Sars-2 virus itself that is cultivated and stored for vaccine use? Is the mRNA then extracted from the Sars-2 virus, contained in the lipid nanoparticle, and then used in the vaccines? If the mRNA is from the virus, how are the labs able to cultivate such a huge quantity of the virus, and therefore the mRNa, and therefore the vaccines? Many thanks

  15. I’m so sorry. I don’t believe in synthetic RNA or DNA. There has to be a source. Otherwise, scientists would be God. There is a source for that no one is talking about. Nope. I don’t believe it. There’s so much we aren’t told. Most of the population cannot be this gullible. Sorry.

    1. The source is the chemist in the lab who synthesizes the molecule. My husband has been a chemist for 40 years. That’s what chemists do. You learn how different substances react, and you combine them under certain conditions to promote a chemical reaction. Making an RNA molecule is a polymerization reaction – linking of 4 types of building blocks. It’s science, not belief.

  16. After translation the synthetic mRNA will be broken down. Could you please help me understand what then happens with these broken down syntheic molecules? Will they continue to be used by the body? Perhaps I need to better understand what is meant by synthetic? Great article. Thank you.

    1. Synthetic means the chemical is manufactured in a lab, by a person, building block by building block. RNA is a nucleic acid, and the one used in the vaccine has one of the 4 types of building blocks very slightly different than in nature. Synthetic means made, not extracted from a virus or organism. Unfortunately, you really do need to understand how DNA encodes RNA which encodes protein works – this is the very essence of genetics, and the true meaning of “genetic code.” Today this is taught in the 9th grade and high schoolers understand it well. But for those of us a bit older, it might all be new. I’ve given the same lecture on the vaccines to adult ed groups and to middle schoolers, and the kids are very familiar with how it all works. So, not our fault if it all seems foreign. And the media often just gloss over it, some not understanding it themselves. Anyway, the synthetic RNAs (molecules) are broken down into their building blocks and then enzymes break them down into their constituent atoms – as happens all the time anyway. I hope this helps! If you have my genetics textbook, this is all explained in chapters 9 and 10.

  17. Dr. Lewis,
    A colleague of mine is afraid to get immunized after viewing a video posted by an infectious disease scientist alleging that the mRNA vaccines will set people up for catastrophic immune and clotting problems in the future. Can you help explain any fallacies that might have been proposed? When we don’t understand fear prevails.
    Sincerely,
    Elizabeth Hoover

    1. I cannot imagine how mRNA-based vaccines would induce catastrophic immune responses or clotting. Vaccines generally don’t do this. But so much is unprecedented. I trusted the concept of the mRNA-based vaccine so thoroughly that I volunteered for the Moderna trial – alas didn’t get in, probably because where I live there aren’t enough people to really test if I’d gotten infected. But we can’t know what will happen in the future. The mRNA disappears in our cells within hours. And the spike proteins that our cells then make would be no different from any other foreign antigen, from exposure to a natural pathogen. My personal decision is that the protection from a vaccine far far outweighs any future risk. Who was the ID person?

  18. Hello,
    I know someone that is allergic to Amino Acids and some other things such as eggs.

    My question is – should this person get the covid 19 shot when they have an allergy to Amino Acids and eggs?.

    Thank you

    1. The COVID vaccines are not conventional vaccines that used to be made with eggs. These vaccines are not. Pfizer and Moderna are mRNA delivered in lipids (fats). J+J is viral DNA delivered in an inactivate flu virus. I’m not sure one can be allergic to amino acids. They comprise proteins. You can’t live without any protein. Plus your body strings amino acids together to manufacture our proteins, like collagen and hemoglobin. This is what genes do. Being allergic to that natural process makes no sense – unless the person you know is allergic to an amino acid that is not among the 20 found in living organisms. Get the vaccine! We can CONTROL the pandemic with widespread vaccination, but the only way to ERADICATE the disease is for vaccination to be both global and universal. I understand that some people cannot get it for medical reasons, but to refuse it otherwise is selfish. That is my opinion, but it is based on science. I hate that the whole thing has been so politicized, ridiculous. Thanks for writing. A good question!

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