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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.

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