On January 11, 2020, scientists in China shared the genetic code of a new coronavirus online. Two days later, on January 13, a team at the company Moderna and the US National Institutes of Health had finished designing a vaccine against the virus [1].

The team never needed a sample of the virus. The design was a string of letters on a computer screen. And the vaccine built from those letters contains no virus at all.

Start where the recipe ends up: inside one of your cells. How does a cell turn a string of letters into a protein?

Be the ribosome

Every cell in your body is packed with tiny machines called ribosomes. A ribosome reads a strand of mRNA and builds a protein from the strand, one building block at a time [2].

The strand is written in four letters: A, U, G and C. The ribosome reads the letters in groups of three, called codons, and each codon calls for one building block, called an amino acid [3].

Small carriers bring the amino acids. Each carrier has three letters at one end, and a carrier docks only if its letters pair with the codon [4]: A pairs with U, and G pairs with C.

Your goal: tap the carrier whose letters pair with the blue codon. Build eight amino acids, then let the cell finish.

The eight amino acids you placed are the real first eight of the coronavirus's spike protein [5]. The finished spike is 1,273 amino acids long. At the speed ribosomes work, about 5 or 6 amino acids per second in one study of mouse cells, one spike takes a few minutes [6].

So a cell already owns the machinery to follow any recipe it is handed. But where do the recipes normally come from?

The cookbook and the copy

Each cell keeps its master cookbook, the DNA, in a central room called the nucleus. When the cell needs a protein, the cell copies one recipe from the DNA onto a strand of mRNA. The strand leaves the nucleus and travels out to the ribosomes [7].

The vaccine skips the copying step. The vaccine's mRNA lands in the outer part of the cell, where the ribosomes work. The mRNA never enters the nucleus, where the DNA is kept [8].

So your cell builds spike proteins from the delivered recipe. But the spike is a piece of the virus. Why is building that piece safe?

A harmless piece

A virus is a short set of instructions for making more virus, wrapped in a coat of proteins. The spike is one protein from that coat: the hook the virus uses to grab a human cell [5].

A spike on its own carries none of the virus's other instructions, so a lone spike can't make more virus [8]. The spike is like a photo of a burglar's crowbar: useless for breaking in, but perfect for showing guards what to watch for.

Time to play the immune system.

Train the defenders

Your goal: tap the defender cell whose cup has the same bumps as the tip of the spike. Then watch what that one cell does.

Most copies pour out antibodies, proteins shaped to grab the spike. Some stay behind as memory cells, and antibodies keep circulating in the blood after the first meeting [10].

The payoff comes later. If the real virus ever shows up, the trained defenders are already waiting, so the second response starts faster and climbs higher.

All of that training needs only a short burst of spike. So what happens to the recipe after the cell has read it?

A message that self-destructs

mRNA is built to be temporary. Cells chop up their own messages all the time, so a recipe stops being followed soon after the cell stops sending the recipe. In one study of mouse cells, a typical mRNA lost half of its copies in about 9 hours [11].

Vaccine mRNA gets the same treatment: the cell breaks the strand down and clears the pieces away [8]. So the cell makes spike for a short while, then stops.

A fragile message is a good thing once the message is inside a cell. But first the message has to travel from the needle into a cell. How does a fragile strand survive that trip?

Wrap the message

The fix is a tiny bubble of fat, called a lipid nanoparticle. The fat wraps the mRNA, shields the strand from the enzymes and helps the strand get into a cell [12].

Your goal: inject the bare message, then the wrapped one, and compare how many spikes each one makes.

The wrapped message became a short-lived spike factory. But for years a second problem held mRNA medicine back: immune cells treated lab-made mRNA as an invader. Who fixed that?

One tweaked letter

In the early 2000s, Katalin Karikó and Drew Weissman studied a puzzle. Lab-made mRNA set off an alarm in immune cells, causing inflammation, but a cell's own mRNA did not [13].

Karikó and Weissman knew that a cell's own RNA often carries chemically tweaked letters, and lab-made mRNA does not. So the pair built mRNA with tweaked letters. The alarm almost disappeared, and the tweaked mRNA made far more protein [13].

The key paper came out in 2005, fifteen years before the pandemic. In 2023, the discovery won Karikó and Weissman the Nobel Prize in Physiology or Medicine [13].

A tweaked message inside a fat bubble: by 2020 the parts were ready. One catch remained, and the catch showed up on delivery trucks. Why did the vials need a freezer?

Why so cold?

At launch, the Moderna vaccine was stored at −20 to −15 °C, close to a kitchen freezer. The Pfizer-BioNTech vaccine was stored at −80 to −60 °C, about as cold as dry ice [12]. The two products differ in their recipes and in their storage rules.

In February 2021, the US Food and Drug Administration (FDA) let the Pfizer-BioNTech vials sit in an ordinary pharmacy freezer for up to two weeks [14]. Storage rules kept changing as the makers gathered more data, and the rules differ by product.

Now you have every part: a recipe, a ribosome, a harmless piece, trained defenders, a self-destructing message, a fat bubble and a freezer. How do the parts fit together in one real dose?

How it really works

One dose, seven steps, and every step is something you have now seen. So where else does the recipe idea show up?

Where it shows up

COVID-19 was the first big job. Two mRNA vaccines were approved in December 2020, and more than 13 billion COVID-19 vaccine doses of all kinds have been given worldwide [13]. The mRNA approach joined three older ways of making a vaccine:

Factory cells are slow to scale up, which is why a vaccine that needs no cell culture was a long-standing goal [13]. Before the pandemic, companies had already been working on mRNA vaccines against Zika and MERS [13].

Because a new mRNA vaccine starts as a new string of letters, researchers are testing mRNA against other diseases too, including flu and cancer, with some candidates in clinical trials [12]. Many of those projects are still experiments, and the results so far vary.

Where to go next

This page opens bigger questions. These are the ones worth chasing:

• There are 64 codons but only 20 amino acids. Why do several codons mean the same thing?
• How does a cell decide which DNA recipes to copy, and when?
• How does a body build a huge variety of defender shapes before meeting any germ?
• Could a cell be sent a recipe for a missing protein, to treat a disease instead of training the immune system?
• How do scientists see the shape of a protein as small as the spike?

What to learn next: search for "the central dogma of biology", then "translation and tRNA", then "clonal selection" and "lipid nanoparticles". Each topic is one step past this page.

Ask Phy

• Walk me through how a ribosome and tRNA build a protein, codon by codon.
• Explain how B cells and T cells each learn from a vaccine, with a simple analogy.
• Compare mRNA, protein and whole-virus vaccines: what goes in the shot, and who builds the piece?

Sources

1. Moderna: "Moderna Announces First Participant Dosed in NIH-led Phase 1 Study of mRNA Vaccine (mRNA-1273) Against Novel Coronavirus" (press release, filed with the SEC, March 16, 2020) — Sequence shared January 11, 2020; vaccine sequence finalized January 13, 2020; a prefusion-stabilized spike.
2. NHGRI Talking Glossary: Ribosome — The ribosome reads mRNA and links amino acids into a chain.
3. NHGRI Talking Glossary: Codon — Three letters per codon; 64 codons.
4. NHGRI Talking Glossary: Transfer RNA (tRNA) — The carrier that brings each amino acid and pairs with the mRNA.
5. UniProt P0DTC2: Spike glycoprotein, SARS-CoV-2 — 1,273 amino acids; starts M F V F L V L L; binds the ACE2 receptor on human cells.
6. BioNumbers 107952: Rate at which ribosomes progress from 5' ends of transcripts (Ingolia, Lareau and Weissman, Cell, 2011) — 5.6 amino acids per second in mouse cells.
7. NHGRI Talking Glossary: Messenger RNA (mRNA) — mRNA is copied from DNA and carries the recipe out of the nucleus.
8. CDC: COVID-19 Vaccine Basics — mRNA enters muscle cells, does not enter the nucleus, and is broken down; cells make a harmless piece of the spike.
9. Janeway, Travers, Walport and Shlomchik: Immunobiology, 5th edition, chapter 1 (NCBI Bookshelf) — Clonal selection: each defender carries one receptor shape, and the ones that fit multiply.
10. NHGRI Talking Glossary: Antibody — Antibodies recognize foreign substances and keep circulating after exposure.
11. Schwanhäusser et al.: "Global quantification of mammalian gene expression control", Nature 473, 337–342 (2011) — Median mRNA half-life about 9 hours in mouse cells (proteins about 46 hours).
12. Hou, Zaks, Langer and Dong: "Lipid nanoparticles for mRNA delivery", Nature Reviews Materials 6, 1078–1094 (2021) — Why mRNA needs a carrier, how the bubble releases it, the parts of the message, storage temperatures, cancer vaccines in trials.
13. The Nobel Prize in Physiology or Medicine 2023: press release — Karikó and Weissman: modified bases calm the alarm and raise protein output; 2005 paper; other kinds of vaccine.
14. FDA: "FDA Allows More Flexible Storage, Transportation Conditions for Pfizer-BioNTech COVID-19 Vaccine" (February 25, 2021) — Preferred storage −80 to −60 °C; up to two weeks in a standard pharmacy freezer.
15. Tan et al.: "High-throughput identification of prefusion-stabilizing mutations in SARS-CoV-2 spike", Nature Communications 14, 2003 (2023) — US COVID-19 vaccines encode a spike with two prolines (K986P, V987P) that hold its pre-fusion shape.
16. Krauson et al.: "Duration of SARS-CoV-2 mRNA vaccine persistence and factors associated with cardiac involvement in recently vaccinated patients", npj Vaccines 8, 141 (2023) — Vaccine mRNA found in nearby (armpit) lymph nodes in most patients within 30 days of a shot, and in none after 30 days.