Lesson 5 — How Vaccines Work

Understanding the Complex: How Do Vaccines Actually Work?

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In 1796, Edward Jenner — a country doctor in rural England — noticed something his colleagues had dismissed as folklore: milkmaids who got cowpox seemed not to get smallpox. Cowpox was a mild disease; smallpox was a killer. Jenner tested the observation methodically. He took material from a cowpox lesion on the hand of a milkmaid named Sarah Nelmes and inoculated an eight-year-old boy named James Phipps. Six weeks later, he exposed the boy to smallpox. The boy did not get sick.

Jenner called his method "vaccination" — from vacca, the Latin word for cow. He had no idea why it worked. The germ theory of disease would not exist for another seventy years; the concept of the immune system as we understand it took a century more. He observed a pattern, tested it carefully, and documented the result. The mechanism, science would discover later, is exactly what we described in lesson four: the cowpox virus's antigens were similar enough to smallpox's that the immune memory formed against cowpox also protected against smallpox.

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The classical approaches

In the two centuries since Jenner, vaccinologists have developed several distinct strategies for presenting antigens to the immune system. Each involves a different tradeoff between efficacy, safety, manufacturing complexity, and stability.

Live-attenuated vaccines use a weakened version of the actual pathogen — weakened through repeated passage in cell culture or laboratory conditions until it can replicate in the body but cannot cause serious disease. The measles-mumps-rubella (MMR) vaccine works this way, as does the oral polio vaccine. Because they closely mimic natural infection, live-attenuated vaccines tend to produce strong, long-lasting immunity — often after a single dose. The tradeoff: they require careful cold-chain storage, and they can, in rare cases, revert to a more virulent form. They are also unsuitable for people with severely compromised immune systems.

Inactivated vaccines use pathogens that have been killed — rendered unable to replicate — but whose structure (and thus antigens) remains recognizable to the immune system. Seasonal influenza vaccines are often inactivated. They are generally safer than live-attenuated vaccines but typically produce a less robust immune response, often requiring multiple doses or adjuvants (immune-stimulating additives) to boost efficacy.

Protein subunit vaccines go further: instead of using the whole pathogen, they use only specific proteins derived from it — the antigens themselves, without the rest of the pathogen. The hepatitis B vaccine works this way, as does the pertussis component of the DTaP vaccine. They are precise and safe; the immune system sees only what you want it to see. But producing the proteins requires sophisticated biotechnology, and the immune response, lacking the inflammatory context of a live infection, may be weaker.

Toxoid vaccines target bacterial toxins rather than the bacteria themselves. Tetanus and diphtheria vaccines use chemically inactivated versions of the toxins these bacteria produce. The immune system builds antibodies against the toxin; when the real toxin appears, it is neutralized before it can cause damage.

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The mRNA approach: blueprint instead of protein

All of the approaches above deliver some form of antigen directly — either the pathogen itself (live or dead), a protein derived from it, or an inactivated toxin. mRNA vaccines work differently. They do not deliver antigen at all. They deliver instructions for making antigen.

mRNA — messenger RNA — is a molecule that cells use every day to carry genetic instructions from the nucleus to the ribosomes, where those instructions are read and proteins are built. An mRNA vaccine delivers a strand of synthetic mRNA encoding a specific protein — in the case of the COVID vaccines, the spike protein of SARS-CoV-2.

The delivery vehicle is critical. Naked mRNA would be degraded by enzymes in the body before it could reach cells. BioNTech and Moderna both encapsulate the mRNA in lipid nanoparticles — tiny spheres of fat-like molecules that fuse with cell membranes and release the mRNA inside.

Once inside the cell, the mRNA is read by ribosomes, which produce copies of the spike protein. Those spike proteins appear on the cell surface. The immune system — detecting a foreign protein — mounts an adaptive immune response. Memory cells form. The mRNA itself is degraded within days; it never enters the nucleus, and it cannot interact with DNA. It leaves no trace in the genome.

This is not merely a theoretical claim. mRNA cannot be reverse-transcribed into DNA without a specific enzyme (reverse transcriptase) that human cells do not possess. The vaccine mRNA does not carry that enzyme. The biology here is well established, and the "it changes your DNA" claim is mechanistically impossible given how both mRNA and human cellular machinery work.

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The mRNA platform, we will see in the next lesson, is not just a new way to make vaccines. It is an entirely new class of medicine — and its implications extend well beyond infectious disease.

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Next lesson: The mRNA revolution — Katalin Karikó's twenty years of rejection, and the cancer vaccines now entering clinical trials.

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Reading time: approx. 10–11 minutes