How Vaccines Work: From Cowpox to mRNA

What a Vaccine Is

A vaccine is a biological preparation that trains the body to defend itself against a specific disease before it ever meets the real thing. Doctors call the protection it gives active acquired immunity: active, because the body's own immune system does the work, and acquired, because the protection is learned during life rather than inherited at birth.

Most vaccines contain something that looks like a disease-causing microorganism without being able to cause the full illness. This can be a weakened or killed form of the microbe, an inactivated version of a toxin it produces, a single protein from its surface, or a set of genetic instructions that lets the body's own cells make such a protein for a short time. The immune system treats this harmless look-alike as a threat, destroys it and, most importantly, remembers it. If the real germ appears later, the body recognizes it quickly and fights it off, often before any symptoms develop.

Most vaccines are used to prevent infectious diseases caused by viruses and bacteria, such as measles, polio, tetanus or influenza. Some also protect against cancer: the vaccine against human papillomavirus (HPV) prevents infections that can lead to cervical cancer, and the hepatitis B vaccine lowers the risk of a type of liver cancer. Scientists are also developing therapeutic cancer vaccines, which aim to help the immune system attack tumors that already exist.

How Vaccines Train the Immune System

To understand vaccines, it helps to know how the immune system handles a new invader. Every germ carries molecules on its surface, often proteins, that the body can identify as foreign. These molecules are called antigens. When the immune system meets an unfamiliar antigen, it launches a response that takes days to build up. That delay is why a first infection with a new disease can make a person very sick.

The main players

• B cells produce antibodies, Y-shaped proteins that latch onto a specific antigen. Antibodies can block a virus from entering cells or mark bacteria for destruction.
• Helper T cells coordinate the response and help B cells make better antibodies.
• Killer (cytotoxic) T cells find and destroy the body's own cells that have been infected by a virus.
• Memory cells are long-lived B and T cells that remain after the infection is over. They are the real goal of vaccination.

A vaccine stages a rehearsal. Because the antigen it delivers cannot cause the full disease, the body has time to go through the slow first response safely. The memory cells left behind mean that a later encounter with the real pathogen triggers a much faster and stronger reaction. For many diseases this is the difference between a serious illness and no illness at all.

Boosters and adjuvants

Some vaccines give lifelong protection after one or two doses, while others need repeated doses called boosters to keep immunity strong. Tetanus protection, for example, fades over the years, so adults are advised to get booster shots. Many vaccines also contain an adjuvant, an ingredient that makes the immune response stronger. Aluminum salts have been used as adjuvants for many decades. Adjuvants allow a vaccine to work well with a smaller amount of antigen.

From Smallpox Scabs to Cowpox: The Birth of Vaccination

Long before anyone knew that germs existed, people noticed that survivors of smallpox almost never caught it again. Smallpox was one of the deadliest diseases in human history, and many societies tried to use this observation. In a practice called variolation, healthy people were deliberately exposed to material from smallpox sores, usually through a small cut in the skin or, in China, by blowing powdered scabs into the nose. Variolation usually caused a milder illness than natural smallpox, but it was risky: some people died, and those infected could spread the disease to others.

Variolation was practiced for centuries in parts of Asia and Africa and in the Ottoman Empire. In 1721 it was promoted in England by Lady Mary Wortley Montagu, who had seen it in Constantinople and had her own children inoculated. In the same year, during a smallpox epidemic in Boston, the minister Cotton Mather encouraged the practice after learning about it from Onesimus, an enslaved African man who described how it was done in his homeland.

The decisive step came from the English country doctor Edward Jenner. Farmers had long said that milkmaids who caught cowpox, a mild disease picked up from cows, did not get smallpox. In 1796 Jenner tested this idea. He took material from a cowpox sore on the hand of a milkmaid, Sarah Nelmes, and introduced it into a small cut on the arm of James Phipps, the eight-year-old son of his gardener. Later he exposed the boy to smallpox material, and the boy did not fall ill. Jenner's method was far safer than variolation and spread quickly through Europe and beyond.

The word vaccine comes from the Latin vacca, meaning cow, a reminder of the cowpox origins of the method. Later, the French scientist Louis Pasteur proposed using the words vaccine and vaccination for all such preventive treatments, in honor of Jenner's work.

Pasteur and the Age of Laboratory Vaccines

Jenner had found a lucky natural shortcut: a related, milder disease. Louis Pasteur showed in the late nineteenth century that scientists could create weakened germs on purpose. Working with chicken cholera, his team found that bacteria grown in old cultures lost much of their power to cause disease but could still protect chickens from fresh, dangerous bacteria. Pasteur realized that weakening, or attenuating, microbes in the laboratory was a general method.

He applied the idea to anthrax, a disease that killed farm animals, and demonstrated an anthrax vaccine in a famous public experiment with sheep in 1881. In 1885 he and his colleagues treated Joseph Meister, a boy who had been bitten by a rabid dog, with a series of injections of a weakened rabies preparation. The boy survived, and the success made Pasteur famous around the world. Rabies has an unusually long incubation period, which is why a vaccine given after a bite can still prevent the disease from developing.

In the twentieth century, vaccines followed against diphtheria, tetanus, whooping cough, tuberculosis, yellow fever, influenza, polio, measles, mumps, rubella and many other diseases. The polio vaccines developed by Jonas Salk (an injected, inactivated vaccine introduced in 1955) and Albert Sabin (a live oral vaccine given as drops) turned a disease that had paralyzed many thousands of children every year into one that is now close to eradication.

The Main Types of Vaccines

All vaccines share one goal, presenting the immune system with a safe version of an antigen, but they reach it in different ways.

1. Live attenuated vaccines contain a living but weakened germ that can multiply a little without causing serious illness. Because they closely imitate a natural infection, they often give strong, long-lasting immunity. Examples include the measles, mumps and rubella (MMR) vaccine and the yellow fever vaccine. They are usually not given to people whose immune systems are severely weakened.
2. Inactivated vaccines contain germs that have been killed with heat or chemicals. They cannot multiply, so they often need several doses. The injected polio vaccine and rabies vaccines are examples.
3. Subunit, recombinant and protein vaccines use only selected pieces of a germ, often a surface protein. The hepatitis B vaccine was among the first made with genetic engineering, using yeast cells to produce the viral protein. The HPV vaccine uses proteins that assemble into empty virus-like shells with no genetic material inside.
4. Toxoid vaccines protect against diseases in which the main damage comes from a toxin produced by bacteria. The toxin is chemically inactivated so it cannot harm the body but still teaches the immune system to neutralize it. Tetanus and diphtheria vaccines work this way.
5. Conjugate vaccines attach sugar molecules from a bacterium's outer coating to a carrier protein. Young children's immune systems respond poorly to such sugars alone, and linking them to a protein solves the problem. Vaccines against Haemophilus influenzae type b (Hib), pneumococcus and meningococcus are conjugate vaccines.
6. Viral vector vaccines use a harmless virus as a delivery vehicle to carry genetic instructions for an antigen into cells. Some COVID-19 vaccines and a vaccine against Ebola use this approach.
7. mRNA vaccines deliver a piece of messenger RNA wrapped in tiny fat particles. Cells read the instructions, make the antigen for a short time and then break the mRNA down. The mRNA never enters the cell nucleus and does not change a person's DNA.

The mRNA Breakthrough

Scientists worked on the idea of mRNA vaccines for decades, but early versions caused unwanted inflammation and broke down too easily. A key discovery came from the Hungarian-born biochemist Katalin Karikó and the American immunologist Drew Weissman, who found that slightly modifying the building blocks of mRNA allowed it to enter cells without setting off a harmful inflammatory reaction. Their work, together with advances in packaging mRNA in lipid nanoparticles, made the COVID-19 mRNA vaccines possible.

When the COVID-19 pandemic began, these vaccines were designed, tested in large clinical trials and authorized within about a year, far faster than any vaccine before. The speed came from years of earlier research, very large trials running different phases in parallel, and governments funding manufacturing before the results were known, not from skipping safety steps. In 2023 Karikó and Weissman received the Nobel Prize in Physiology or Medicine for their discoveries. Because an mRNA vaccine can be redesigned simply by changing the genetic sequence, researchers are now testing the technology against other infections and against cancer.

Herd Immunity: Protection That Spreads

Vaccines protect not only the person who receives them. When enough people in a community are immune, a germ cannot find enough new hosts to keep spreading, and outbreaks die out. This effect is called herd immunity or community immunity. It shields people who cannot be vaccinated, such as newborn babies, some people with serious illnesses and those whose immune systems do not respond well to vaccines.

The share of people who need to be immune depends on how contagious a disease is. Measles is one of the most contagious diseases known, so vaccination coverage of about 95 percent is needed to prevent outbreaks. When coverage drops, even in a single town or school, measles can return quickly.

Key Achievements in Numbers

• Smallpox killed hundreds of millions of people in the twentieth century alone. A worldwide vaccination campaign led by the World Health Organization (WHO) found and contained the last outbreaks, and in 1980 the World Health Assembly declared smallpox eradicated. It was the first human disease ever eliminated from the planet.
• Rinderpest, a devastating disease of cattle, was declared eradicated in 2011, the second disease wiped out completely, again thanks to vaccination.
• Polio cases have fallen by more than 99 percent since a global eradication effort started in 1988, and wild poliovirus survives in only a very small number of countries.
• WHO launched its Expanded Programme on Immunization in 1974 to bring basic childhood vaccines to every country. Today vaccines are estimated to prevent several million deaths every year.

How Vaccine Safety Is Checked

The safety and effectiveness of vaccines are among the most studied topics in medicine. Before a vaccine is approved, it passes through laboratory studies and then clinical trials in several phases: small groups of volunteers first, then hundreds, then often tens of thousands of people, with results compared against a group that did not receive the vaccine. Regulators review the data before allowing the vaccine to be used.

Monitoring continues after approval. Health agencies run reporting systems and large studies that look for rare side effects that only show up when millions of people are vaccinated. The most common reactions are mild and short-lived: a sore arm, slight fever or tiredness for a day or two, signs that the immune system is responding. Serious allergic reactions are very rare, which is why people are usually asked to wait a few minutes after a shot.

Vaccines have also faced misinformation. A 1998 paper claiming a link between the MMR vaccine and autism was found to be fraudulent and was retracted, and its lead author lost his medical license. Many large studies involving millions of children have found no such link. Even so, the fear it created contributed to falling vaccination rates and to measles outbreaks in several countries.

Lesser-Known Facts About Vaccines

• The virus used in the modern smallpox vaccine is called vaccinia. Genetic studies show it is related to cowpox but is not identical to it, and its exact origin is still debated.
• Many influenza vaccines are still grown in chicken eggs, which is why people with severe egg allergies were once advised to be careful. Newer methods use cell cultures instead.
• Flu vaccines are updated regularly because the influenza virus changes constantly. WHO experts recommend new strain compositions twice a year, once for the Northern Hemisphere and once for the Southern Hemisphere.
• Not every vaccine is a shot. Oral vaccines exist against polio, rotavirus and cholera, and one type of flu vaccine is sprayed into the nose.
• Many vaccines must be kept cold, typically between 2 and 8 °C, from the factory to the clinic. This chain of refrigerators, cool boxes and freezers is known as the cold chain, and maintaining it in remote areas is one of the biggest challenges of global immunization.
• Vaccines protect animals too. In parts of Europe, vaccine-filled baits dropped from aircraft for wild foxes helped eliminate fox rabies from several countries.

Why Vaccines Still Matter

Many diseases that once filled hospitals, such as diphtheria, whooping cough and measles, have become rare in places with high vaccination rates. Because few people today have seen these illnesses, it is easy to forget how dangerous they were. The germs, however, have not disappeared, and they can return whenever immunity in a population weakens.

Research continues on vaccines against diseases that are still difficult to prevent, including malaria, tuberculosis and HIV. In 2021 WHO recommended the first malaria vaccine for wide use among children in regions where the disease is common, an achievement that took decades of work because the malaria parasite is far more complex than a virus. From Jenner's experiment with a milkmaid's cowpox to vaccines designed on a computer from a genetic code, the idea has stayed the same: teach the body in advance, so it is ready when the real danger comes.