The Forgotten History of Vaccines: From Variolation to mRNA

The textbook story of vaccines opens with Edward Jenner deliberately inoculating eight-year-old James Phipps with cowpox in 1796 and discovering that this protected the boy against smallpox. It is the founding story of modern immunology and it is partial in a way that hides most of what is interesting. Smallpox prevention was a thousand years old when Jenner started; Jenner's contribution was a safer technique, not the underlying idea. The history that gets you from there to mRNA is a long story of people trying to convince an immune system to recognize an enemy it has not yet met.

Variolation: a thousand years before Jenner

The Chinese practice of inoculating against smallpox by drying scabs from a mild case and blowing the powder up the nose of a healthy child appears in medical texts by the 11th century and was likely older. The Indian Ayurvedic tradition used a similar technique with skin scratches. The practice spread through the Ottoman Empire by the 16th and 17th centuries and was introduced to Europe in 1721 by Lady Mary Wortley Montagu, who had seen it work in Constantinople and had her own daughter inoculated in London under medical observation.

The technique worked but was dangerous. Roughly one to two percent of variolated patients died of the deliberately-induced smallpox; the natural disease killed twenty to thirty percent of those it infected, so on a population basis the math favored variolation. The American Continental Army was variolated in 1777 by order of George Washington, who had survived natural smallpox as a young man and understood what it could do to an army camped together. The Continental Army's losses to smallpox dropped from roughly 17 percent to under one percent.

Variolation is the technological context Jenner inherited. The conceptual leap of inducing immunity by deliberate exposure was already common medical practice. Jenner's contribution was the observation that milkmaids who had contracted cowpox seemed never to get smallpox, and the experimental confirmation that this could be deliberately induced with much lower risk than variolation. The cowpox technique used a different virus, related enough to provoke cross-immunity but mild enough not to kill anyone. Within twenty years it had largely replaced variolation in Europe.

The hundred-year gap

For nearly a century after Jenner, smallpox was the only vaccine. The reason is that the field had no theory: nobody knew what a virus was, what cowpox actually contained, why variolation worked, or what an immune system was. Pasteur's 1880s rabies and anthrax vaccines were the first deliberate attempts to derive new vaccines from theory rather than empirical observation, and his theory — that you could attenuate a pathogen by aging or culturing it until it lost virulence while retaining its ability to provoke immunity — was correct in important cases and wrong in others.

The 20th century filled in the gaps. Diphtheria toxoid (1923) was the first vaccine made from a chemically inactivated toxin. Inactivated whole-virus vaccines (influenza in 1936, polio in 1955) showed that you could kill a pathogen with formaldehyde and still get immunity. Live attenuated vaccines (Sabin polio in 1962, MMR through the 1960s and 70s) recapitulated Pasteur's strategy with much better cell-culture techniques. Subunit vaccines (hepatitis B in 1986) used purified pieces of pathogen surface protein rather than the whole organism. Each technology required decades of basic immunology and biochemistry to support it.

The polio campaign deserves a paragraph for the scale of what it did. Polio paralyzed half a million children annually worldwide in the early 1950s. The Salk inactivated vaccine (1955) and Sabin oral vaccine (1962) reduced this by two orders of magnitude within a decade in the countries that adopted them. The 1988 WHO Global Polio Eradication Initiative reduced annual cases from 350,000 to under fifty by 2024. Wild poliovirus is currently endemic in two countries (Pakistan and Afghanistan) and the eradication is technically achievable. The moral and political work required to do this — vaccinating into active conflict zones, training village health workers, maintaining cold chains in places without reliable electricity — is one of the great unfinished public-health projects.

The mRNA breakthrough

The COVID-19 mRNA vaccines deployed in late 2020 were not invented for COVID-19. The underlying technology had been in development since the late 1980s, when researchers first observed that synthetic mRNA introduced into cells could be translated into protein. The obstacle for the next thirty years was that the immune system rapidly destroys foreign mRNA, and the chemical modifications needed to evade that destruction were not worked out until Katalin Karikó and Drew Weissman's 2005 paper showing that pseudouridine substitution dramatically reduced inflammatory response and increased protein expression. Karikó had spent the 1990s with mRNA work that nobody at the University of Pennsylvania thought was a viable career path; her 2023 Nobel Prize in Physiology or Medicine recognized work that took thirty years to find an application that proved its value.

The mRNA approach inverts the traditional vaccine pattern. Conventional vaccines deliver a piece of the pathogen (or an attenuated form of it) and let the immune system respond to that. mRNA vaccines deliver instructions for the cell to manufacture a piece of the pathogen — typically the spike protein on the virus's surface — and let the immune system respond to the protein the cell makes. The lipid nanoparticle delivery system that made this practical was largely worked out by 2018; the SARS-CoV-2 sequence was published on January 11, 2020; Moderna had a candidate vaccine in trials within 63 days. The speed was possible because the pieces had been assembled over decades for other reasons.

What the mRNA platform makes possible

The structural significance of mRNA is that the platform is reusable. The lipid nanoparticles, the manufacturing process, the delivery mechanism are pathogen-independent. Switching to a new target requires changing the mRNA sequence, which is a relatively trivial molecular biology exercise compared to growing virus in chicken eggs for influenza vaccines or culturing live cells for polio vaccines. mRNA vaccines for influenza, RSV, malaria, and various cancer-specific neoantigens are in clinical trials in 2026; the cancer applications are particularly interesting because each patient's tumor has a unique antigen profile and the platform allows per-patient vaccine design.

The technology has its own weaknesses. mRNA vaccines require deep-cold storage that is hard to maintain in low-resource settings. They induce a strong but relatively short-lived immune response, which is why COVID boosters became routine. They cost more per dose to manufacture than well-established conventional vaccines. The platform is genuinely transformative without being a replacement for everything that came before.

The deeper observation

The two-century gap between Jenner and Karikó was filled with incremental work that nobody expected to compound the way it did. Pasteur's attenuation theory, the discovery of viruses, the development of cell culture, the elaboration of immune memory mechanisms, the structural biology of antigens, the chemistry of nucleic-acid modifications — each was a separate research program with its own funders, its own success criteria, its own dead ends. mRNA vaccines required all of them. The pattern that recurs in technology history is that transformative platforms are syntheses of decades of work in apparently unrelated fields, and the people who synthesize them are often working at the intersection of disciplines that did not previously talk to each other. Karikó's 1990s mRNA work was uninteresting to virologists, who already had vaccines, and to immunologists, who already had antibodies, and to molecular biologists, who already had cloning. The application that proved the technology came from a domain that did not yet exist when the underlying chemistry was being worked out.