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Scientists shed new light on an old mystery: the origins of the smallpox vaccine

Edward Jenner performing the first vaccination against smallpox
Gaston Melingue, oil on canvas, 1879
A painting of Edward Jenner performing the first vaccination against smallpox.

The story of Edward Jenner, a British country doctor who pioneered the smallpox vaccine at the end of the 18th century, is one of the most famous in medicine.

On May 14, 1796, Jenner inoculated the 8-year-old son of his gardener several times with pus taken from a fresh cowpox lesion on the hand of a young milkmaid, Sarah Nelms. Jenner had become intrigued with a bit of local folklore that noted how milkmaids who contracted cowpox, a mild illness, never came down with smallpox, a dreaded disease that was killing more than 400,000 people annually in Europe alone.

Jenner believed that the pus in the cowpox blisters somehow protected the milkmaids from developing smallpox.

The gardener’s son, James Phipps, developed a cowpox lesion and a fever, but then fully recovered. Two months later, in July, Jenner inoculated the boy again — this time with fresh smallpox. Phipps did not become ill. Jenner concluded (rightly) that the cowpox inoculation had given the boy protection from the more serious smallpox. (Yes, yes, this experiment was terribly unethical, but that’s a topic for another day.)

Jenner decided to call his new procedure vaccination, from the Latin vaccinus, meaning “of or from a cow.”

Although it took some time, Jenner’s technique soon became widespread, saving countless lives. In 1979, after an aggressive 10-year global immunization campaign, the World Health Organization announced the eradication of the disease.

It marked one of the greatest public health successes in history.

A long-standing mystery

For more than two centuries, the central element of this story — that cowpox was the source of Jenner’s smallpox vaccine — has remained unchallenged, at least in popular history books. In the scientific world, however, questions about the source of the vaccine have been percolating for decades.

In the 1930s, scientists discovered, much to their surprise, that the virus in smallpox vaccines used at that time was not cowpox, but a related virus, which has since been named vaccinia. The exact origins of vaccinia are unknown.

That finding led many medical historians to wonder about the true identify of the virus used by Jenner back in 1798.

We may now be closer to an answer. In a research letter published Thursday in the New England Journal of Medicine (NEJM), an international team of virologists reported the results of a DNA analysis of the earliest sample of smallpox vaccine ever studied.

The original wooden and glass containers
New England Journal of Medicine
The original wooden and glass containers that held the capillaries with the Mulford 1902 smallpox vaccine.

The sample, which was in a private collection, was manufactured in 1902 by a Philadelphia company called H. K. Mulford.

The researchers found that the sample’s genome was 99.7 percent similar to horsepox, not cowpox.

“We now have, for the first time, scientific evidence that horsepox virus was indeed used in the past to immunize against smallpox,” said virologist Andreas Nitsche from the Robert Koch Institute in Berlin, in a released statement.

Not final proof

That doesn’t mean that the virus Jenner used on Phipps was horsepox. But it might have been. Cows can become infected with horsepox, producing similar-looking pustular lesions.

So the milkmaid Sarah Nelms could have had horsepox, not cowpox.

Indeed, even Jenner suspected that cowpox began as a disease of horses that was then transmitted to cows. And throughout Europe during the 19th century, pus collected from both cowpox and horsepox lesions were used interchangeably to immunize against smallpox.

“The origin of the Mulford 1902 vaccine stock is unknown, but it was probably obtained from Europe because horsepox was absent from the Americas,” the researchers write.

The sample thus serves as a link between 19th-century and modern smallpox vaccines — and “strengthens the hypothesis that the horsepox virus may be the ancestor of the vaccinia lineage,” they add.

For more information: The letter reporting the DNA findings of the smallpox vaccine sample can be read online on the New England Journal of Medicine's website.

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