DNA sequenced from 150-year-old smallpox vaccination kits sheds some light on the evolutionary history of the viral strains used in smallpox vaccines.

Throughout the 1860s and 1870s, several Philadelphia doctors left their vaccination kits to the collections of the Mütter Museum – some with bits of scab material still clinging to the insides of the tin boxes and microscopic residue from pus on the glass slides. 150 years later, molecular anthropologist Ana Duggan, ancient geneticist Jennifer Klunk, and their colleagues found fragments of both human and viral DNA in that material. The DNA sequences from the vaccination kits offer a snapshot of the early days of vaccination, when doctors used horsepox and cowpox interchangeably and collected their vaccine ingredients straight from infected human pustules.

The virus that helped protect people in Philadelphia against smallpox during and after the Civil War turns out to be closely related to the modern vaccinia virus: a milder relative of smallpox.

On the shelves of the Mütter Museum’s collection of medical artifacts, Duggan, Klunk, and their colleagues found five smallpox vaccination kits dating from 1859 to 1873. At the time, doctors who wanted to mix up a dose of smallpox vaccine actually collected fluid and bits of scab from people infected with horsepox or cowpox. The kits they carried for the job included glass plates for mixing up lymph fluid from pustules, tin boxes for carrying bits of scab material, and lancets for applying the infected mess to a scratch or cut on the patient’s skin.

Duggan, Klunk, and their colleagues sequenced DNA from traces of 150-year-old scab materials in the tin boxes, as well as microscopic residues left behind on the glass plates and inside the boxes (sterilization wasn’t a big deal yet in the 1860s). They compared the fragments of viral DNA with the genomes of modern members of the genus Orthopox, including smallpox, vaccinia, cowpox, and horsepox. Statistical models sorted the viral DNA from the 19th-century vaccines into the same group as vaccinia virus.

Vaccinia is probably an accidental hybrid of the cowpox and horsepox viruses used as smallpox vaccines through the 1800s and early 1900s, but we can’t trace its family tree in much more detail than that.

The Weird Family Tree Of Smallpox Vaccine Strains

As Edward Jenner figured out in 1796, most orthpox viruses are so genetically similar that infection with one can help develop immunity against others (please do not try this at home). Jenner started with smallpox, but others later started using horsepox as well. There was no standardization in vaccine production until the early 20th century, and most of the time there was very little record about where the material used to make the vaccine had come from, let alone what it actually contained.

A group of virologists discovered vaccinia in 1939, when the tested the contents of eggs which were used in vaccine production at the time. The probably expected to find a strain of either cowpox or horsepox. Instead, they found an entirely new virus – one that had evolved in a vaccine manufacturing lab, not an animal host out in the wild.

As a side note, “cowpox” and “horsepox” may technically be misnomers. Although people first discovered the viruses in cows and horses, respectively, Duggan, Klunk, and their colleagues point out that “neither cows nor horses are considered the natural reservoirs of these viruses.” What are their natural reservoirs? Virologists and ecologists are still working on that question.

Meanwhile, an orthopox virus call Cantalogo, which infects dairy cows in Brazil, may be a former vaccine strain that accidentally made it out into the wild sometime in the 1800s. Duggan, Klunk, and their colleagues suggest that a "horsepox" strain found in Mongolia in 1976 may also be an escaped vaccinia strain, since statistical models also sort it into the same lineage as vaccinia virus.

“Vaccination Was A Uniquely Human Process”

The virus strains in all 5 vaccination kits were very closely related, and they were also very closely related to a commercially-made vaccine sample from 1902. The 1902 vaccine sample had also been manufactured in Philadelphia, like all 5 of the Mütter Museum’s kits from the 1860s and 1870s. Duggan, Klunk, and their colleagues say that could be a hint that by the 1860s, there weren’t many orthopox virus strains going around in Philadelphia, and doctors and pharmaceutical companies may already have been getting the vaccine ingredients from a common source.

In the late 1800s, “a common source” meant a strain of virus found in infected people.

“Vaccination was a uniquely human process,” wrote Duggan, Klunk, and their colleagues. “Vaccination material was still being produced within humans and transferred directly from donors to patients.” That changed in the early 20th century, as consumers and regulators started realizing that there were some health and safety concerns involved in putting infected pus from one person directly into another. Around the same time, pharmaceutical companies started realizing it was more cost-effective to mass-produce viral strains for vaccines in animals. Today, the strains of vaccinia virus used for smallpox vaccines are produced in various cell cultures.

In much of the American South, Black children were often infected with cowpox or horsepox so that doctors or vaccine manufacturers could harvest pus and scabs to make vaccines. That practice came about nearly a century after Boston minister Cotton Mather (yes, the same Cotton Mather from the Salem Witch Trials) took the idea for inoculation against smallpox from an enslaved African man in his household, Onesimus. And it’s a clearly racist iteration of the same socioeconomic hierarchy that led Edward Jenner to test the first smallpox vaccine on his gardener’s son.

Medical history is littered with things that make you furious just reading about them.

We have no way to know who supplied vaccination material to doctors in 1860s Philadephia, but human DNA from the vaccination kits suggests that the scabs and pus came from people of European descent, and two thirds of the samples were female. It’s reasonable to imagine that these individuals were probably not financially well-off or socially well-connected, but even with scraps of their DNA in hand, they remain anonymous.

Duggan, Klunk, and their colleagues published their results in the journal Genome Biology.

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