As the world anxiously pins its hopes on vaccines to halt the coronavirus pandemic, scientists are still learning from the first global scourge to be eradicated by vaccination.

Ancient-DNA sleuths analyzing Civil War-era artifacts with 21st-century sequencing techniques have recreated five genomes of viral vaccines mustered to fight smallpox in the 1860s, finding they were quite different from those used a century later to finally wipe out the disease. 

Remarkably, scientists were able to recover viral molecules from the scabs, blisters, pus, and other biological traces lingering on knife-like lancets, tin boxes, and glass slides tucked into leather vaccination kits discovered at a Philadelphia museum of medical history. Doctors carried these custom-built cases to inoculate soldiers and citizens from smallpox while the North and South fought on nearby battlefields more than 150 years ago. Vaccines were made not in labs or factories then, but instead were grown in a human chain of people exposed to related but mild cousins of smallpox.

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Their work reveals how smallpox viruses used in those early vaccines slowly evolved within the larger family of orthopoxviruses, with a surprising variety of strains marshaled to fight a deadly virus. While hesitant to tie their discoveries to current vaccine efforts, the researchers said their work is a reminder that distantly related viruses can play a role in protection, depending on how rapidly the target pathogen evolves.

“One of the reasons you have lifelong immunity is because the virus shifts so little over the course of its history,” said Hendrik Poinar, director of the McMaster University Ancient DNA Centre and a co-author of the paper published Sunday in Genome Biology. “This work points to the importance of looking at the diversity of these vaccine strains. We don’t know how many could provide cross-protection from a wide range of viruses, such as flus or coronaviruses.”

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Knowing the genomic sequence of old smallpox vaccines can shed light on the viruses used in the past to immunize against the disease, said Clarissa Damaso, an associate professor of virology and molecular biology at the Federal University of Rio de Janeiro in Brazil. She was not involved in the research. “These samples are now the oldest smallpox vaccine samples ever sequenced. I think we need to dig into this more and more, trying to find older vaccine samples and closer to the path taken from Edward Jenner to the 1900s.”

It’s a discovery that almost didn’t happen. While giving a tour to a new employee, Robert Hicks, then director of the Mütter Museum in Philadelphia, spotted the Civil War vaccination kits in a drawer meant to hold phlebotomy instruments. Immediately recognizing them for what they were, he had museum staffers send the kits — which had been donated by physicians who used them in the 1860s — to the Centers for Disease Control and Prevention in case they carried smallpox. 

Civil War vaccination kit
Civil War vaccination kit JD Howell, McMaster University

Nine specimens were tested for the presence of variola, which is the smallpox virus; vaccinia, the virus used in vaccination; and other viruses in the orthopoxvirus family. Vaccinia  — but not variola — was detected on scabs, and returned to the museum. No results were obtained from the lancets or glass swabs, but Anna Dhody, acting co-director and curator of the Mütter Museum, suggested the kits be sent to McMaster for genomic sequencing designed to detect “ancient” DNA  — genetic material that’s more than a century old. A co-author of the current paper, she had previously worked with Poinar at McMaster on pandemic cholera strains from 1849.

Dhody, who has a background in forensic science, hoped Poinar would find something in the kits, based on her knowledge of how medicine was practiced in the 19th century. 

Doctors didn’t wash anything prior to the discovery of germ theory,” she said. “And I am sure that they did not wash them before they donated them to us.” 

To understand the source of the vaccines, McMaster scientists reconstructed and analyzed five different genomes. They were all slightly different vaccinia strains, and all only distantly related to the virus that causes smallpox. Their slow evolution likely meant they kept enough similarity to variola to prevent smallpox. Decades later, “vaccine farms” produced vaccine from animals, and production became an industrial process in the 1900s, but scientists don’t believe cowpox or horsepox were present in the 1800s vaccines. Nor did they show up in the very first smallpox vaccines, other research has shown.

The new paper’s most important finding is that smallpox vaccines used in the U.S. during the 19th century were significantly different from those used in the 20th century to finally eradicate smallpox in 1980, said Jose Esparza, a virologist formerly affiliated with the World Health Organization and the Bill and Melinda Gates Foundation who studies and collects smallpox vaccine artifacts, including a vial from 1902. “The mystery of the origin and evolution of the smallpox vaccine remains to be solved.” 

By the 1860s, when the Civil War was convulsing the United States, vaccination had changed little since a discovery made by Edward Jenner in 1796. The British doctor observed then that milkmaids rarely contracted smallpox, a virus so deadly that 30% of patients died; survivors were disfigured and sometimes blinded by the disease. Infection with cowpox, a milder disease in the same orthopoxvirus family as the smallpox-causing variola, protected the milkmaids, he suspected, so to test his theory Jenner scraped pus from milkmaids’ sores into the skin of an 8-year-old boy, later safely exposing him to smallpox and ushering in the age of vaccination.

If we shudder at experimenting on a child, we might also recoil from the way vaccines were first made and distributed: The lifesaving molecules were incubated in one person to be passed on to the next by transferring scabs or pus from one person to the scratched arms of the next. This “passage” often took advantage of women or enslaved Africans, sometimes on ocean voyages bringing vaccines between the New World and the Old. Three of the five genomes reconstructed from the Mütter kits came from females. 

In the decade before Jenner was testing his hypothesis about milkmaids and smallpox in England, the College of Physicians was founded in Philadelphia. In 1863 the college created the Mütter Museum, where those leather vaccine kits were later deposited. Philadelphia was also home to the Civil War’s second largest hospital, after Washington, D.C.

These tools of pioneering public health workers are among other medical treasures meticulously preserved at the museum. The slides and lancets showed no signs of biological residue, but successful sampling left them undisturbed, raising hopes for uncovering more secrets deep in ancient DNA from other historical artifacts.

“From an ancient DNA perspective and from a medical history perspective, nondestructive sampling of museum artifacts is going to be really important,” said Ana Duggan, a genomics researcher at the Public Health Agency of Canada, an adjunct researcher at the McMaster Ancient DNA Centre, and co-author of the new paper. Today, “the history of vaccination is important to the practice of public health.”

As 23 initiatives around the world race toward clinical trials of Covid-19 vaccine candidates, people long for a solution. Poinar worries that the public expects a vaccine sooner than it can safely be ready. 

“There are still so many unknowns about SARS-Cov-2 that it’s going to take longer than most people think or want to wait,” he said. “I think we expect science to move quickly, but part of the benefit we have in hindsight is it takes a long time to get all the answers. If you want something effective and safe, you have to wait.”

Other people might not want to receive the vaccine at all, whenever one is available, Poinar said. One lesson gleaned from studying smallpox is that the most successful and celebrated vaccination campaign in history fought a fierce and visible foe.

“One of the stark differences is when you have something like smallpox ravaging 30% of the population, killing lots of small children, and it’s horribly disfiguring, you can imagine the compliance rate is very high,” he said. “People wanted that [vaccine]. It was fear of smallpox, which I don’t think we see now [with Covid-19] because it’s invisible.”

  • I’m pleased to see that a major piece of the puzzle of the origin of Vaccina has been found. It is my understanding that proactive therapy with live, disease-causing pathogens (as practiced with smallpox before Jenner) is called “inoculation”, and proactive therapy with largely harmless related or attenuated species is “vaccination” — Jenner being the first practitioner of the latter for any disease (or at least the first knowing practitioner). Even though smallpox has been conquered, Vaccina science is still important because it is often suggested as a live virus vector for use in gene therapies. True, most of these therapies are based on an adenovirus vector, but you really should have more than one arrow in that quiver because there may be times when your favorite vector doesn’t hit the right tissue target, can’t be used with the payload, etc.

  • As the article says, this was Vaccinia and not Variola (the virus of smallpox). In that regard, it is perhaps worth noting that Variola given into the skin (“variolation”) was also protective against smallpox and was widely used before Vaccinia became available. It was so effective that Gen. George Washington ordered all of the Continental Army troups to be vaccinated this way so that they would not succumb to smallpox disease while in battle (https://www.history.com/news/smallpox-george-washington-revolutionary-war ). Evidently, there was no discussion of “vaccine hesitancy” with the General.

  • Dear Ms. Cooney
    Thank you for a brilliant essay. I learned a lot!!!
    Joseph McDermott

  • That is a very well-done and informative article. Every question I thought of when I saw the headline and as I read was answered. And, of course, I learned things I had not thought of! Thank you very much.

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