Smallpox – A Short History of Vaccination (Part 1)

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Disclaimer: While this blog discusses the more interesting and dubious practices of the world’s first vaccine this does not reflect the practices of modern virology that are heavily regulated and standardized today.

What do Mozart, George Washington, Queen Elizabeth (I), and Abraham Lincoln all have in common? They are just a few famous historical figures that had smallpox.[i]

Some of you might not be familiar with smallpox and that’s a good thing. After all, smallpox was declared eradicated from the world in 1980.[ii] “Eradicated” meaning it has been destroyed entirely in nature. No one gets smallpox today. It is the only human virus that is confined to the history books, but how did smallpox become a thing of the past?

The Darnley Portrait of Queen Elizabeth (I), c. 1575. She was known for her high forehead and pale face, but did you know she wore this lead makeup to try and cover her smallpox scars? She was also painted with 16th century level photoshop. (Source)

The story starts in Africa, India, and China with a practise called “variolation.” Before the 1700s, it was known that you couldn’t get smallpox twice. Variolation was simple: they took the pus or scabs from someone with smallpox and introduced this to a non-immune person’s arms or legs. Variolation comes from “variola,” the scientific name for the smallpox virus. As you can imagine, variolation was incredibly dangerous because patients weren’t getting a weaker version of the virus as we do today.

Additionally, anyone who was variolated became a carrier of smallpox and could pass the disease onto anyone who was in contact with them. While it was practised for centuries, variolation only came to Europe in the 18th century and to the “New World” in 1721.[iii]

But how did the world switch from “variolation” to “vaccination?” Scientist Edward Jenner is often accredited as the father of vaccines. Jenner knew that milkmaids were protected from smallpox if they had already contracted cowpox. So he took the cowpox from milkmaid Sarah Nelmes and inoculated 8-year-old James Phipps, on May 14, 1796. The logic was that the boy would suffer from the lesser symptoms of cowpox and would later be immune to the deadly smallpox. Six weeks passed and Jenner exposed James to smallpox. The boy showed no sign of infection. Jenner published his findings in 1798 and referred to this process as “vaccination” from the Latin word vacca meaning “cow.” [iv] It would be the first of many vaccines!

“The First Vaccination”. Dr. Jenner inoculating 8-year-old James Phipps. Source: Museum of Healthcare, accession #002050177

The story of milkmaids and vaccines is what I learnt in high school (c. 2017), and it’s a compelling narrative. Jenner is painted as this resourceful physician who would later go on to save millions with his vaccines, but the story is more nuanced than what I was first led to believe. Jenner did not discover that dairymaids who had cowpox couldn’t get smallpox, that was relatively common knowledge at the time. But he was the first physician to put vaccination into practise.

What about the rest of the story? How much does that hold up? The Museum of Health Care has a smallpox vaccine from the year 1900! But, after virologist Dr. Josê Esparza at the University of Maryland and his team analysed its genetic code, they found that our vaccine was more related to horsepox than cowpox. What happened there? Why was horsepox being used as a vaccine, and why did no one talk about it?

According to Dr. Esparza, there’s a couple reasons why Jenner wasn’t public with his horsepox research. Firstly, horsepox was not well understood. Jenner knew that cowpox came from “horse grease” but he didn’t have the knowledge to prove the relationship between the two Orthopox viruses.[v] Secondly, Jenner may have publicly focused on cowpox to make the story less confusing and therefore more marketable.[vi] While Jenner focused on pushing vaccination, John Loy proved Jenner’s previous “horse grease” theory in 1801.[vii] He found that horse grease and horsepox were two separate things but there was a connection to cowpox. Following Loy’s discovery, Italian physician Luigi Sacco investigated getting a smallpox vaccine from horses. Sacco even proposed changing the name from vaccine to equine from the Latin word for horse “equus”.[viii]

Figure 3. Here we have two very different depictions of Edward Jenner. One as a humble country doctor and the other that resembles a Greek god. Source (Left) (Right)

From that point on, physicians saw cowpox and horsepox as interchangeable when it came to immunising for smallpox. One physician in Vienna, Jean De Carro, even mixed the two![ix] Horsepox and cowpox both belong to the genus of Orthopox viruses, so it makes sense why they were considered the same in the early days of virology. Jenner died in 1823, but by 1817 he was using horsepox to vaccinate.

It wasn’t just the museum’s vaccine that was genetically similar to horsepox. Dr. Esparza and his team sequenced 24 other vaccines. One was a true horsepox strain while the rest were closely related. It is rare to find a true horsepox or cowpox vaccine because the vaccine process wasn’t regulated like it is today. So physicians would take whatever they could get to immunise the public and that wasn’t always a pure strain.

The vaccine also mutated and evolved on its own because it wasn’t grown in a lab. Instead, it was grown in humans. Yes, that’s right, humans.

There was some skepticism about getting vaccines from cows. Certain physicians thought it was best to keep the vaccine alive in humans (specifically Caucasian humans).[x] But who would volunteer to get sick and travel as a vaccine incubator? The answer came from the vulnerable demographics of the population. Governments and monarchies often turned to children, orphaned children, who could not have much say in the matter. These orphans were used to bring the vaccine across continents. They would take turns getting sick and vaccinating each other in hopes that by the time they arrived at their destination, one of the children still had usable pustule. 

For the confederate soldiers in the United States (U.S.), they were so desperate to get their hands on the smallpox vaccine that they couldn’t afford to discriminate. African Americans were often used to keep the smallpox vaccine alive.[xi] Specifically, African American children because it was believed that children were more “pure” and less likely to carry other diseases like syphilis.

Eventually the U.S. turned to vaccine farms for mass production in 1870.[xii] Cows were inoculated with the vaccine and their pus harvested. Today, vaccines are controlled and grown in labs to limit these mutations.

Figure 4. Mulford 1900 smallpox vaccine that is genetically related to horsepox and not cowpox. (Source)

I cannot stress enough that the smallpox vaccine evolved significantly from its origins. It cut out some genetic code here and there, just to make life easier for the virus jumping from human to human. The changes between true horsepox and the modern smallpox vaccine might be the key to advancing our understanding of viruses. Why were certain genetic codes cut? What sequences make a more effective vaccine? The future of understanding vaccines starts with understanding the evolution from horsepox to the modern smallpox vaccine.

So the first vaccine has a more nuanced story than found in your typical textbooks. But how were they able to eradicate an entire disease? And is smallpox truly eliminated from the world? For those answers and more, check out Part 2!

Hannah Samuels, Public Programs Assistant, Summer 2021 reveals the behind the scenes research, editing and discoveries she made while writing her two-part blog series about the history of vaccination.

Sources Used (Click to expand)

[i] Adam Reingold, Smallpox: Is It Over? (Bearport Publishing, 2010), 29.

[ii] “Smallpox | CDC,” February 19, 2019,

[iii] José Esparza, Andreas Nitsche, and Clarissa Damaso, “Investigations on the historical origin and evolution of the smallpox vaccine,” Gaceta Médica de Caracas 128, no. S1 (December 5, 2020): 89,

[iv] José Esparza et al., “Equination (Inoculation of Horsepox): An Early Alternative to Vaccination (Inoculation of Cowpox) and the Potential Role of Horsepox Virus in the Origin of the Smallpox Vaccine,” Vaccine 35, no. 52 (December 2017): 7223,

[v] Esparza et al., “Equination (Inoculation of Horsepox),” 7224.

[vi] Esparza et al., 7224.

[vii] Esparza et al., 7224.

[viii] Esparza et al., 7225.

[ix] Esparza et al., 7225.

[x] Robert D. Hicks, “Scabrous Matters: Spurious Vaccinations in the Confederacy,” in War Matters: Material Culture in the Civil War Era, ed. Joan E. Cashin (Chapel Hill: The University of North Carolina Press, 2018), 137.

[xi] Hicks, “Scabrous Matters.”

[xii] Esparza et al., “Equination (Inoculation of Horsepox),” 2744.

<strong>Hannah Samuels</strong><br>(Public Programs Assistant, 2021)
Hannah Samuels
(Public Programs Assistant, 2021)

Hannah is a Concurrent Education student who recently completed her undergraduate degree in history at Queen’s University. Her teaching subjects are history and biology. She enjoys researching social histories and natural science. In her spare time, Hannah stress bakes, reads classic literature, and over-analyses social interactions with friends.

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