[The key ingredient in our oldest vaccine is a mystery that goes
back 200 years.]
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NO ONE KNOWS WHAT’S INSIDE THE SMALLPOX VACCINE  
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Sarah Zhang
August 26, 2022
The Atlantic
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_ The key ingredient in our oldest vaccine is a mystery that goes
back 200 years. _

, Getty; The Atlantic

 

At the heart of history’s most successful eradication campaign is a
mystery. The smallpox vaccine—now also being deployed against
monkeypox—contains a live virus that confers immunity against
multiple poxviruses. But it is not smallpox or a weakened version
thereof. Nor is it monkeypox. Nor is it cowpox, as suggested by the
vaccine’s famous origin story
[[link removed]] involving pus
taken from an infected milkmaid to immunize an 8-year-old boy.

It is something else entirely: a unique poxvirus whose origins have
been lost, or perhaps never known at all. Scientists call
it _vaccinia_, and it is pretty much found only in the vaccines. No
one knows where vaccinia came from in nature. No one has ever found
its animal reservoir. No one knows quite what vaccinia _is_—even as
it has been used to inoculate billions of people and saved hundreds of
millions of lives. It is a ghost of a virus that has survived by being
turned into a vaccine.

José Esparza first began wondering about vaccinia in the 1980s, when
he was assigned an office at the World Health Organization next to the
smallpox archives. By then, the disease had already been eradicated,
and people had, he says, “little interest in understanding the
origins of the vaccine.” He went on to have a long career working on
HIV and other viruses at the WHO and the Bill & Melinda Gates
Foundation, but in retirement, he has returned to solving the mystery
of vaccinia. It is a “hobby,” but also a bit of an obsession. For
years now, he has been scouring museums and eBay for old vials of
smallpox vaccine, scoring a couple every year. (“EBay—you can find
anything you can imagine!” he says.) These vials no longer contain
live virus, but the technology now exists to sequence the fragments of
viral DNA that remain.

This DNA has revealed tantalizing if perplexing clues. Vaccinia turns
out to be most genetically similar to another poxvirus called
horsepox. But scientists have only ever sequenced one horsepox sample
in the world, and they may never find another; the disease largely
disappeared in the early 20th century
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If horsepox really is the progenitor of vaccinia, how did that happen?
And how did it then become lost to time?

The best-known version of the smallpox-vaccine story goes like this:
In 1796, the British doctor Edward Jenner noticed that milkmaids
exposed to a mild disease called cowpox were unusually protected from
smallpox. He found a young woman with fresh cowpox lesions and
scratched material from one into the arm of a boy—the son of
Jenner’s gardener, no less—who became mildly ill but survived. He
indeed became immune to smallpox. The first vaccine was born.

Jenner was not really the first doctor
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observation about cowpox. But he did document his experiments in a now
seminal book
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Intriguingly, he mentions horses in the book’s introduction. On the
second page, in fact, he speculates that cowpox originated as
“grease,” a horse disease that may have spread from equines to
farmworkers to cows to dairy maids. He couldn’t prove this, though;
it would take several more decades for scientists to understand that
diseases are caused by invisible microbes that spread among people and
animals. This brief allusion to horses gets forgotten in favor of a
“beautiful tale of the milkmaids,” Esparza says.

Nevertheless, smallpox vaccines soon began spreading around the world.
Nineteenth-century vaccines were a far cry from the standardized
pharmaceutical products we’re used to today. Preservation of the
material on glass or thread was unreliable, so the smallpox vaccine
was maintained in the bodies of young children: Liquid from a pox on
one child would be transferred into the arm of another, resulting in a
pox whose contents could be transferred to another, and so on. And it
had to be children, because adults tended to already have immunity to
smallpox. In 1803, Spain sent 22 orphan boys on a Royal Philanthropic
Vaccine Expedition
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bring the smallpox vaccine to its colonies. The number of boys was
chosen precisely to span the length of the transatlantic voyage: Every
nine or 10 days at sea, doctors would transfer the vaccine to the arms
of two new boys—two in case one did not take, so that the ship would
arrive in the Americas with the last set of boys still having sores.

The chain of arm-to-arm transfer did sometimes fail, however. When an
established source of vaccine wasn’t available, doctors who’d
heard about Jenner’s experiment went back to the animals. Cows were
used, as were horses. The physician Luigi Sacco
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for example, who popularized vaccination in northern Italy,
successfully inoculated patients with vaccines derived from
grease-infected horses. As doctors such as Sacco experimented with new
sources, multiple vaccines probably came into circulation. There was
no single canonical vaccine.

Not until the mid-19th century
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when scientists figured out how to maintain the smallpox vaccine in
calves, did it become a mass-manufactured product. The use of horses
faded from living memory. Vaccinia and cowpox eventually became
interchangeable names for the virus in the vaccine. In fact, the
words _vaccine_ and _vaccinia_ both derive from _vacca_, which is
Latin for cow.

By the 1930s, though, scientists were realizing that vaccinia and
cowpox were not one and the same. When a British
microbiologist injected one virus or the other into rabbits
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he saw that they induced slightly different immune responses. To the
immune system, vaccinia and cowpox are not interchangeable. But the
molecular techniques of the time were not sophisticated enough to nail
down how they differed.

Meanwhile, other theories flourished
[[link removed]]:
Vaccinia was a domesticated version of cowpox or smallpox, transformed
through arm-to-arm passage in the 19th century. Or it was a hybrid of
the two. Or perhaps it was a prototype poxvirus that gave rise to all
other poxviruses. In the 1970s, poxvirologist Derrick Baxby speculated
that horsepox was one possible origin for vaccinia—harkening back to
Jenner’s description of grease in horses 200 years earlier. But
horsepox had gone extinct, he lamented, with no laboratory experiments
having ever been conducted.

Baxby did not know this at the time, but thousands of miles away, a
poxvirus had, in fact, been killing horses in Mongolia. Only in the
early 2000s, some 25 years later, would scientists rediscover and
sequence an archived
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this forgotten outbreak, which they attributed to horsepox. The
results were presented at an international meeting of poxvirologists
in 2002. “A lot of their ears perked up,” says Edan Tulman, one of
the scientists who sequenced the Mongolia virus at Plum Island Animal
Disease Center at the time. The virus it most resembled turned out to
be none other than modern vaccinia. Yet, it also has genes that “no
other modern-day vaccinia” does, suggesting that it is indeed closer
to the wild poxvirus that first gave rise to vaccinia, says Elliot
Lefkowitz, who studies microbial genomics at the University of Alabama
at Birmingham. The results added new fuel to the horsepox-origin
hypothesis.

Old smallpox vaccines have also confirmed a link—they share even
more similarities with horsepox. One of the vials Esparza bought off
of eBay, manufactured by a Philadelphia company in 1902, contained
vaccinia whose core genome was 99.7 percent identical
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Esparza and two close collaborators—Clarissa Damaso at Federal
University of Rio de Janeiro and Andreas Nitsche at the Robert Koch
Institute in Germany—have since sequenced about 30 old
smallpox-vaccine genomes, which have not all been published yet. They
have also reanalyzed five published partial genomes
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Civil War–era smallpox vaccines at the Mütter Museum. Four looked
like 1976 horsepox virus, and a fifth was so similar, Damaso says,
that it’s basically “true horsepox virus.”

In fact, all of the vaccinia that the team has found from old vaccines
have resembled horsepox, which naturally brings up another question.
If doctors in the 19th century were using both cows and horses as
sources, how come only horsepox-like viruses survived in vaccines?
Perhaps doctors and early manufacturers were inadvertently selecting
for horsepox when choosing the best vaccines, suggests David Evans, a
poxvirologist at the University of Alberta in Canada. “That’s just
a guess,” he says, but “cowpox doesn’t really grow particularly
well in humans.” Or perhaps, Damaso muses, cowpox could have been a
misnomer this whole time. Just as monkeys are not the natural
reservoir
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monkeypox, scientists now think that cows are not the natural
reservoir of cowpox—it actually seems to be rodents
[[link removed]]. Poxviruses have
historically been named after the animal in which they were first
found, but they usually infect a broad range of hosts. Could the virus
causing “cowpox” in cows during Jenner’s time actually be what
we now classify as “horsepox,” a virus that was possibly infecting
cows, humans, and horses? The vaccinia of today is, in fact, capable
of infecting multiple species. People who got older versions of the
smallpox vaccine sometimes spread it to others
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also spilled over into animals, including buffalo
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cattle
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And in cattle, the disease manifests a lot like cowpox.
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Mysteriously, horsepox seems to have disappeared from the
world—perhaps because modern husbandry practices have prevented it
from spreading. Mongolia hasn’t recorded any new outbreaks, and
Europe hasn’t recorded any in more than a century. A few years ago,
Esparza contacted virtually every vet agency in the world looking for
any evidence of horsepox, and found none. He’s also tried,
unsuccessfully, to hunt for the virus in horses and wild rodents in
Mongolia.

Proving conclusively that horsepox is the origin of vaccinia is hard,
now that wild horsepox is gone from the world. The questions that
linger are unanswerable without more samples: Was the horsepox found
in Mongolia in 1976 really the same disease that had afflicted horses
thousands of miles away and nearly three centuries earlier in Europe,
when the smallpox vaccine was first invented? And even if so, could
the Mongolia virus be a very old escaped vaccine virus that spread
from inoculated humans to animals, rather than a wild horsepox virus?

This much is clear, though: The 1976 Mongolia virus and vaccinia have
a common poxvirus ancestor, which likely circulated among animals in
Europe around Edward Jenner’s time. That ancestor, whether horsepox
or not, became the progenitor of all viruses in smallpox vaccines
today—but has itself disappeared.

Since Jenner’s time, the process of making vaccines has become far
more controlled and standardized. The vaccinia in the Jynneos vaccine
used against monkeypox today is still live, but it’s no longer
capable of replicating in human cells; it lost this ability after
being passaged through chicken cells hundreds of times
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Vaccinia remains a mystery because it arose before the advent of a
modern, regulated pharmaceutical industry. No one kept careful
records; even if they did, they wouldn’t have known what to record.
It all happened before anyone had an understanding of germ theory. It
happened even before the discovery of viruses. Remarkably, the vaccine
worked. And it worked so well that we were able to eradicate a human
disease for the first and only time.

SARAH ZHANG [[link removed]] is a
staff writer at _The Atlantic. _In 2021, she was a Livingston Award
finalist for her reporting on Down syndrome. Before joining _The
Atlantic_, she was a staff writer at _Wired_. She covers science and
health.

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