The unidentified virus that protects against monkeypox

The monkeypox vaccine is made from a long-lost virus that no one has ever been able to identify. How did this happen? Could it still be found in the wild?

A strange medical panic swept through London at the turn of the nineteenth century. Pamphlets with information were distributed. There have been alarmist books written. Dubious treatments surfaced. The public was repeatedly warned that it was in danger of… morphing into cow-humans.

A small group of controversial doctors had been raising concerns about a groundbreaking medical procedure that involved taking a virus thought to infect cattle and using it to protect people from smallpox’s cousin.

The technique was named “vaccination,” after the Latin word “vaccinus,” which means “of a cow,” and early evidence suggested that it was extremely effective, protecting 95% of people from an infection that usually killed around 30% of its victims and permanently disfigured the majority of the rest. There was even early hope that it would completely eradicate the disease.

It didn’t take long, however, for the first vaccine sceptics to emerge. These rebel physicians, in particular, were convinced that the “bestial humour” – the cowpox virus – had no place in the human body. Among the more absurd claims was that vaccinated children had begun to develop bovine characteristics, such as blotches on dairy cows, or that they were at risk of developing oxen-like thoughts. One prominent advocate suggested that vaccinated women might develop a taste for bulls.

The thing is, the early vaccine sceptics were completely wrong. Of course, the new technique did not instil the essence of the bovine in innocent people – cowpox was just a normal virus that would eventually drive smallpox extinct. But it could also have had nothing to do with cows at all.

To this day, no one knows where the virus that wiped out smallpox originated. Nonetheless, this mysterious microbe is still being used, including in vaccines currently being deployed against monkeypox, which the World Health Organization has declared a global health emergency.

After spending the previous five decades primarily in Africa, The monkeypox virus began spreading around the world in May 2022. To combat it, scientists have turned to two previously used smallpox vaccines, ACAM2000 and JYNNEOS. These are the only ones authorised in the United States to protect against the emerging virus (the EU also recently approved the JYNNEOS version). They, too, are a piece of the puzzle.

For more than a century, the scientific community assumed that the smallpox vaccine was made from cowpox – an explanation that is still found on many websites and curriculums around the world. However, molecular tests revealed in 1939, nearly 150 years after vaccination was invented, that it is not. These findings have recently been confirmed by genetic sequencing. Instead, the vaccines used to eradicate smallpox, as well as those used today to combat monkeypox, are based on an unknown virus that no one has been able to identify – a “ghost” pathogen found only in vaccine form.

Despite an 83-year hunt, no one knows how, why, or when this imposter appeared in the smallpox vaccine, or if it still exists in the wild. Only one thing is certain: millions of people died as a result of the smallpox epidemic. Without it, the current monkeypox outbreak would have spread even faster.

“Until 1939, people assumed that what we call vaccinia, the smallpox vaccine, was the same as cowpox,” says José Esparza, a virologist and fellow at Germany’s Robert Koch Institute. “Then it was discovered that they were not the same. Since then, we’ve accepted that cowpox is one virus and vaccinia is another unknown virus.”

How did this happen? Where could this virus have originated? Will we ever be able to find it in its natural environment?

A very English affliction  

Edward Jenner, a silver-haired surgeon who announced his discovery in 1796, is widely credited with inventing vaccination. The typical story of how he did it is a captivating tale of beautiful milkmaids, epiphanies, and ethically dubious experiments. However, this is not entirely correct.

The most well-known version is as follows. Jenner observed that milkmaids frequently had unusually clear skin, free of the pockmarks that plagued a large proportion of the population – up to 85% of those who recovered from smallpox may have been left with a significant number of distinctive facial scars. He realised that those who had contracted the milder illness of cowpox while at work were less likely to contract smallpox. To demonstrate this, he infected an unsuspecting eight-year-old boy with the former and then deliberately exposed him to the latter to see if he was still susceptible and would get sick (luckily, he wasn’t, and he survived).

In fact, the chance discovery occurred nearly three decades earlier, with a country doctor who had recently relocated to the Gloucestershire market town of Thornbury. There, John Fewster established a practise for “variolation,” an ancient method of preventing smallpox by rubbing a small amount of pus from a smallpox pustule into an uninfected incision.

The procedure had been used for centuries across Asia, from India to Tibet, but was largely unknown to Europeans until Lady Mary Wortley Montagu discovered it in Istanbul – then known as Constantinople – and popularised it in 18th-century Britain. If everything went as planned, the technique usually resulted in a single smallpox mark at the site of infection, indicating that the person’s immune system had learned to recognise the virus. If it went wrong and the infection spread, as it did in about 2-3% of cases, the patient frequently died.

However, in Thornbury, a number of residents did not react to variolation at all – no pock marks were produced, and the procedure was unsuccessful despite repeated attempts. Fewster was perplexed. And then one day, A farmer explained that he had recently been infected with cowpox and was therefore immune.

“At the time, cowpox was largely confined to the south-west of Britain,” says Arthur Boylston, a retired pathologist and author of Defying Providence: Smallpox and the Forgotten 18th-Century Medical Revolution. He claims that it was never particularly common, with outbreaks occurring only every few years, and that while farmers in the area were generally aware of its existence, only the younger generation had linked it to smallpox protection.

This folk wisdom is thought to have made its way to Jenner, who attended the same medical society as Fewster.

Jenner collected pus from a cowpox mark on the hand of a dairy maid who had caught it from a cow named Blossom on May 14, 1796. An eight-year-old boy was vaccinated with this. Six weeks later, the child was variolated, and Jenner realised that the groundbreaking technique had worked when he did not develop a pustule.