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Can Past Coronavirus Infection Protect Against COVID-19? Hints from Smallpox Vaccine

In ordinary times, a new report describing experiments on bits of smallpox scabs nestled in Civil War museum artifacts would have been mildly interesting. But these days, clues in old poxvirus genomes are especially intriguing because they may explain how some people resist COVID-19, perhaps thanks to a past run-in with a different coronavirus. According to another recently published study, these individuals haven’t tested positive for COVID-19 or SARS or had contact with people who have, yet they have immune memory – T cells that recognize a coronavirus that infects bats.

Could exposure to one type of coronavirus protect against infection by another?

“The origins and genomic diversity of American Civil War era smallpox vaccine strains,” published in Genome Biology, looks at a possible precedent to answer that question. Such cross-reactivity happens when an antibody or T cell recognizes a surface molecule common to more than one species of pathogen. It’s a little like recognizing Eric Clapton in different bands.

A Brief History of Smallpox Vaccination

The forerunner of vaccine technology, inoculation, dates back to eleventh century China, where people who survived smallpox were known to never get it again. Could rubbing scab material from someone who’d recovered into cut skin of a healthy person prevent the infection? Smallpox killed thirty percent of victims and left survivors disfigured, often blind, and disabled. Pus-filled sores could converge until the skin sloughed off in dripping sheets.

In inoculation, the preparation came from the pathogen, not from a stand-in, as is the strategy in vaccination.

The success of the American Revolution is partly attributed to smallpox inoculation. The infection was new to the colonists, and therefore devastating.

In 1751 George Washington contracted smallpox in Barbados, where he was visiting with his brother, who had tuberculosis and sought the tropical air. They visited a family that had the pox, and George got sick a few days later. “Was strongly attacked with the small Pox,” the future president wrote in his diary, before taking to his bed for three weeks, suffering chills and fever, muscle aches, a stomachache, and the oozing rash.

Years later, General Washington realized that his men lacked the natural protection against smallpox that the British had developed from living with the disease for many years. Most had it as kids and were immune.

Washington used a type of inoculation called variolization. It was named for the smallpox virus, called variola, which is Latin for “spotted.” A thread dipped into pus was placed into a small cut in the arm of the recipient, who might feel pretty awful for awhile, or even die. Because variolized people could transmit active infection for a few weeks, Washington instituted strict quarantine measures. The combination of inoculation, quarantine, and soldiers who had survived infection built the herd immunity that saved the continental army from the viral scourge.

In 1796, the wife of a British ambassador to Turkey witnessed the Chinese method of inoculation and mentioned it to English country physician Edward Jenner. Intrigued, Jenner was inoculated the Chinese way, and then thought of a different approach: vaccination.

Jenner and others had observed that young girls who milked cows could contract a mild illness, cowpox, but they didn’t get smallpox. The cows became ill from a virus from horses. A slightly different virus from variola, vaccinia, causes cowpox – but to Jenner the infections must have looked like extremes of the same condition. Could exposure to the milder one protect against the worse one?

The country doctor’s idea led to invention of the first vaccine (from the Latin vacca, for “cow”). It wasn’t an inoculation because the preparation wasn’t made from smallpox virus (variola), but from a different one (vaccinia). (I hate when the media talk about “finding a vaccine,” as if it’s like a mushroom lurking beneath a rotting log.)

Jenner tried his first vaccine on a volunteer, 8-year-old James Phipps. The doctor dipped a needle in pus oozing from a cowpox sore on the hand of milkmaid Sarah Nelmes, then scratched the boy’s arm with it. He then exposed the boy to people with smallpox, but James never became ill. The vaccine worked. Jenner further tested the vaccine on his own child. But some question the Sarah Nelmes narrative – Jenner might not have been the first to come up with the idea to use cowpox to protect against smallpox.

Eventually, improved versions of Jenner’s vaccine rid the world of a disease that had once killed millions. Smallpox vaccination became unnecessary by the 1970s, with the last natural case recorded in 1977. In 1980, the World Health Organization declared it eradicated – the only infectious disease to achieve that designation. I have a scar from my childhood smallpox vaccination.

Although the story of Edward Jenner is famous, the details of exactly which viruses he used to protect against smallpox are murky. And as time went by and vaccination became more widespread, the viruses making up the vaccine mutated, as viruses do.

For a long time, smallpox vaccination was more a folk remedy than a precisely engineered medical product. By 1939, the recipe had changed so much that the vaccine strain was no longer recognizable as pure cowpox virus.

Civil War Vaccination Kits Yield Genomic Data

The tangled history of smallpox vaccination is what inspired scientists and historians from the McMaster University Ancient DNA Centre, the Mütter Museum in Philadelphia, and the University of Sydney to sequence the genomes of viruses used as smallpox vaccines during and after the Civil War, from 1859 through 1873. The Mütter Museum has a fantastic collection of medical oddities, five smallpox “vaccination kits” among them. It’s one of my favorite museums.

A vaccination kit was like a shaving kit. A rolled up rectangle of leather contained lancets to pierce skin, small glass plates on which to mix and prepare fluid from blisters and beneath scabs, and tin boxes with sliding lids to store scab pieces.

The researchers sequenced all of the DNA in the vaccination kits.

All the samples held the hallmarks of ancient DNA – small pieces with frayed ends, like chopped up shoelaces. The human DNA matched people from west Eurasia. That was a surprise, because the investigators had expected some of it to be from people of African ancestry. In the southern states, African-American children were among other children who had been vaccinated, six times in each arm, to provide scabs to make more vaccine.

The researchers cleverly deduced from the human DNA in the kits that person-to-person vaccination – from deliberate arm-rubbing – had occurred. Of three people represented in the samples, two were clearly female (two X chromosomes), but a third was mostly female, with some Y. At some point, a man had been involved, leaving some of his cells in a vaccinated woman.

Sequencing the viral genomes in the kits revealed five vaccine strains, all vaccinia – descendants of the original cowpox of milkmaid fame. The doctors in Philadelphia during the Civil War all used pretty much the same viral strains to vaccinate all soldiers. At the time Philadelphia had the second largest hospital system in the north and had become known as “the birthplace of American medicine.” The Mütter Museum opened in 1863.

Vaccinia-like viral strains continue to evolve and spread, beyond horses and cows. One guise of vaccinia is Cantagalo virus in cows and farmers in Brazil, and another is buffalopox in India, Egypt, and Indonesia, which can infect humans. The poxviruses jump species, as do coronaviruses, Ebola virus, influenza viruses, and many others.

Does Smallpox Vaccine Foretell Protection from other Coronaviruses?

Several types of vaccines are being developed to prevent COVID-19. Perhaps the history of smallpox vaccination suggests a strategy based on harnessing other coronaviruses that evoke a human immune response.

“Understanding the history, the evolution and the ways in which these viruses can function as vaccines is hugely important in contemporary times. This work points to the importance of looking at the diversity of these vaccine strains found out in the wild. We don’t know how many could provide cross protection from a wide range of viruses, such as flus or coronaviruses,” said evolutionary geneticist and co-author Hendrik Poinar, director of the McMaster University Ancient DNA Centre.

The good news is that the vaccinia strains that so powerfully protected against smallpox are quite distantly related to the variola virus that causes smallpox. The slow mutation rate of DNA viruses might make that possible. The bad news is that coronaviruses have RNA as their genetic material and not DNA, which mutates much faster. Still, it’s worth exploring further how exposure to a bat coronavirus appears to protect some people from SARS-CoV-2, the virus behind COVID-19.

Opening photo credit: JD Howell, McMaster University. The section about Edward Jenner is from my textbook, Human Genetics: Concepts and Applications (McGraw-Hill Education).



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