Smallpox Vaccine Saved Billions of Lives—Yet Scientist Had No Idea What Virus They Used in it

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People line up in Paris to receive their smallpox vaccine in 1942. LAPI/Roger Viollet/Getty Images

The world's very first vaccine, developed in 1798 to eradicate smallpox, remains one of the greatest mysteries in the history of medicine. The vaccine has saved countless lives since it was first introduced by British physician and scientist Edward Jenner, who many call the father of modern immunology. But how exactly the immunization worked has never been fully understood.

Historians and physicians typically think the vaccine is composed of the cowpox virus, a cousin of smallpox. But a closer investigation offers compelling new information that suggests the effective ingredient in the smallpox vaccine is another virus entirely.

A genomic analysis of a sample of the smallpox vaccine from 1902 provides evidence that the vaccine used to eradicate smallpox disease—which is caused by the variola virus—was made of horsepox, a genetically similar but different virus entirely.

A marble statue by Giulio Monteverde in the Palazzo Bianca, Genoa of British physician Edward Jenner immunizing his baby son against smallpox. Jenner is credited for discovering the smallpox vaccine. Hulton Archive/Getty images

The new paper published Wednesday in the New England Journal of Medicine calls into question much of what we thought we knew about one of the most significant discoveries in early medicine. For the study, researchers led by the Robert Koch Institute in Berlin, Germany, obtained one of the earliest known samples of the smallpox vaccine from a private collection that was originally produced by H.K. Mulford Co. from Philadelphia. (After a merger decades later this manufacturer would become Merck & Co.)

The original vial from 1902 that contained the smallpox vaccine sequenced for the study. JOSE ESPARZA

"If a cow is inoculated with one of these three viruses it's very difficult to see the differences. In the past, any disease that would give pustular lesions would be called cowpox," Clarissa Damaso, an expert in virology and molecular biology from the Federal University of Rio de Janeiro, Brazil and coauthor of the study, told Newsweek. "This is the first time that we've proved scientifically that horsepox has been used for a smallpox vaccine."

Scientists have wondered about the origins of the vaccine before. According to the authors of the paper, some scientists analyzing a chicken embryo in the 1930s discovered the smallpox virus wasn't the cowpox virus after all.

Smallpox, cowpox and horsepox are different viruses but the same genus. It is possible, says Damaso, that the cowpox and horsepox viruses were used interchangeably, without anyone's knowledge, to formulate the vaccine. The vaccines currently available for smallpox contain another virus that is now called vaccinia, and is not a direct match to either cowpox or horsepox.

A gun designed to make mass immunization more efficient. It enabled the user to give many people a small dose of vaccine, and was used during the smallpox eradication campaign. The medication is forced through the skin at high pressure without using a needle. SSPL/Getty Images

Until now, scientists and historians believed the vaccine originated from the cowpox virus because Jenner famously formulated the serum after withdrawing fluid from the pustules of cow milkers infected with the virus that had come into contact with the sick animals. He found that inoculating uninfected people with this material appeared to cause immunity to smallpox.

Smallpox, which has existed for some 3,000 years, was eradicated in 1980 through the Smallpox Eradication Programme. This program, which lasted from 1966 to 1980, marked the first coordinated effort to fight a disease on a global scale. The last known outbreak occurred in Somalia in 1977, according to the World Health Organization (WHO). There has been only one known case since in 1978, which was a result of unsafe practices at an unregulated lab in Birmingham, England. The incident killed one person, and spurred the need for stricter regulations.

An example of smallpox eruptions on arm and palm from 1969. The smallpox lesions, or pustules, eventually form scabs that will fall off leaving marks on the skin. The patient is contagious to others until all of the scabs have fallen off. Smith Collection/Gado/Getty images

Today, the smallpox virus still resides at high containment repositories in the headquarters of the U.S. Centers for Disease Control and Prevention in Atlanta, Georgia, and at the State Research Centre of Virology and Biotechnology (VECTOR) in Novosibirsk, Russia. Both facilities follow international agreements for use and handling, and the World Health Organization is tasked with periodic routine inspections to assess the safety of these facilities.

Smallpox vaccines in 1941. Bettmann/Getty images

The World Health Assembly plans to destroy supplies of the virus in these labs, an issue last raised in 2014, says Damaso. However, it's still undecided when the international scientific community will pull the plug. The virus, which is very large, has proven useful for medical research to develop experimental treatments for other diseases such as cancer. Genes from other organisms can be added to the viral genome, for example, in order to study their effects, for example. Or genes can be added that stimulate the immune system to fight cancer. "Basically it has been used as a vector for transporting genes since the 1980s," says Damaso.

Hesitation about destroying smallpox supplies in these labs also stems from the fact that scientists still have yet to develop antiviral treatments for the disease. Some experts believe such a treatment is a necessary precaution for the future of public health. "Everyone talks about the possibility of smallpox re-emerging because of bioterrorists," says Damaso. "We cannot rule out the possibility that we'll never use the vaccine again."