It is mind-boggling that researchers still don’t know exactly what virus was used in the most successful vaccine ever developed. But the mystery around the identity of the virus used by British physician Edward Jenner to create the smallpox vaccine back in 1798 has gained further traction after an international group of researchers led by Andreas Nitsche at the Robert Koch Institute in Berlin investigated a historical vaccine specimen from a private collection. The vaccine dates back to 1902 and was manufactured by H.K. Mulford Co. from Philadelphia, which later would merge with Sharpe and Dohme and finally with Merck & Co. in 1953.

For centuries, researchers assumed that the active ingredient in the vaccine providing immunity against smallpox was the cowpox virus because Jenner took pustular material from milkers infected with cowpox (a smallpox-like disease in cows that has mild symptoms in humans) to inoculate people, a process that became known as vaccination (vacca being Latin for cow). Indeed, it has been shown that inoculation with cowpox virus confers immunity against smallpox, without causing severe symptoms or side-effects.

However, in the late 1930s questions on the identity of the virus used by Jenner arose when serological analysis done with embryonated chicken eggs revealed that the virus found in the smallpox vaccine at the time was not in fact cowpox virus. The virus in the smallpox vaccine, renamed vaccinia virus, has no known natural hosts and its origin is still being investigated.

In a study published on October 12 in the prestigious New England Journal of Medicine and entitled “An Early American Smallpox Vaccine Based on Horsepox,” a team of researchers from the Robert Koch Institute in Germany, Jose Esparza from the Institute of Human Virology in Baltimore, United States, and Clarissa Damaso from the Federal University of Rio de Janeiro, Brazil, support that based on sequencing data, the virus found in the Mulford vaccine specimen (which is the earliest smallpox vaccine specimen ever investigated) is closely related to horsepox virus, rather than cowpox virus. “We now have, for the first time, scientific evidence that horsepox virus was indeed used in the past to immunize against smallpox”, says the group leader Andreas Nitsche from the Robert Koch Institute.

Historical records suggest that in the 18th and 19th centuries both viruses (horsepox and cowpox viruses) were used interchangeably to immunize against smallpox, however no scientific evidence of the presence of horsepox virus in smallpox vaccine specimens had ever been demonstrated. Curiously, all existing smallpox vaccine specimens contain not horsepox or cowpox viruses but rather vaccinia. The research group is in search of more donors of historical samples to further investigate these issues and hopefully make new and exciting discoveries. One hypothesis is that different lineages of the smallpox vaccine, with different origins and evolutionary history, were used in the past to develop the vaccine that has saved the lives of millions of people in the last centuries.

Altogether, the study shows that at least some early smallpox vaccines were made using horsepox virus (although it can’t be ruled out that cowpox or even vaccinia virus were also used in the past) but over the 20th century somehow the virus in the smallpox vaccine has become the vaccinia virus as we know today.

Although smallpox has been eradicated, smallpox vaccine, containing the virus currently referred to as vaccinia, is a powerful ally for doctors and researchers, who use it as a vehicle to develop new vaccines against other infectious diseases and even cancer, bringing far-reaching benefits to public health. In fact, vaccinia virus has been successfully used to kill pancreatic and prostate cancer cells, being considered a novel and promising biotherapeutic approach in the fight against cancer.

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