Vaccines have saved millions, if not billions, of human lives over the last two centuries. The smallpox vaccine was the first of such weapons in our medical arsenal, and while its success is undeniable, its composition has puzzled medical researchers for decades.

The virus in the vaccine was supposed to be cowpox, a relative of smallpox that is not deadly to humans. But the virus (called vaccinia) in the vaccine is not cowpox. Now, an international team of researchers have analyzed a 1902 vial of the smallpox vaccine and have found strong evidence that the virus used in that inoculation is actually related to horsepox, rather than cowpox.

As reported in the New England Medical Journal, the vaccine produced by the Philadelphia company H.K. Mulford Co. has a 99.7 percent similarity to the horsepox virus. While this connection has long been suspected, this is the first evidence that horsepox was actually used in the original vaccine. Still, this does not rule out the possibility that cowpox and horsepox were used interchangeably in the past to vaccinate against smallpox.

The vaccine itself was first developed by English physician Edward Jenner in 1798, after observing that milkmaids who caught cowpox, a similar disease, would not later catch smallpox. The disease manifested itself as pustules on the cows' udders, and the milkmaids would develop similar pustules on their hands.

Several viruses of the pox family can jump across species, so what we identify as cowpox today might have been just one of the viruses present on the cows. Horsepox might have been present too. Back then, however, it would have been impossible to distinguish between the exact virus causing the illness. The pustules were on the cows, so it was cowpox.

This new finding, then, provides evidence "of the suspected role of horsepox in the origin of the smallpox vaccine, a role that was suspected even by Jenner himself," write the authors. 

The smallpox vaccine is one of the most incredible success stories of science, changing the fate of countless people. Thanks to mass vaccinations on a global scale, the last natural infection occurred in 1977. Before the eradication of the virus in the 1980s, up to half a billion people had died in the 20th Century alone. Now the virus is only stored safely in two facilities – the US Centers for Disease Control and Prevention in Atlanta and the State Research Centre of Virology and Biotechnology in Novosibirsk, Russia.