No One Knows What’s Inside the Smallpox Vaccine

At the heart of history’s most successful eradication campaign is a mystery. The smallpox vaccine—now also being deployed against monkeypox—contains a live virus that confers immunity against multiple poxviruses. But it is not smallpox or a weakened version thereof. Nor is it monkeypox. Nor is it cowpox, as suggested by the vaccine’s famous origin story involving pus taken from an infected milkmaid to immunize an 8-year-old boy.

It is something else entirely: a unique poxvirus whose origins have been lost, or perhaps never known at all. Scientists call it vaccinia, and it is pretty much found only in the vaccines. No one knows where vaccinia came from in nature. No one has ever found its animal reservoir. No one knows quite what vaccinia is—even as it has been used to inoculate billions of people and saved hundreds of millions of lives. It is a ghost of a virus that has survived by being turned into a vaccine.

José Esparza first began wondering about vaccinia in the 1980s, when he was assigned an office at the World Health Organization next to the