William Woodville, one of the early vaccinators and director of the London Smallpox Hospital is thought to have contaminated the cowpox matter – the vaccine – with smallpox matter and this essentially produced variolation. Other vaccine material was not reliably derived from cowpox, but from other skin eruptions of cattle.During the earlier days of empirical experimentation in 1758, American Calvinist Jonathan Edwards died from a smallpox inoculation. Some of the earliest statistical and epidemiological studies were performed by James Jurin in 1727 and Daniel Bernoulli in 1766. In 1768, Dr John Fewster reported that variolation induced no reaction in persons who had had cowpox. Edward Jenner was born in Berkeley, England as an orphan. As a young child, Jenner was variolated with the other schoolboys through parish funds, but nearly died due to the seriousness of his infection. Fed purgative medicine and going through the bloodletting process, Jenner was put in one of the variolation stables until he recovered. At the age of 13, he was apprenticed to apothecary Daniel Ludlow and later surgeon George Hardwick in nearby Sodbury. He observed that people who caught cowpox while working with cattle were known not to catch smallpox. Jenner assumed a causal connection but the idea was not taken up at that time.
The term vaccinia now refers only to the smallpox vaccine, while cowpox no longer has a Latin name. The development of whole genome sequencing in the 1990s made it possible to compare orthopoxvirus genomes and identify their relationships with each other. The horsepox virus was sequenced in 2006 and found to be most closely related to vaccinia. In a phylogenetic tree of the orthopoxviruses, horsepox forms a clade with vaccinia strains, and cowpox strains form a different clade.Horsepox is extinct in the wild, and the only known sample was collected in 1976. Because the sample was collected at the end of the smallpox eradication campaign, scientists considered the possibility that horsepox is a strain of vaccinia that had escaped into the wild. However, as more smallpox vaccines were sequenced, older vaccines were found to be more similar to horsepox than modern vaccinia strains. A smallpox vaccine manufactured by Mulford in 1902 is 99.7% similar to horsepox, closer than any previously known strain of vaccinia. Modern Brazilian vaccines with a documented introduction date of 1887, made from material collected in an 1866 outbreak of "cowpox" in France, are more similar to horsepox than other strains of vaccinia. Five smallpox vaccines manufactured in the United States in 1859–1873 are most similar to each other and horsepox, as well as the 1902 Mulford vaccine. One of the 1859–1873 vaccines was identified as a novel strain of horsepox, containing a complete gene from the 1976 horsepox sample that has deletions in vaccinia.