The vaccine fuelled the most successful ever disease eradication programme - several million people received it during the 1970s.
Now, scientists in Cardiff are starting a small-scale clinical trial to see if a modified version of the vaccine can raise the body's defences against human papillomavirus (HPV).
This virus is widely thought to be somehow key to the development of the majority of cervical cancers.
Nearly all cervical cancer cells contain the HPV virus in one form or another.
Each year, more than 3,000 women in the UK are diagnosed with cervical cancer.
Small trial
The Welsh trial - funded by the Cancer Research Campaign - follows testing of the new vaccine on almost a hundred people across Europe.
It is hoped that the new vaccine will stimulate the immune system to attack all cervical cells which have been infected with HPV - thus destroying cancerous cells.
Dr Stephen Man, from the University of Wales, said: "It's crucial that the immune response can find its way from the bloodstream to the affected cells in the cervix, where it's needed.
"Otherwise it's like being given a fast car, but not knowing where you're supposed to be going."
Rich history
While some vaccines contain weakened versions of the same virus which causes disease, the smallpox vaccine is constructed from a similar virus, vaccinia, which does not cause disease in humans.
To tailor it to trigger an attack on HPV-infected cells, molecules produced by this virus are inserted into the vaccine.
Professor Gordon McVie, Director General of the Cancer Research Campaign, acknowledged that there was much work to be completed before a reliable cervical cancer vaccine could be mass-produced for women.
He said: "This trial represents an important step from the lab to the clinic.
"When Edward Jenner frist developed the smallpox vaccine back in 1796, he could never have imagined that it would still have such an impact on our health over two centuries later."