"A pox o' your throat, you bawling, blasphemous, incharitable dog!"

- Sebastian in Act I, Scene I,

"The Tempest" by William Shakespeare





So horrific was smallpox, a disease that often left its victims pockmarked or brain-damaged - if not dead - that in Elizabethan England, wishing a pox on someone bore the weight of today's four-letter words.

Indeed, the vaccine that effectively eradicated smallpox was aimed at one of the most odious infections ever to cause death, debility - and fear. Vilifying someone with the curse "a pox on your house," medical historians say, was a direct reference to smallpox.

Until its eradication, smallpox was the worst of diseases caused by a class of viruses - poxviruses - that affect virtually every species on Earth. Variola, the one that causes smallpox, was specific to humans. And until the aggressive eradication campaign of the 1960s and '70s, the infection had been passed person-to-person in an unbroken chain since the beginning of humankind.

"Unlike any other disease, smallpox has had the greatest impact on world events," said Dr. Jeffrey Koplan, former director of the Centers for Disease Control and Prevention and now vice president of academic health affairs at Emory University in Atlanta.

"Smallpox changed dynasties and successions - aligned countries against each other; military battles were won or lost because of it," Koplan said. During America's colonial era, it was used as a biological threat by the British. Throughout the Western Hemisphere, variola was the pathogen that helped Europeans conquer the Americas.

"This was an Old World disease that bears more responsibility for conquering the New World than Europe's military might," said historian Elizabeth Fenn of Duke University. References to the disease, she said, pervade literature, history, religion, medicine and biology.

In nature, poxviruses abound: swinepox, sheep pox, fowlpox and a subfamily that infects insects. Chicken pox, a human disease, is not among them because it is a herpes virus, a completely different viral family.

Though poxviruses are generally species- specific, meaning they are mostly found among specific hosts, people had known for hundreds of years that infection by one usually confers immunity to another. Exploiting that observation, Edward Jenner was able to develop a vaccine against smallpox, based on the cowpox virus.

The following poxviruses can cause human infection:

Cowpox: Acquired by humans before widespread bovine vaccination when milking cows. Though called cowpox, it is most prevalent in rats.

Monkeypox: A mild, smallpox-like disease usually seen in a variety of primates and squirrels. The disease has been transmitted to children in Central Africa but is not fatal.

Orf virus: Detected globally in sheep and goats and is marked by scabby formations on the animals' mouths. The pathogen can cause a mild infection in humans, usually on the hands.

Pseudocowpox: Cattle disease that can cause ulcerations in humans, usually on the hands, that heals without therapy. The disease occurs globally and gets its "pseudo" prefix because it belongs to a different viral subfamily than cowpox.

Vaccinia: The virus used in the vaccine, a mutated version of a cowpox microbe. It imparts immunity to smallpox.



GLOSSARY

The advent of a vaccine for smallpox ushered in a new era of medicine: that of immunization. A special vocabulary also evolved over two centuries and became associated with the smallpox vaccine. Other special vocabulary had already become part of the language as a result of the disease.

Bifurcated needle: The two-pronged lancet developed in the early 1960s to deliver a precise dose of smallpox vaccine. The needle, now considered an antique, was designed to penetrate to the skin's malpighian layer, the innermost stratum of the skin's epidermal layer. It is through the malpighian that the body is best able to distribute the vaccine through the blood supply and to cause "a take."

Eczema vaccinatum: Generalized lesions caused by vaccination for smallpox. The condition occurs in people with eczema and can be fatal.

Greatpox: A now extinct term used at one time in England to distinguish the large skin eruptions caused by syphilis from the smaller, more pervasive skin manifestations of smallpox, a disease associated with epidemics.

Inoculation: Injection of microorganisms, cells or toxic materials into the body. This can be accomplished by using a needle and syringe as well as by scalpel or other sharp object. While sharp objects were used in the past, today inoculation can be accomplished by needle-free jet injection. A forerunner to inoculation was a process called ingrafting, used in Turkey.

Milkers' nodules or nodes: The bumpy manifestations that occurred along with skin ulcerations in people who milked cows or goats. The nodules were caused by infection with a pox virus.

Scarification: A term that arose with the advent of vaccination, referring to the process of making small incisions in the skin. Doctors in the 18th and 19th centuries accomplished scarification with scalpel-like instruments called scarifiers or scarificators.

Take: Generally referred to as "a take," meaning a positive reaction to a smallpox vaccination, usually a scab that indicates full immunity against the disease. The term, though dated, was revived last year when clinical trials of the vaccine began.

Vaccine: The word is derived from the Latin, vaccinus, which mean pertinent to cows. The term was first used to describe the process of immunizing people against smallpox.

Variola: The virus that causes smallpox.

Variolation/variolization: Inoculation against smallpox.