[Editor's Note: This is the second in our brief series of articles celebrating the anniversary of the discovery of the Smallpox Vaccine. Please share both of these articles freely]

It was on today in 1796 that an Englishman by the name of Edward Jenner extruded pus from the cowpox-infected skin of a milkmaid and scratched it into the arm of a young boy. After the boy recovered from the minor infection that resulted, Jenner inoculated him again with fresh smallpox ooze, from which the boy experienced no subsequent symptoms. This represented the first of many successful efforts on his part to prove that being infected with cowpox in a controlled way was a safe and effective method to protect humans from smallpox.  

Jenner later coined the term vaccination to describe this procedure, based on the Latin word for cow (vacca) and cowpox (vaccinia). While he was not the first person to perform this technique to prevent smallpox, his rigorous efforts to scientifically reproduce his results and publish them in the medical literature were the nidus for future efforts to prevent infections through vaccination. This effort bloomed into one of the four most successful public health promotion strategies of the 20th century, along with pasteurized milk, chlorinated water, and flushing toilets.

Variola, or The Small Pockes

“Smallpox” refers to a several different infectious syndromes caused by two closely related viruses, Variola major and Variola minor. These viruses have several interesting characteristics which make them both a scourge of our species as well as prime candidates for vaccine control: they only infect humans, there is no asymptomatic carrier state, and they are not transmitted by an animal or insect vector. Both viruses are transmitted primarily through an infected person coughing up virus-packed saliva droplets that are inhaled by another, although direct contact with infected body fluids or contaminated surfaces also results in transmission. V. major can cause four distinctly horrible clinical smallpox presentations: ordinary, which causes a classical blistering rash with fever, and kills anywhere from 30-75% of patients; modified smallpox, which occurs in those who have been vaccinated and is rarely fatal; malignant, which has more severe symptoms with a “flat” rash and can kill 80% of the infected; and hemorrhagic, which is a rare but catastrophic form that kills nearly everyone presenting with it. V. minor causes a milder illness, with fatality rates of approximately 1%.  

Smallpox first appeared among humans around 10,000 BC in Africa, and likely spread to India and China through the inadvertent efforts of Egyptian merchants. Mummies from the 18th to 20th Egyptian Dynasties demonstrate the earliest evidence of facial pockmarking due to the disease, as exemplified by the remains of pharaoh Ramses V, who died in 1156 BC. It was brought to Europe somewhere in the 5th to 7th centuries AD, where it caused frequent epidemics during the Middle Ages. It was during this time that the Swiss Bishop Marius of Avenches first called the disease variola from the Latin words for stained (varius) and mark on the skin (varus). It wasn’t until the 15th century in England that is became popularly known as the “small pockes”, a name introduced to differentiate it from the “great pockes”, or syphilis. Portuguese and Spanish conquistadors then brought it to the Americas in the 1700’s, completing the spread of smallpox to all of the most populous areas of the known world.

In this way, smallpox both became spread by major historical events, as well as influencing them. It was responsible for killing nearly 7 million people in the epidemic-level event known as the plague of Antonine, which occurred in 108 AD at the start of the decline of the Roman Empire. The Muslim conquests and subsequent Crusades, and well as arrival of Europeans in the West Indies, all served to expansively transmit the infection through human population centers. In an amazingly low point for us as a species, the disease was involved in one of the first recorded biological warfare events, namely the deliberate spread of smallpox by British forces to the Native Americans during the French-Indian War, as suggested by the letters of Sir Jeffrey Amhurst. A further source of intensification of the disease in the Americas was the transport of slaves from smallpox-endemic regions of Africa. It wasn’t until vaccination efforts were scientifically clarified and instituted at the population level that we were able to curb the spread of this lethal infection. 

Variolation Begat Vaccination 

It was noted from an early time that those who survived a smallpox infection were unable to become reinfected. As early as the 5th century BC, smallpox survivors were recruited to attend to those ill with the infection for that reason. It was later found that inoculating, or variolating, a non-infected person subcutaneously with pus from an infected individual usually gave that person a less severe illness than if they had acquired the infection naturally, as well as protective immunity. This crude process of stabbing healthy people with virus-laden bloody pus was still risky: 2% of the variolated individuals developed disseminated smallpox and died, those ill after variolation could potentially transmit it to the non-immune, and other bloodborne infections could be transmitted during the inoculation procedure, such as syphilis.

Variolation was practiced well before the 18th century in endemic regions such as Africa and India, likely as a last ditch effort to protect a population as a smallpox epidemic loomed. The technique was brought to Turkey in the 17th century, where it was noted by travelers from England, including the aristocrat Lady Mary Wortley Montague. Herself a survivor of smallpox, she brought the technique back to England and had her 4-year-old daughter variolated in the presence of King George I’s royal physicians in 1721. That same year, variolation made its way to North America, where it was put to use by the infamous Cotton Mather and Dr. Zabdiel Boylston to curb a smallpox epidemic in Boston. They later produced data demonstrating a reduction in mortality rates from 14% in those naturally infected with smallpox to 2% in those variolated, which became the first ever documented use of comparative statistics for a public health intervention.

This success laid the groundwork for variolation to give way to vaccination. It was a common observation among European country folk that people infected with cowpox were unable to later get smallpox, and several individuals in the mid-to-late 1700’s purposefully inoculated friends and family members with the former disease to prevent the latter. However, starting in 1796, Edward Jenner was the first to do so in an ongoing series and with scientific rigor. Despite resistance to his work by the Royal Society, inclusive of their refusal to publish his initial data, as well as a burgeoning anti-vaccination movement, his tireless efforts eventually resulted in the acceptance of vaccination by the medical community and the public at large. In subsequent years, vaccination spread throughout Europe and to the United States, resulting in the formation of national vaccination programs.

This was truly the death knell for smallpox, and the start of what was arguably the greatest public health achievement in our history on this Pale Blue Dot. With the elucidation of the germ theory of disease, the etiologic agent of cowpox was identified, and named the vaccinia virus for rather obvious reasons. As the 19th and 20th centuries progressed, the live vaccinia virus vaccine was purified, able to be reliably mass produced, and administered to patients in a sanitary manner. The World Health Organization initiated an intensified worldwide eradication program in 1965, resulting in the last naturally acquired infection occurring in Somalia in 1977; the last ever infection happened in a lab accident in the United Kingdom in 1978. On May 8, 1980, the WHO officially resolved that the great viral scourge of humanity was gone from the natural world, and smallpox vaccination programs ceased.

Futures Bleak and Bright

The future of smallpox remains one of life in prison, although the death penalty is being considered. After the 1978 lab accident, all known Variola samples were secured at either the CDC in Atlanta, Georgia, USA, or the VECTOR Institute in Koltsovo, Novosibirsk Oblast, Russia. We are all far too familiar with the concerns that some stockpiles of Variola virus could now or in the future come into the possession of those who would use them as a bio-weapon, and the reinstitution of smallpox vaccination for military and high-risk personnel over the last decade. Several calls have been made to destroy all the remaining live Variola samples in existence, and the debate is complex: on one hand, they represent a clear potential danger to a general population in whom there is no longer any circulating immunity, but on the other, the research opportunities are great, and have already yielded dividends in the form of the sequence of the Variola genome, a greater understanding of the poxviruses still occurring in nature, and the development of new anti-viral drugs. Another referendum is expected on the matter this year, so we must wait and see if smallpox gets another stay of execution.

The future of vaccination as a public health tool remains strong, despite storm clouds on the horizon. The fear-based misinformation spread to the general populous by a small group of anti-vaccinationists amplified through a credulous, sensationalist media has cost us some ground in public health, with pockets of decreased vaccination rates and resultant spikes in vaccine-preventable disease. Despite this, much like Edward Jenner, the scientific and skeptical communities are working tirelessly to raise informed awareness and overcome these setbacks. 215 years after the Jenner’s first vaccination, the history of smallpox reinforces what we already know: engaging the public with a rational mindset and scientific evidence, even if it seems to be a grueling process at times, will ultimately succeed in bringing greater health and less suffering to humanity. At the very least, we aren’t stabbing people with bloody pus anymore.



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2. Leonard, W. Dr. Osler's Challenge To The Anti-Vaccinationists. Boston Med Surg J 1910; 163:961

3. Riedel S. Edward Jenner and the history of smallpox and vaccination. Proc (Bayl Univ Med Cent). 2005 January; 18(1): 21–25.

4. Mcfadden G. Killing a Killer: What Next for Smallpox? PLoS Pathog. 2010 January; 6(1): e1000727.

5. http://emergency.cdc.gov/agent/smallpox/disease/ accessed May 13, 2011

6. http://www.who.int/csr/disease/smallpox/en/ accessed May 13, 2011


John Cmar, MD, is an Infectious Diseases specialist at Sinai Hospital of Baltimore, and an Instructor of Medicine at the Johns Hopkins University School of Medicine. In his role as Associate Program Director for the Johns Hopkins Internal Medicine residency program at Sinai, he attempts to impart sanity and skepticism in the practice of medicine to the residents and students he teaches. Among his favorite duties are teaching an annual course series on the strengths and weaknesses of Evidence-Based Medicine, as well as giving everyone around him a healthy fear of the microbes that will one day kill us all.