What is Smallpox? The Gruesome History and Successful Eradication

Author Chandana Balasubramanian , 03-Oct-2022

Smallpox is caused by the variola virus (VARV), a highly virulent species belonging to the genus orthopoxvirus of the poxvirus family [1,2,3]. The disease is highly contagious and can spread quickly from one person to another through direct or indirect contact [4,5]. The most common symptoms of smallpox were a fever and a characteristic rash that left many permanently scarred. Some infected individuals also became blind. 


Smallpox is one of the oldest and deadliest infectious diseases known to man. Also known as ‘pox,’ ‘red plague,’ and ‘speckled monster,’ it has the dubious distinction of having wiped out a significant percentage of the world’s population. According to the World Health Organization (WHO), the case fatality rate of smallpox is as high as 30%. Smallpox deaths are estimated to be 500 million in a hundred years and 300 million in the 20th century alone [5]. Fortunately, smallpox is no longer found naturally in the world [3]. 


Although smallpox has been eradicated, the virus can be used as a biological weapon. Due to this danger, the Centers for Disease Control and Prevention (CDC) considers smallpox a Category A bioterrorism agent. The CDC defines Category A agents as those that are high-priority and are a risk to national security because they are:

  • highly contagious
  • have high mortality rates
  • can cause widespread illness and public panic
  • and require special action to prepare a public health response [4].




Historians lack clarity concerning the origins of smallpox. It is believed to have initially appeared in North-Eastern Africa around 10,000 BC [3]. Egyptians’ mummified bodies had rashes, leading some to believe that the disease did exist some 3,000 years ago. However, early clinical descriptions of the condition were documented in China in the 4th century. Scripts describing the disease were also discovered in India and Asia Minor during the 7th and 10th centuries [6].

Eventually, wars helped the smallpox virus travel all across the world, bringing widespread illness and fatalities with it. In the 11th century, smallpox began spreading to Europe because of ‘The Crusades,’ a series of religious wars. By the 15th century, smallpox had wandered over to Western Africa, brought to the continent by a colonizing Portuguese military [6]. In the 16th century, the disease spread to the Caribbean and Central and South America, causing widespread devastation [7]. 

Smallpox did not arrive on American shores until the 17th century. As more Europeans fled their homeland for new shores, smallpox traveled with them to the North American continent [6]. The transatlantic slave trade was another significant factor fueling the smallpox epidemic in America. People from Africa were brought to America in overcrowded and highly unhygienic conditions that served as a hotbed for smallpox and other infectious diseases. Smallpox spread rapidly among Native Americans and decimated their population [3].

The story of smallpox is gruesome. In the 18th century, around 400,000 people died each year in Europe due to smallpox, and nearly one-third of those who survived went blind. During this period, the case fatality rate varied from 20% to as high as 60%. By the end of the 19th century, the infant case fatality rate was extremely high, with 80% in London and 98% in Berlin, Germany — nearly all infants who contracted the disease died [3]. 

During this period, emerging scientific breakthroughs began to offer hope in the fight against smallpox. In 1796, Dr. Edward Jenner observed that milkmaids who recovered from cowpox were immune to smallpox. This British country doctor is credited with inventing the first smallpox vaccine using the cowpox virus. In 1887, the variola virus was first visualized under a microscope by John B. Buist [8]. Later, in 1935, the pathogen was cultivated for the first time by Torres and Teixeria [8,9]. 

Although vaccine development efforts started in the 18th and 19th centuries by physicians like Dr. Edward Jenner and Dr. William Osler (the father of Modern Medicine), an effective vaccine was developed only in the 1950s. Encouraged by this development, the World Health Assembly launched its first smallpox eradication campaign in the late 1950s. 

At first, the smallpox vaccines were delivered by a large, unwieldy injector which slowed down vaccination drives. However, a bifurcated needle developed in the late 1960s changed the game, allowing for larger-scale vaccination campaigns. The needle was relatively inexpensive and easy to sterilize. It was also simple to use and required very little training, which made mass vaccination drives possible. The needle could hold a small drop of vaccine between its prongs — the ideal amount needed for immunization. This way, vaccine manufacturers could reduce the volume of vaccine required per dose, which meant more people could be vaccinated for the same amount of vaccine produced [10, 22]. 

The eradication of smallpox is one of humankind’s biggest achievements. The global vaccination effort was unprecedented and involved a concerted effort by many countries. The eradication program was hugely successful, and the last case of smallpox was reported in Bangladesh in 1975. In 1980, smallpox was declared eradicated by the World Health Assembly [10].

Although smallpox had been eradicated, many laboratories continued to stock the variola virus for research. In 1981, the US, the UK, Russia, and South Africa were the only countries involved in variola virus research. By 1984, the UK and South Africa had destroyed most of their stock, leaving behind the US and Russia [6].  

Later, evidence of smallpox being developed as a bioweapon in Russia began making news. There were also allegations that Russia was developing more virulent strains of the virus to be used as bioterrorism agents. Many nations were concerned, which led to the development of renewed smallpox vaccinations during the early 2000s [10].




Smallpox was prevalent all across the globe, including Africa, Asia, Europe, North America, and South America. Though it was not widespread in Australia, the incidence of the disease was reported in the 18th century [6]. 

Similar to that of chickenpox and measles, the incidence of smallpox was higher during winter and early spring. Children were most affected by smallpox as adults were protected by the immunity developed through vaccination and previous smallpox infections. But, in rural areas, people of all age groups were affected if they were not vaccinated [11].

History provides enough evidence to show that several smallpox outbreaks had occurred from time to time until it was declared eradicated in 1980. In the 20th century, this ‘speckled monster’ claimed around 300 to 500 million lives worldwide. It was responsible for nearly 10% of deaths in the last 1,000 years [12].

During the early 1900s, Russia reported around 50,000 to 100,000 cases yearly. Cases peaked in Europe and Russia in 1919 during the first world war, with Russia reporting over 186,000 cases – the highest number of cases reported by a country in a year at the time. In the same year, Romania reported 20,523 cases, Czecho-Slovakia reported 11,209 cases, and Yugoslavia reported 5,278 cases. Around 34,365 cases were reported in Italy and 5,012 in Germany. In Spain alone, 13,347 smallpox-related deaths occurred between 1919 and 1928.

England also saw a series of outbreaks during the 1920s. Around 81,249 cases were reported between 1922 to 1934. In the same period, Switzerland reported 5,522 cases. The US reported 46,712 in 1930, and the numbers came down to 1,000 in 1942 [13]. The country saw its last natural disease outbreak in 1949 [14]. 

Algeria, Iraq, Morocco, and Turkey also had a series of outbreaks during the early 1940s. Over 5,000 cases and 174 deaths were reported in Turkey during this period [13].

The last notable outbreak occurred in Yugoslavia in 1972. A total of 175 people contracted the infection, and 35 (almost 20%) died. This was the time when massive vaccination programs were being carried out. Within weeks, around 18 million people were vaccinated, and the country was soon declared free of smallpox [15].


How is it Spread?


Smallpox is highly contagious and becomes even more so as it progresses in severity, especially during the early rash and pustular rash and scabs phases [16]. Smallpox is uniquely a human disease that is transmitted only by humans. 

It can spread from one person to another:

  • When a person gets exposed to the respiratory or saliva droplets that are released when an infected person coughs, sneezes or talks
  • When a person touches surfaces (bedding or clothing, for instance) contaminated with the virus and then touches their mouth or nose [5,17]
  • Although rare, the virus can also spread through aerosols – infectious respiratory droplets in the air [7]


Biology of the Disease


Little is known about the variola virus today because smallpox was eradicated before modern research tools were invented. It is a poxvirus, a family of large brick-shaped viruses that contain a double-stranded DNA genome. 

The variola virus usually enters a new host through the respiratory tract since body secretions from the mouth and nose are the primary modes of transmission. Once the virus enters the human body, it gets implanted in the inner lining of the respiratory tract. The virus then migrates to the lymph nodes and begins to multiply. Soon, a large amount of viral load is released into the bloodstream. The virus in white blood cells gets localized in tiny blood vessels of the dermis (second layer of the skin) and under the oral and pharyngeal mucosa. This step causes rashes all over the body. The infection continues to spread as the virus infects adjacent cells [11].  




Smallpox symptoms usually take 10 to 14 days to appear following exposure to the virus. The first phase of the disease usually lasts 2 – 4 days with the following symptoms: 

  • High fever
  • Head and body aches
  • Severe back pain
  • Fatigue
  • Abdominal pain (less often)
  • Vomiting (less often)


After two to four days, the disease progresses into the second phase, also known as the ‘early rash’ phase. During this phase, characteristic smallpox rashes appear on the tongue and mouth and turn into sores. These sores break open, and the rashes spread to different body parts, including the face, hands, and legs. By the fourth day, the sores are filled with a thick fluid. At this stage, the infected individual has a fever that is highly contagious.

The disease then progresses onto the next phase, known as the ‘pustular rash and scabs’ phase. This stage lasts for around ten days. During this phase, the smallpox sores become round and hard to touch. After a few days (usually after five days), the sores form a crust that dries up and begins to fall off.

By the end of the second week, most of the sores begin to fall, leaving a mark on the skin. This phase is generally called the ‘scabs fall off’ phase and lasts six days. In four weeks, all crusts disappear, and the person is no longer contagious [5,16].




Ideally, a smallpox diagnosis must be made as early as possible since infected people can spread the disease before rashes appear. A diagnosis will have to be accurate without much delay in reporting results. 

An RT-PCR assay can help diagnose smallpox cases with high sensitivity and specificity. This diagnostic tool is FDA approved and is specifically helpful in differentiating variola virus from monkeypox and cowpox viruses. Portable RT-PCR machines and lyophilized reagents are found to further increase the speed of diagnosis while maintaining high sensitivity and specificity [7].




There is no effective medical treatment for smallpox. But recently developed antiviral drugs have effectively stopped smallpox virus growth in the lab. These drugs include tecovirimat, brincidofovir, and cidofovir. Since smallpox has been eradicated (and it is unethical to induce the disease solely for research), the drugs have not been tested on people infected with smallpox. The drugs were found to be safe and caused only minor side effects on healthy people and those sick with other viral infections (apart from smallpox) [18].




In 1980, the World Health Assembly declared that smallpox had been eradicated. As a result, smallpox vaccination campaigns were discontinued in all parts of the world. However, smallpox vaccines are still considered lifesavers in the event of an outbreak in the future. 

Currently, two smallpox vaccines (ACAM2000 and JYNNEOSTM) are licensed in the US. In addition, an investigational vaccine is available but for emergencies only [18,19]. The smallpox vaccine is a live version of the vaccinia virus, another poxvirus similar to, but milder than, the smallpox virus. According to the CDC, the vaccine is safe for people with healthy immune systems, but certain precautions must be taken since it contains a live virus

Mild smallpox vaccine adverse events include the formation of lesions, fever, body pain, swelling of lymph nodes, fatigue, headache, nausea, rashes, and soreness at the vaccination site [10]. Smallpox vaccine stockpiles are available in several countries in case of a bioterror attack or a new outbreak [21]. 

In addition to a vaccine stockpile, other preventive measures are necessary to prevent future outbreaks, including: 

  • Constant vigilance: As soon as a medical professional suspects or diagnoses someone with smallpox, everyone in contact must be isolated, vaccinated, and monitored. The disease is highly contagious; secondary attacks affect 80% of all other household members [20].
  • Vaccinations: The smallpox vaccine should be administered within four days after exposure to the virus to help prevent fatalities. 
  • Wear protective gear: Healthcare workers must use protective gear like gloves and masks and ensure that all bedding, medical scrubs, and other material are placed in biohazard bags before being laundered.
  • Sanitized hospital rooms: Hospital rooms must be decontaminated as soon as a hospitalized smallpox patient recovers and is discharged [11].

[1] S. Melamed, T. Israely, and N. Paran, “Challenges and achievements in prevention and treatment of smallpox,” Vaccines (Basel), vol. 6, no. 1, p. 8, 2018.

[2] M. Hasan and E. McLean, “A computational analysis to construct a potential post-exposure therapy against pox epidemic using miRNAs in silico,” J. Bioterror. Biodef., vol. 07, no. 01, 2016.

[3] S. Riedel, “Edward Jenner and the history of smallpox and vaccination,” Proc. (Bayl. Univ. Med. Cent.), vol. 18, no. 1, pp. 21–25, 2005.

[4] CDC, “Bioterrorism Agents/Diseases,” Center for Disease Control and Prevention, 15-May-2019. [Online]

[5] WHO, “Smallpox,” World Health Organization. [Online] 

[6] CDC, “History of smallpox,” Centers for Disease Control and Prevention, 21-Feb-2021. [Online]

[7] H. Meyer, R. Ehmann, and G. L. Smith, “Smallpox in the post-eradication era,” Viruses, vol. 12, no. 2, p. 138, 2020.

[8] C. T. Ambrose, “Osler and the infected letter: A history of disinfecting mail with Osler and the infected letter: A history of disinfecting mail with special reference to smallpox special reference to smallpox,” [Online]

[9] C. T. Ambrose, “Osler and the infected letter,” Emerg. Infect. Dis., vol. 11, no. 5, pp. 689–693, 2005.

[10] E. A. Belongia and A. L. Naleway, “Smallpox vaccine: the good, the bad, and the ugly,” Clin. Med. Res., vol. 1, no. 2, pp. 87–92, 2003.

[11] D. A. Henderson et al., “Smallpox as a biological weapon medical and public health management,” [Online] 

[12] C. Thèves, P. Biagini, and E. Crubézy, “The rediscovery of smallpox,” Clin. Microbiol. Infect., vol. 20, no. 3, pp. 210–218, 2014. 

[13] WHO, “Recent Trend of Smallpox in Europe,” World Health Organization. [Online] 

[14] CDC, “Smallpox,” Centers for Disease Control and Prevention, 19-Feb-2019. [Online]

[15] I. Ilic and M. Ilic, “Historical review: Towards the 50th anniversary of the last major smallpox outbreak (Yugoslavia, 1972),” Travel Med. Infect. Dis., vol. 48, no. 102327, p. 102327, 2022.

[16] CDC, “Signs and symptoms,” Centers for Disease Control and Prevention, 15-Feb-2019. [Online]. 

[17] CDC, “Transmission,” Centers for Disease Control and Prevention, 15-Feb-2019. [Online]. 

[18] CDC, “Prevention and treatment,” Centers for Disease Control and Prevention, 08-Aug-2022. [Online]

[19] CDC, “Vaccines,” Centers for Disease Control and Prevention, 11-Aug-2022. [Online].

[20] “Smallpox,” Cleveland Clinic. [Online].

[21] “Smallpox vaccines,” [Online]. 

[22] R. Wittek, “VACCINIA VIRUS (POXVIRIDAE),” in Encyclopedia of Virology, A. Granoff and R. G. Webster, Eds. Elsevier, 1999, pp. 1865–1872.

Chandana Balasubramanian

Chandana Balasubramanian is an experienced healthcare executive who writes on the intersection of healthcare and technology. She is the President of Global Insight Advisory Network, and has a Masters degree in Biomedical Engineering from the University of Wisconsin-Madison, USA.

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