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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

## Overview

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Smallpox is estimated to be at least 16,000 years old, and up until 1977, when it became the only human infectious disease to have been completely eradicated, smallpox played a major role in human history. The first clinical evidence of the disease was found in an Egyptian mummy, Ramses V. Smallpox has also been used as a weapon throughout history. The most recent example was the weaponization of smallpox during World War II. After successful vaccination campaigns in the 19th and 20th centuries, the WHO certified the eradication of smallpox in 1980.[1]

## Historical Perspective

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### Impact on Historical Figures and History

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Famous victims of this disease include Date Masamune of Japan (who lost an eye to the disease), Ramses V,[2] the Shunzhi Emperor and Tongzhi Emperor of China (official history), Mary II of England, Maximilian III Joseph, Elector of Bavaria and Peter II of Russia. Guru Har Krishan 8th Guru of the Sikhs in 1664, Peter III of Russia in 1744 and Abraham Lincoln in 1863.[3] Joseph Stalin, who was badly scarred by the disease early in life, often had photographs retouched to make his pockmarks less apparent.

Families prominent in history often had several people fall victim to the disease. For example, several relatives of Henry VIII survived the disease but were scarred by it. These include his sister Margaret, Queen of Scotland, his fourth wife, Anne of Cleves, and his daughter, Elizabeth I of England in 1562. His son and heir Edward VI died very shortly after apparently recovering from the disease. Some scholars assert that his death may have been due to complications from smallpox. A more distant relative Mary Queen of Scots contracted the disease as a child but had no visible scarring. Deaths from smallpox often impacted dynastic succession. Louis XV of France succeeded his great-grandfather through a series of deaths of smallpox or measles among those earlier in the succession line and himself died of the disease in 1774.

### Outbreak in North America

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Between 1775 and 1782, a smallpox epidemic raged across much of North America, killing more than 130,000 people. Among other places it affected:

* The town of Boston during the British occupation and the American siege of 1775
* The American invasion of Quebec, 1775
* Smallpox ravaged the populations of escaped slaves who fled to the British lines in the South during the american revolutionary war
* New Orleans, 1778
* Tens of thousands of people died throughout Mexico beginning in 1779
* It swept through the Pueblos of New Mexico beginning in 1780
* It probably travelled among the people of the Great Plains
* It showed up in the interior trading posts of the Hudson's Bay Company in 1782

### Outbreak in Europe

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The 1972 outbreak of smallpox in Yugoslavia was the last major outbreak of smallpox in Europe. It was centred in Kosovo and Belgrade, Serbia (both then part of SFR Yugoslavia. A Muslim pilgrim had contracted the smallpox virus in the Middle East. Upon returning to his home in Kosovo, he started the epidemic in which 175 people were infected, 35 of whom died. The epidemic was efficiently and ruthlessly contained by enforced quarantine and mass vaccination.

#### Background

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By 1972, vaccination for smallpox had long been widely available and the disease was considered to be eradicated in Europe. The population of Yugoslavia had been regularly vaccinated against smallpox for 50 years, and the last case was reported in 1930. This was the major cause for the initial slow reaction by doctors, who did not promptly recognize the symptoms of the disease.

#### The outbreak

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In early 1972, a 38-year-old Muslim clergyman from Damnjan near Đakovica, Kosovo, undertook the pilgrimage to Mecca. He also visited holy sites in Iraq, where there were known cases of smallpox. He returned home on February 15. The following morning he felt achy and tired, but attributed this to the long bus journey. He soon realised that he had some kind of infection, but, after feeling feverish for a couple of days and developing a rash, he recovered - probably because he had been vaccinated two months earlier.

On March 3, Latif Musa, a thirty-year-old schoolteacher, who had just arrived in Djakovica to enroll at the local higher institute of education, fell ill. He had no known direct contacts with the clergyman, so he might have been infected by one of the clergyman's friends or relatives who visited him during his illness, or by passing the clergyman in the street.

When Musa visited the local medical center two days later, the doctors tried to treat his fever with penicillin (smallpox is a virus, so this was ineffective). His condition didn't improve, and after a couple of days his brother took him to the hospital in Čačak, 150 km to the north in Serbia. The doctors there could not help him, so he was transferred by ambulance to the central hospital in Belgrade.

On March 9, Musa was shown to medical students and staff as a case of an atypical reaction to penicillin, which was a plausible explanation for his condition. On the following day, Musa suffered massive internal bleeding and, despite efforts to save his life, died in the evening.

The cause of death was listed as "reaction to penicillin". In fact he had contracted black pox, a highly contagious form of smallpox. Before his death, Musa directly infected 38 people (including nine doctors and nurses), eight of whom would consequently die.

#### Reaction

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By March 22, medical authorities realised that Musa had died of smallpox. The government's reaction was swift. Martial law was declared. Measures included blockades of villages and neighbourhoods, roadblocks, prohibition of public meetings, closure of borders and prohibition of all non-essential travel. Hotels were requisitioned for quarantines in which 10,000 people who may have been in contact with the virus were held under guard by the army. The authorities undertook a massive revaccination of the population, helped by the World Health Organization. Donald Henderson, the world's foremost authority on smallpox, was flown in to help the effort.

Within two weeks, almost the entire population had been revaccinated. By mid-May the spread of the disease was stopped and the country returned to normal life. During the epidemic, 175 people contracted smallpox and 35 of them died.

#### Legacy

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The Yugoslav government received international praise for the successful containment of the epidemic, which was also one of the finest hours for Donald Henderson and the WHO, as well as one of crucial steps in the eradication of smallpox.

Two months of martial law, the fear and the helplessness during of the epidemic left a lasting mark on an entire generation. Another, more tangible mark, was left in the shape of the small scars on millions of arms, left by the vaccination.

#### Timeline

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* February 15 1972 - A clergyman returns from pilgrimage to Mecca infected with the smallpox virus.
* February 16 - The clergyman feels unwell.
* February 21 - Ljatif Muzza, a thirty-year old school teacher, arrives in Djakovica to continue his studies.
* March 3 - Muzza falls ill with a highly contagious form of smallpox.
* Between March 3 and March 9 Muzza is misdiagnosed and moved to hospitals in Čačak and then Belgrade. During this time, he directly infects 38 people.
* March 9 - Muzza is shown to medical students in the Belgrade hospital as a case of reaction to penicillin.
* March 10 - Muzza develops massive internal bleeding and dies.
* March 22 - Doctors correctly diagnose the cause of Muzza's death and government begins measures to contain the epidemic.
* Early April - Mass revaccination begins. Donald Henderson arrives.
* Late May - The epidemic is over. 175 people were infected, 35 died.

### Inoculation

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Smallpox inoculation sign, 1801Adapted from Wikimedia Commons[4]

By that time, a preventive treatment for smallpox had finally arrived. It was a process called inoculation, also known as insufflation or variolation. Inoculation was not a sudden innovation, as it is known to have been practiced in India as early as 1000 BC.[5] The Indians rubbed pus into the skin lesions. The Chinese blew powdered smallpox scabs up the noses of the healthy after discovery, by a Buddhist nun, that this inoculated non-immune people. The patients would then develop a mild case of the disease and from then on were immune to it. This technique is known as variolation and although variolation had a 0.5-2% mortality rate, this was considerably less than the 20-30% mortality rate of the disease itself. The process spread to Turkey where Lady Mary Wortley Montagu, wife of the British ambassador, learned of it from Emmanuel Timoni (ca. 1670–1718), a doctor affiliated with the British Embassy in Istanbul. She had the procedure performed on her son and daughter, aged 5 and 4 respectively. They both recovered quickly and the procedure was hailed as a success and reported to the Royal Society in England. Timoni, from the University of Padova, Italy and a member of the Royal Society of London since 1703, published “an account, or history, of the procuring the smallpox by incision” in December 1713 in the Philosophical Transactions. His work was published again in 1714 in Leipzig and was followed by those of Pylarino (1715), Leduc (1722), and Maitland (1722).

In 1721, an epidemic of smallpox hit London and left the British Royal Family in fear. Reading of Lady Wortley Montagu’s efforts, they wanted to use inoculation on themselves. Doctors told them that it was a dangerous procedure, so they decided to try it on other people first. The test subjects they used were condemned prisoners. The doctors inoculated the prisoners and all of them recovered in a couple of weeks. So assured, the British royal family inoculated themselves and reassured the English people that it was safe.

But inoculation still had its critics. Prominent among them were religious preachers who claimed that smallpox was God’s way of punishing people and that inoculation was a tool of Satan. This resistance only encouraged Montagu and the others to work even harder. By 1723 inoculations were extremely common in England, but even scientific opposition (such as the Fellow of the Royal College of Physicians Pierce Dod) continued for some time.

In 1721, Onesimus was the slave of a Boston preacher when smallpox came to Boston via a ship arriving from Barbados.[6] His owner, Cotton Mather asked his slave if he ever had smallpox. Onesimus said, “Yes and no,” and explained a technique from his homeland in Africa, thought to be in Sudan. He explained that pus from an infected person was deliberately rubbed into a scratch or cut of a non-infected person, and when successful, the person had immunity. This remedy from an African slave was the precursor to inoculations. Cotton Mather, the son of a former Harvard University dean, was waging a campaign of his own to promote the process, although religious resistance to inoculation was very strong. At one point, Cotton Mather was in danger from a crowd that wanted to hang him. After six patients died from the procedure, he was called a murderer. But, when the population of Boston returned after the end of a smallpox epidemic in 1722, he was an instant hero. Out of the population of Boston, 7% had died from smallpox. Out of the 300 people that chose to inoculate themselves, only 2% died. In 1750, the English magazine, Gentleman's Magazine, reprinted a 1725 pamphlet that argued in support of smallpox inoculations. By 1774, it was considered odd not to choose inoculation. Onesimus was later freed by Mather, not for his knowledge and help in combating smallpox, but because Mather considered him to be disobedient.

Even though inoculation was a powerful method of controlling smallpox, it was far from perfect. Inoculation caused a mild case of smallpox which resulted in death in about 2% of the cases. It was also difficult to administer. Sick patients had to be locked away to prevent them from transmitting the disease to others. Thus George Washington initially hesitated to have his Revolutionary War troops inoculated during a smallpox outbreak in February 1777, writing, “should We inoculate generally, the Enemy, knowing it, will certainly take Advantage of our Situation;” but the virulence of the outbreak soon prompted him to order inoculation for all troops and recruits who had not had the disease.[7]

In 1796, a young boy in England was inoculated by Edward Jenner. The boy suffered from the disease for an entire month and recovered completely.

### Weaponization of Smallpox

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In World War II, scientists from the United Kingdom and the United States were involved in research into producing a biological weapon from smallpox. Plans of large scale production were never carried through as they considered that the weapon would not be very effective due to the wide-scale availability of a vaccine.[8]

The first smallpox weapons factory in the Soviet Union was established in 1947 in the city of Zagorsk, close to Moscow [9]. It was produced by injecting small amounts of the virus into chicken eggs. An especially virulent strain (codenamed India-1967 or India-1) was brought from India in 1967 by a special Soviet medical team that was sent to India to help to eradicate the virus. The pathogen was manufactured and stockpiled in large quantities throughout the 1970s and 1980s.

An outbreak of weaponized smallpox occurred during its testing in the 1970s. General Prof. Peter Burgasov, former Chief Sanitary Physician of the Soviet Army, and a senior researcher within the Soviet program of biological weapons described this incident:

“On Vozrozhdeniya Island in the Aral Sea, the strongest recipes of smallpox were tested. Suddenly I was informed that there were mysterious cases of mortalities in Aralsk. A research ship of the Aral fleet came 15 km away from the island (it was forbidden to come any closer than 40 km). The lab technician of this ship took samples of plankton twice a day from the top deck. The smallpox formulation— 400 gr. of which was exploded on the island—”got her” and she became infected. After returning home to Aralsk, she infected several people including children. All of them died. I suspected the reason for this and called the Chief of General Staff of Ministry of Defense and requested to forbid the stop of the Alma-Ata—Moscow train in Aralsk. As a result, the epidemic around the country was prevented. I called Andropov, who at that time was Chief of KGB, and informed him of the exclusive recipe of smallpox obtained on Vozrazhdenie Island.” [10][11]

A production line to manufacture smallpox on an industrial scale was launched in the Vector Institute in 1990.[9] The development of genetically altered strains of smallpox was presumably conducted in the Institute under leadership of Dr. Sergei Netyosov in the middle of the 1990s, according to Kenneth Alibek, although this has never been proven due to the classified nature of the program[9]

## References

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1. ↑ De Cock KM (2001). "(Book Review) The Eradication of Smallpox: Edward Jenner and The First and Only Eradication of a Human Infectious Disease". Nature Medicine. 7: 15&ndash, 6.
2. ↑ Koplow, David (2003). Smallpox: The Fight to Eradicate a Global Scourge. Berkeley and Los Angeles, CA: University of California Press. ISBN 0-520-23732-3.
3. ↑ "President Abraham Lincoln: Health & Medical History". 2007-03-24. Retrieved 2007-06-18.
4. ↑ "Wikimedia Commons".
5. ↑ Bourzac K (2002). "Smallpox: Historical Review of a Potential Bioterrorist Tool". Journal of Young Investigators. 6 (3): –.
6. ↑ "BLACK HISTORY MONTH II: Why Wasn't I Taught That? (B. Willoughby)". Tolerance in the News. Retrieved 2006-09-23.
7. ↑ Grizzard FE, Washington G, Chase PD, Twohig D (1985). George Washington to Major General Horatio Gates, 5–6 February 1777. In: The papers of George Washington. 8. Charlottesville: University Press of Virginia. ISBN 0-8139-1787-5.CS1 maint: Multiple names: authors list (link)
8. ↑ http://www.viewzone.com/smallpox.html
9. ↑ 9.0 9.1 9.2 Alibek K, Handelman S (1999). Biohazard: The Chilling True Story of the Largest Covert Biological Weapons Program in the World—Told from Inside by the Man Who Ran It. New York: Delta. ISBN 0-385-33496-6.
10. ↑ Shoham D, Wolfson Z (2004). "The Russian biological weapons program: vanished or disappeared?". Crit. Rev. Microbiol. 30 (4): 241–61. PMID 15646399.
11. ↑ "Smallpox - not a bad weapon". Interview with General Burgasov (in Russian). Moscow News. Retrieved 2007-06-18.CS1 maint: Unrecognized language (link)

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