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The terms inoculation, vaccination, and immunization are often used synonymously to refer to artificial induction of immunity against various infectious diseases. However, there are some important historical and current differences. In English medicine, inoculation referred only to the practice of variolation until the very early 1800s. When Edward Jenner introduced smallpox vaccine in 1798, this was initially called cowpox inoculation or vaccine inoculation. Soon, to avoid confusion, smallpox inoculation continued to be referred to as variolation (from variola = smallpox) and cowpox inoculation was referred to as vaccination (from Jenner's use of variolae vaccinae = smallpox of the cow). Then, in 1891, Louis Pasteur proposed that the terms vaccine and vaccination should be extended to include the new protective procedures being developed. Immunization refers to the use of all vaccines but also extends to the use of antitoxin, which contains preformed antibody such as to diphtheria or tetanus exotoxins. Inoculation is now more or less synonymous in nontechnical usage with injection and the like, and questions along the lines of "Have you had your flu injection/vaccination/inoculation/immunization?" should not cause confusion. The focus is on what is being given and why, not the literal meaning of the technique used.[ citation needed ]

Vaccination administration of a vaccine to protect against disease

Vaccination is the administration of a vaccine to help the immune system develop protection from a disease. Vaccines contain a microorganism in a weakened or killed state, or proteins or toxins from the organism. In stimulating the body's adaptive immunity, they help prevent sickness from an infectious disease. When a sufficiently large percentage of a population has been vaccinated, herd immunity results. The effectiveness of vaccination has been widely studied and verified. Vaccination is the most effective method of preventing infectious diseases; widespread immunity due to vaccination is largely responsible for the worldwide eradication of smallpox and the elimination of diseases such as polio, measles, and tetanus from much of the world.

Immunization process by which an individuals immune system becomes fortified against an agent

Immunization, or immunisation, is the process by which an individual's immune system becomes fortified against an agent.

Artificial induction of immunity is the artificial induction of immunity to specific diseases – making people immune to disease by means other than waiting for them to catch the disease. The purpose is to reduce the risk of death and suffering.


Inoculation also has a specific meaning for procedures done in vitro . These include the transfer of microorganisms into and from laboratory apparatus such as test tubes and petri dishes in research and diagnostic laboratories, and also in commercial applications such as brewing, baking, oenology (wine making), and the production of antibiotics.[ citation needed ] In almost all cases the material inoculated is called the inoculum, or less commonly the inoculant, although the term culture is also used for work done in vitro.[ citation needed ]

<i>In vitro</i> test-tube experiments

In vitro studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology and its subdisciplines are traditionally done in labware such as test tubes, flasks, Petri dishes, and microtiter plates. Studies conducted using components of an organism that have been isolated from their usual biological surroundings permit a more detailed or more convenient analysis than can be done with whole organisms; however, results obtained from in vitro experiments may not fully or accurately predict the effects on a whole organism. In contrast to in vitro experiments, in vivo studies are those conducted in animals, including humans, and whole plants.

Microorganism microscopic living organism

A microorganism, or microbe, is a microscopic organism, which may exist in its single-celled form or in a colony of cells.

Petri dish

A Petri dish, named after the German bacteriologist Julius Richard Petri, is a shallow cylindrical glass or plastic lidded dish that biologists use to culture cells – such as bacteria – or small mosses.


The term inoculation entered medical English through horticultural usage meaning to graft a bud (or eye) from one plant into another. It is derived from the Latin in + oculus (eye). [1] Though "innoculation/innoculate" (with a double "nn" rather than a single "n") is sometimes seen, this is incorrect, possibly erroneously thought to be related to innocuous, which is derived from the Latin in + nocuus (not harmful).


Inoculation originated as a method for the prevention of smallpox by deliberate introduction of material from smallpox pustules into the skin. This generally produced a less severe infection than naturally-acquired smallpox, but still induced immunity to it. This first method for smallpox prevention, smallpox inoculation, is now also known as variolation. Inoculation has ancient origins and the technique was known in India and China. [2]

Smallpox infectious disease that has been eradicated

Smallpox was an infectious disease caused by one of two virus variants, Variola major and Variola minor. The last naturally occurring case was diagnosed in October 1977 and the World Health Organization (WHO) certified the global eradication of the disease in 1980. The risk of death following contracting the disease was about 30%, with higher rates among babies. Often those who survived had extensive scarring of their skin and some were left blind.

In biology, immunity is the balanced state of multicellular organisms having adequate biological defenses to fight infection, disease, or other unwanted biological invasion, while having adequate tolerance to avoid allergy, and autoimmune diseases.

Variolation or inoculation was the method first used to immunize an individual against smallpox (Variola) with material taken from a patient or a recently variolated individual in the hope that a mild, but protective infection would result. The procedure was most commonly carried out by inserting/rubbing powdered smallpox scabs or fluid from pustules into superficial scratches made in the skin. The patient would develop pustules identical to those caused by naturally occurring smallpox, usually producing a less severe disease than naturally acquired smallpox. Eventually, after about two to four weeks, these symptoms would subside, indicating successful recovery and immunity. The method was first used in China and the Middle East before it was introduced into England and North America in the 1720s in the face of some opposition. The method is no longer used today. It was replaced by smallpox vaccine, a safer alternative. This in turn led to the development of the many vaccines now available against other diseases.


The earliest hints of the practice of inoculation for smallpox in China come during the 10th century. [3] A Song dynasty (960–1279) chancellor of China, Wang Dan (957–1017), lost his eldest son to smallpox and sought a means to spare the rest of his family from the disease, so he summoned physicians, wise men, and magicians from all across the empire to convene at the capital in Kaifeng and share ideas on how to cure patients of it until a divine man from Mount Emei carried out inoculation. However, the sinologist Joseph Needham states that this information comes from the Zhongdou xinfa (種痘心法) written in 1808 by Zhu Yiliang, centuries after the alleged events. [3]

Song dynasty Chinese historical period

The Song dynasty was an era of Chinese history that began in 960 and lasted until 1279. The dynasty was founded by Emperor Taizu of Song following his usurpation of the throne of the Later Zhou, ending the Five Dynasties and Ten Kingdoms period. The Song often came into conflict with the contemporary Liao and Western Xia dynasties in the north. It was eventually conquered by the Mongol-led Yuan dynasty. The Song government was the first in world history to issue banknotes or true paper money nationally and the first Chinese government to establish a permanent standing navy. This dynasty also saw the first known use of gunpowder, as well as the first discernment of true north using a compass.

Kaifeng Prefecture-level city in Henan, Peoples Republic of China

Kaifeng, known previously by several names, is a prefecture-level city in east-central Henan province, China. It is one of the Eight Ancient Capitals of China, for being the capital seven times in history, and is most famous for being the capital of China in the Northern Song dynasty.

Mount Emei mountain

Mount Emei is a mountain in Sichuan Province, China, and is one of the Four Sacred Buddhist Mountains of China. Mt. Emei sits at the western rim of the Sichuan Basin. The mountains west of it are known as Daxiangling. A large surrounding area of countryside is geologically known as the Permian Emeishan Large Igneous Province, a large igneous province generated by the Emeishan Traps volcanic eruptions during the Permian Period. At 3,099 metres (10,167 ft), Mt. Emei is the highest of the Four Sacred Buddhist Mountains of China.

The first clear and credible reference to smallpox inoculation in China comes from Wan Quan's (1499–1582) Douzhen xinfa (痘疹心法) of 1549, which states that some women unexpectedly menstruate during the procedure, yet his text did not give details on techniques of inoculation. [4] Inoculation was first vividly described by Yu Chang in his book Yuyi cao (寓意草), or Notes on My Judgment, published in 1643. Inoculation was reportedly not widely practised in China until the reign of the Longqing Emperor (r. 1567–1572) during the Ming dynasty (1368–1644), as written by Yu Tianchi in his Shadou jijie (痧痘集解) of 1727, which he alleges was based on Wang Zhangren's Douzhen jinjing lu (痘疹金鏡錄) of 1579. [4] From these accounts, it is known that the Chinese banned the practice of using smallpox material from patients who actually had the full-blown disease of Variola major (considered too dangerous); instead they used proxy material of a cotton plug inserted into the nose of a person who had already been inoculated and had only a few scabs, i.e. Variola minor[ citation needed ]. This was called "to implant the sprouts", an idea of transplanting the disease which fit their conception of beansprouts in germination. Needham quotes an account from Zhang Yan's Zhongdou xinshu (種痘新書), or New book on smallpox inoculation, written in 1741 during the Qing dynasty (1644–1912), which shows how the Chinese process had become refined up until that point:

Wan Quan, also known as Wan Mizhai, was a Ming dynasty pediatrician. He was the third in his family to practice medicine. He advocated that children be frequently exposed to sunlight and fresh air and trained to resist cold. He also believed that frightening a child was harmful to him or her, as was overfeeding or overmedicating.

Longqing Emperor emperor of the Ming Dynasty

The Longqing Emperor, personal name Zhu Zaiji (朱載坖), was the 13th emperor of the Ming dynasty from 1567 to 1572. He was initially known as the Prince of Yu (裕王) from 1539 to 1567 before he became the emperor. His era name, Longqing, means "great celebration".

Ming dynasty Former empire in Eastern Asia, last Han Chinese-led imperial regime

The Ming dynasty was the ruling dynasty of China – then known as the Great Ming Empire – for 276 years (1368–1644) following the collapse of the Mongol-led Yuan dynasty. The Ming dynasty was the last imperial dynasty in China ruled by ethnic Han Chinese. Although the primary capital of Beijing fell in 1644 to a rebellion led by Li Zicheng, regimes loyal to the Ming throne – collectively called the Southern Ming – survived until 1683.

Method of storing the material. Wrap the scabs carefully in paper and put them into a small container bottle. Cork it tightly so that the activity is not dissipated. The container must not be exposed to sunlight or warmed beside a fire. It is best to carry it for some time on the person so that the scabs dry naturally and slowly. The container should be marked clearly with the date on which the contents were taken from the patient.
In winter, the material has yang potency within it, so it remains active even after being kept from thirty to forty days. But in summer the yang potency will be lost in approximately twenty days. The best material is that which had not been left too long, for when the yang potency is abundant it will give a 'take' with nine persons out of ten people—and finally it becomes completely inactive, and will not work at all. In situations where new scabs are rare and the requirement great, it is possible to mix new scabs with the more aged ones, but in this case more of the powder should be blown into the nostril when the inoculation is done. [4]

Two reports on the Chinese practice were received by the Royal Society in London in 1700; one by Dr. Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers. But no action was taken. [5]


According to Voltaire (1742), the Turks derived their use of inoculation to neighbouring Circassia.

The Circassian women have, from time immemorial, communicated the small-pox to their children when not above six months old by making an incision in the arm, and by putting into this incision a pustule, taken carefully from the body of another child. This pustule produces the same effect in the arm it is laid in as yeast in a piece of dough; it ferments, and diffuses through the whole mass of blood the qualities with which it is impregnated. The pustules of the child in whom the artificial small-pox has been thus inoculated are employed to communicate the same distemper to others. There is an almost perpetual circulation of it in Circassia; and when unhappily the small-pox has quite left the country, the inhabitants of it are in as great trouble and perplexity as other nations when their harvest has fallen short... The Circassians are poor, and their daughters are beautiful, and indeed, it is in them they chiefly trade. They furnish with beauties the seraglios of the Turkish Sultan, of the Persian Sophy, and of all those who are wealthy enough to purchase and maintain such precious merchandise. [6]

Voltaire does not speculate on where the Circassians derived their technique from, though he reports that the Chinese have practiced it "these hundred years". The Turkish practice was presented to the Royal Society in 1714 and 1716, when the physicians Emanuel Timoni [7] and Giacomo Pylarini independently sent letters from Constantinople. [8]


Variolation is documented in India from the eighteenth century, thanks to the 1767 account by J. Z. Holwell. [9] Holwell's extensive 1767 description included the following, [10] that points to the connection between disease and "multitudes of imperceptible animalculae floating in the atmosphere":

They lay it down as a principle, that the immediate cause of the smallpox exists in the mortal part of every human and animal form; that the mediate (or second) acting cause, which stirs up the first, and throws it into a state of fermentation, is multitudes of imperceptible animalculae floating in the atmosphere; that these are the cause of all epidemical diseases, but more particularly of the small pox. [9]

Holwell ascribes this account to his Brahman informants. However, such a theory has not yet been discovered in any Sanskrit or vernacular treatise. [11] Holwell's use of the word "animalculae" suggests that he may have been aware of the observations of Antonie van Leeuwenhoek made in about 1683. Other parts of Holwell's account, especially his use of the idea of "immediate" and "mediate" causation, and the concept of "fermentation," suggest that these notions may not necessarily be entirely of Indian origin but may also be influenced by contemporary developments in microbiology.

Several historians have suggested that variolation may be older than the eighteenth century in India, [12] but historical evidence for this assertion is lacking. The widespread rumour since the nineteenth century that vaccination was documented in India before the discoveries of Edward Jenner can all be traced to propaganda tracts written in Sanskrit and the Indian vernaculars by colonial officers, in the pious hope of convincing Indians to accept the newly discovered Jennerian procedure. [13] [14] A landmark anthropological study by Ralph Nicholas described the mid-twentieth century rituals of appeasement to Śītalā, the Indian goddess of smallpox, in Bengal. [15]

Holwell's account proves beyond doubt that smallpox inoculation was practised in India in the eighteenth century. Yet no Sanskrit or vernacular Indian sources yet discovered mention the practice. Some details of the practice described by Holwell such as sniffing suggest Chinese practice.[ citation needed ]


Early travellers to Ethiopia report that variolation was practiced by the Amhara and Tigray peoples. The first European to report this was Nathaniel Pearce, who noted in 1831, that it was performed by a debtera who would collect "a quantity of matter" from a person with the most sores from smallpox, then he "cuts a small cross with a razor in the arm" of his subject and put "a little of the matter" into the cut which was afterwards bound up with a bandage. Subsequent visitors who described this practice included W. C. Harris and Dr. Petit of the French scientific mission of 1839–1841. [16]

West Africa

The knowledge of inoculating oneself against smallpox seems to have been known to West Africans, more specifically the Akan. A slave named Onesimus explained the inoculation procedure to Cotton Mather during the 18th century; he reported to have gotten the knowledge from Africa. [17]

Importation to the West

Mary Wortley Montagu, by Charles Jervas, after 1716 Mary Wortley Montagu by Charles Jervas, after 1716.jpg
Mary Wortley Montagu, by Charles Jervas, after 1716

In January 1714 Philosophical Transactions of the Royal Society published an account of a letter John Woodward had received from Emmanuel Timonius in Constantinople. [18] Smallpox inoculation was advocated as a proven method of curbing the severity of the disease.

The practice was introduced to England by Lady Mary Wortley Montagu. Lady Montagu's husband, Edward Wortley Montagu, served as the British ambassador to the Ottoman Empire from 1716 to 1718. She witnessed firsthand the Turkish use of inoculation in Istanbul, [19] and was greatly impressed: [20] she had lost a brother to smallpox and bore facial scars from the disease herself. When a smallpox epidemic threatened England in 1721, she called on her physician, Charles Maitland, to inoculate her daughter. She invited friends to see her daughter, including Sir Hans Sloane, the King's physician. Sufficient interest arose that Maitland gained permission to test inoculation at Newgate Prison in exchange for their freedom on six prisoners due to be hanged, an experiment which was witnessed by a number of notable doctors. [21] All survived, and in 1722 the Prince of Wales' daughters received inoculations. [22]

The practice of inoculation slowly spread amongst the royal families of Europe, usually followed by more general adoption amongst the people.

The practice is documented in America as early as 1721, when Zabdiel Boylston, at the urging of Cotton Mather, successfully inoculated two slaves and his own son. Mather, a prominent Boston minister, had heard a description of the African practice of inoculation from his Sudanese slave, Onesimus, in 1706, and later from Timoni's report to the Royal Society, [23] but had been previously unable to convince local physicians to attempt the procedure. [24] Following this initial success, Boylston began performing inoculations throughout Boston, despite much controversy and at least one attempt upon his life. The effectiveness of the procedure was proven when, of the nearly three hundred people Boylston inoculated during the outbreak, only six died, whereas the mortality rate among those who contracted the disease naturally was one in six. [25] Boylston traveled to London in 1724. There he published his results and was elected to the Royal Society in 1726.

Natural experiment in inoculation
around Boston, 1721
 TotalDied% Mortality
Variolatedc. 3006c. 2%
Unvariolatedc. 6000c. 1000"about 14%" [26]

In France, considerable opposition arose to the introduction of inoculation, and it was banned by the Parlement. Voltaire, in his Lettres Philosophiques, wrote a criticism of his countrymen for being opposed to inoculation and having so little regard for the welfare of their children, concluding that "had inoculation been practised in France it would have saved the lives of thousands.". [27]

Inoculation grew in popularity in Europe through the 18th century. Given the high prevalence and often severe consequences of smallpox in Europe in the 18th century (according to Voltaire, there was a 60% incidence of first infection, a 20% mortality rate, and a 20% incidence of severe scarring), [28] many parents felt that the benefits of inoculation outweighed the risks and so inoculated their children. [29]


Two forms of the disease of smallpox were recognised, now known to be due to two strains of the Variola virus. Those contracting Variola minor had a greatly reduced risk of death – 1–2% – compared to those contracting Variola major with 30% mortality. Infection via inhaled viral particles in droplets spread the infection more widely than the deliberate infection through a small skin wound. The smaller, localised infection is adequate to stimulate the immune system to produce specific immunity to the virus, while requiring more generations of the virus to reach levels of infection likely to kill the patient. The rising immunity terminates the infection. So the twofold effect is to ensure the less fatal form of the disease is the one caught, and to give the immune system the best start possible in combating it.

Inoculation in the East was historically performed by blowing smallpox crusts into the nostril. In Britain, Europe and the American Colonies the preferred method was rubbing material from a smallpox pustule from a selected mild case (Variola minor) into a scratch between the thumb and forefinger. [30] This would generally be performed when an individual was in normal good health, and thus at peak resistance. The recipient would develop smallpox; however, due to being introduced through the skin rather than the lungs, and possibly because of the inoculated individual's preexisting state of good health, the small inoculum, and the single point of initial infection, the resulting case of smallpox was generally milder than the naturally occurring form, produced far less facial scarring, and had a far lower mortality rate. As with survivors of the natural disease, the inoculated individual was subsequently immune to re-infection.


Comparison of smallpox (left) and cowpox (right) inoculations 16 days after administration Inoculation day 16.png
Comparison of smallpox (left) and cowpox (right) inoculations 16 days after administration

In 1798, the English surgeon/scientist Edward Jenner published the results of his experiments and thus introduced the far superior and safer method of inoculation with cowpox virus, a mild infection that also induced immunity to smallpox. Jenner was not the first person to inoculate with cowpox nor the first to realize that infection with cowpox gave immunity to smallpox. However, he was the first to publish evidence that it was effective and to provide advice on its production. His efforts led to smallpox inoculation falling into disuse and eventually being banned in England in 1840. [31]

See also

Related Research Articles

Edward Jenner English physician, scientist and pioneer of vaccination

Edward Jenner, FRS FRCPE was an English physician and scientist who was the pioneer of smallpox vaccine, the world's first vaccine. The terms "vaccine" and "vaccination" are derived from Variolae vaccinae, the term devised by Jenner to denote cowpox. He used it in 1796 in the long title of his Inquiry into the Variolae vaccinae known as the Cow Pox, in which he described the protective effect of cowpox against smallpox.

Vaccine biological preparatory medicine that improves immunity to a particular disease

A vaccine is a biological preparation that provides active acquired immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from weakened or killed forms of the microbe, its toxins, or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as a threat, destroy it, and to further recognize and destroy any of the microorganisms associated with that agent that it may encounter in the future. Vaccines can be prophylactic, or therapeutic.

Cowpox Human disease

Cowpox is an infectious disease caused by the cowpox virus. The virus, part of the genus Orthopoxvirus, is closely related to the vaccinia virus. The virus is zoonotic, meaning that it is transferable between species, such as from animal to human. The transferral of the disease was first observed in dairymaids who touched the udders of infected cows and consequently developed the signature pustules on their hands. Cowpox is more commonly found in animals other than bovines, such as rodents. Cowpox is similar to, but much milder than, the highly contagious and often deadly smallpox disease. Its close resemblance to the mild form of smallpox and the observation that dairy farmers were immune from smallpox inspired the first smallpox vaccine, created and administered by English physician Edward Jenner.

Smallpox vaccine vaccine

Smallpox vaccine, the first successful vaccine to be developed, was introduced by Edward Jenner in 1796. He followed up his observation that milkmaids who had previously caught cowpox did not later catch smallpox by showing that inoculated cowpox protected against inoculated smallpox.

John Zephaniah Holwell English surgeon and temporary Governor of Bengal

John Zephaniah Holwell FRS was a surgeon, an employee of the English East India Company, and a temporary Governor of Bengal (1760). He was also one of the first Europeans to study Indian antiquities.

Vaccinia species of virus

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James Phipps English child given cowpox vaccine

James Phipps was the first person given the cowpox vaccine by Edward Jenner. Jenner knew of a local belief that dairy workers who had contracted a relatively mild infection called cowpox were immune to smallpox.

Benjamin Jesty British farmer and doctor

Benjamin Jesty was a farmer at Yetminster in Dorset, England, notable for his early experiment in inducing immunity against smallpox using cowpox.

Joseph Adams M.D. F.L.S. was a British physician and surgeon.

James Jurin FRS FRCP was an English scientist and physician, particularly remembered for his early work in capillary action and in the epidemiology of smallpox vaccination. He was a staunch proponent of the work of Sir Isaac Newton and often used his gift for satire in Newton's defence.

The history of smallpox extends into pre-history, the disease likely emerged in human populations about 10,000 BC. The earliest credible evidence of smallpox is found in the Egyptian mummies of people who died some 3000 years ago. Smallpox has had a major impact on world history, not least because indigenous populations of regions where smallpox was non-native, such as the Americas and Australia, were rapidly decimated and weakened by smallpox during periods of initial foreign contact, which helped pave the way for conquest and colonization. During the 18th century the disease killed an estimated 400,000 Europeans each year, including five reigning monarchs, and was responsible for a third of all blindness. Between 20 and 60% of all those infected—and over 80% of infected children—died from the disease.

"A Pox on Our House" is the seventh episode of the seventh season of the American medical drama House. It aired on November 15, 2010.

William Woodville English botanist

William Woodville (1752–1805) was an English physician and botanist.

Dr John Fewster (1738–1824) was a surgeon and apothecary in Thornbury, Gloucestershire. Fewster, a friend and professional colleague of Edward Jenner, played an important role in the discovery of the smallpox vaccine. In 1768 Fewster realized that prior infection with cowpox rendered a person immune to smallpox.


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  9. 1 2 Holwell, John Zephaniah (1767). An Account of the Manner of Inoculating for the Small Pox in the East Indies with ... Observations on the ... Mode of Treating that Disease in those Parts. London: T. Becket & P. A. de Hondt.
  10. see p. 25
  11. Meulenbeld, Gerrit Jan (1999–2002). A history of Indian medical literature. Groningen: Egbert Forsten.
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  13. Wujastyk, Dominik (2001). "`A Pious Fraud': The Indian Claims for Pre-Jennerian Smallpox Vaccination". In G. J. Meulenbeld and Dominik Wujastyk. Studies in Indian Medical History (in English and Sanskrit) (2 ed.). Motilal Banarsidass. pp. 121–54. Retrieved 3 January 2014.
  14. Boylston, Arthur (July 2012). "The origins of inoculation". Journal of the Royal Society of Medicine. 105 (7): 309–13. doi:10.1258/jrsm.2012.12k044. PMC   3407399 . PMID   22843649.
  15. Nicholas, Ralph (1981). "The Goddess Śītalā and Epidemic Smallpox in Bengal". Journal of Asian Studies. 41 (1): 21–44. doi:10.2307/2055600. JSTOR   2055600. PMID   11614704.
  16. Richard Pankhurst, An Introduction to the Medical History of Ethiopia (Trenton: Red Sea Press, 1999), pp. 26ff
  17. Waldstreicher, David. Runaway America: Benjamin Franklin, Slavery, and the American Revolution. Macmillan; p. 40, ISBN   0-8090-8314-0
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  19. "How Islamic inventors changed the world". The Independent . London. 11 March 2008. Retrieved 17 February 2012.
  20. Donald R. Hopkins, Princes and Peasants: Smallpox in History (University of Chicago Press, 1983)
  21. Wooton, David (2006). Bad Medicine: Doctors Doing Harm Since Hippocrates. Oxford, England: Oxford University Press. p. 153. ISBN   978-0-19-921279-8.
  22. Strathern, Paul (2005). A Brief History of Medicine. London: Robinson. p. 179. ISBN   978-1-84529-155-6.
  23. Gross & Sepkowitz 1998 , p. 56
  24. Silverman, Kenneth. The Life and Times of Cotton Mather, Harper & Row, New York, 1984. ISBN   0-06-015231-1, p. 339.
  25. White, Andrew Dickson (1896). A History of the Warfare of Science with Theology in Christendom. 2. New York: D. Appleton and Company. p. 57.
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  27. Lettres Philosophiques. Voltaire. (English translation on-line )
  28. In fact, the mortality rate of the Varoiola Minor form of smallpox then found in Europe was 1–3% as opposed to 30–50% for the Variola Major type found elsewhere; however, blindness, infertility, and severe scarring were common. Figures from "The Search for Immunisation", In Our Time, BBC Radio 4 (2006).
  29. David V. Cohn, Ph.D. "Lady Mary Montagu". Founders of Science. Archived from the original on January 2, 2004. In England in 1718 she wrote to various influential persons urging inoculation and sent essays to subject to magazines. She had both her children inoculated – one in Turkey and one in England. Despite opposition from religious and medical groups, inoculation caught on. It was the primary defense against death and serious debilitation by smallpox for the next 80 years until the discovery of vaccination by Jenner.
  30. "Smallpox: Variolation". 2003-10-18. Retrieved 2009-11-02.
  31. Wolfe, Robert M; Sharp, Lisa K (24 August 2002). "Anti-vaccinationists past and present" (PDF). British Medical Journal . London. 325 (7361): 430–32. doi:10.1136/bmj.325.7361.430. PMC   1123944 . PMID   12193361.

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