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Inoculation is the placement of something that will grow or reproduce, and is most commonly used in respect of the introduction of a serum, vaccine, or antigenic substance into the body of a human or animal, especially to produce or boost immunity to a specific disease. It can also be used to refer to the communication of a disease to a living organism by transferring its causative agent into the organism, the implanting of microorganisms or infectious material into a culture medium such as a brewers vat or a petri dish, or the placement of microorganisms or viruses at a site where infection is possible. The verb to inoculate is from Middle English inoculaten, which meant "to graft a scion" (a plant part to be grafted onto another plant); which in turn is from Latin inoculare, past participle inoculat-.
This article covers variolation, culation as a method of purposefully infecting a person with smallpox (Variola) in a controlled manner so as to minimise the severity of the infection and also to induce immunity against further infection. See vaccination for post-variolation methods of safeguarding as if by inoculation by administering weakened or dead pathogens to a healthy person or animal with the intent of conferring immunity against a targeted form of a related disease agent.
Today the terms inoculation, vaccination and immunization are used more or less interchangeably and popularly refer to the process of artificial induction of immunity against various infectious diseases. The microorganism used in an inoculation is called the inoculant or inoculum.
variolation is documented in India from the eighteenth century, thanks to the valuable 1767 account by J. Z. Holwell. Holwell's extensive 1767 description included the following statement, on p.25, 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.
Holwell ascribes this account to his Brahman informants. However, such a theory has not yet been discovered in any Sanskrit or vernacular treatise. 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 a non-Indian source for his ideas outlined in this passage, which remain of great research interest.
Several historians have suggested that variolation may be older than the eighteenth century in India, 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. A landmark anthropological study by Ralph Nicholas described the mid-twentieth century rituals of appeasement to Śītalā, the Indian goddess of smallpox, in Bengal.
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. That such a major medical procedure would not be documented by the normally verbose members of the Brahman caste remains a historical puzzle. Some details of the practice described by Holwell (sniffing) suggest Chinese practice.
The British historian Joseph Needham and the American historian Robert Temple write that the practice of inoculation for smallpox began in China during the 10th century. 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. From Mount Emei in Sichuan, a Daoist hermit, a nun known as a "numinous old woman" and "holy physician"—who Temple says was associated with the 'school of the ancient immortals' and thus most likely specialized in 'internal alchemy'—introduced the technique of inoculation to the capital. 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.
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. 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. 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. This was called "to implant the sprouts", an idea of transplanting the disease which fit their conception of beansprouts in germination. Robert Temple 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:
As for other methods used in China, the technique of scratching the skin and putting pox onto the scab seems to have developed later than the first accounts made in China, and possibly came from Central Asia—according to Temple.
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 that it was performed by a debtera who would collect "a quantity of matter" from a person with the most sores from small pox, 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.
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. 
The practice was introduced to the west by Lady Mary Wortley Montagu (May 26, 1689 – August 21, 1762). 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, and was greatly impressed: 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 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. All survived, and in 1722 the Prince of Wales' daughters received inoculations.
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, but had been previously unable to convince local physicians to attempt the procedure. 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. 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
|Variolated||c 300||6||c 2%|
|Unvariolated||c 6000||c 1000||"about 14%"|
In France, considerable opposition arose to the introduction of inoculation. 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.".
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), many parents felt that the benefits of inoculation outweighed the risks and so inoculated their children.
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. 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.
In 1796, the British scientist Edward Jenner published the results of his experiments and thus introduced the far superior and safer method of inoculation with the cowpox virus, a non-fatal virus that also induced immunity to smallpox. Jenner was not the first person to inoculate with cowpox, nor was he the first to realize that infection with cowpox gave immunity to smallpox. His efforts led to smallpox inoculation falling into disuse and eventually being banned in England in 1840.