was destroyed in the late 1980s when smallpox failed to return. after the september 11 attacks in 2001, many governments began building up vaccine stockpiles again for fear of bioterrorism. several companies sold off their stockpiles of vaccines manufactured in the 1970s, and production of smallpox vaccines resumed. aventis pasteur discovered a stockpile from the 1950s and donated it to the u.s. government. stockpiles of newer vaccines must be repurchased periodically since they carry expiration dates. the united states had received 269 million doses of acam2000 and 28 million doses of mva-bn by 2019, but only 100 million doses of acam2000 and 65,000 doses of mva-bn were still available from the stockpile at the start of the 2022 monkeypox outbreak. first-generation vaccines have no specified expiration date and remain viable indefinitely in deep freeze. the u.s. stockpile of wetvax was manufactured in 1956–1957 and maintained since then at −4 °f (−20 °c), and it was still effective when tested in 2004. replicating vaccines also remain effective even at 1:10 dilution, so a limited number of doses can be stretched to cover a much larger population. smallpox vaccine stockpiles country, region, or organizationyeardoses (millions)composition (generation) world health organization (geneva)20132.7 300,000 acam2000 (2nd) 2.4 million various (1st) world health organization(pledged)201827various (1st, 2nd, 3rd) france20065555 million pourquier (1st) germany2022100 mva-bn (3rd) 30+ million lister/elstree-bn (2nd) 24 million various (1st) italy 2022 5 japan200656lc16m8 (3rd) netherlands2017 ?lister/elstree-rvim (2nd): 588–589 south korea202235lancy-vaxina (1st) united states2022185 65,000 mva-bn (3rd) 100 million acam2000 (2nd) 85 million wetvax (1st) history variolation main article: variolation the mortality of the severe form of smallpox – variola major – was very high without vaccination, up to 35% in some outbreaks. a method of inducing immunity known as inoculation, insufflation or "variolation" was practiced before the development of a modern vaccine and likely occurred in africa and china well before the practice arrived in europe. it may also have occurred in india, but this is disputed; other investigators contend the ancient sanskrit medical texts of india do not describe these techniques. the first clear reference to smallpox inoculation was made by the chinese author wan quan (1499–1582) in his douzhen xinfa (痘疹心法) published in 1549. inoculation for smallpox does not appear to have been widespread in china until the reign era of the longqing emperor (r. 1567–1572) during the ming dynasty. in china, powdered smallpox scabs were blown up the noses of the healthy. the patients would then develop a mild case of the disease and from then on were immune to it. the technique did have a 0.5–2.0% mortality rate, but that was considerably less than the 20–30% mortality rate of the disease itself. two reports on the chinese practice of inoculation 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. according to voltaire (1742), the turks derived their use of inoculation from neighbouring circassia. voltaire does not speculate on where the circassians derived their technique from, though he reports that the chinese have practiced it "these hundred years". variolation was also practiced throughout the latter half of the 17th century by physicians in turkey, persia, and africa. in 1714 and 1716, two reports of the ottoman empire turkish method of inoculation were made to the royal society in england, by emmanuel timoni, a doctor affiliated with the british embassy in constantinople, and giacomo pylarini. source material tells us on lady mary wortley montagu; "when lady mary was in the ottoman empire, she discovered the local practice of inoculation against smallpox called variolation." in 1718 she had her son, aged five variolated. he recovered quickly. she returned to london and had her daughter variolated in 1721 by charles maitland, during an epidemic of smallpox. this encouraged the british royal family to take an interest and a trial of variolation was carried out on prisoners in newgate prison. this was successful and in 1722 caroline of ansbach, the princess of wales, allowed maitland to vaccinate her children. the success of these variolations assured the british people that the procedure was safe. ...scarred the wrists, legs, and forehead of the patient, placed a fresh and kindly pock in each incision and bound it there for eight or ten days, after this time the patient was credibly informed. the patient would then develop a mild case , recover, and thereafter be immune. —dr. peter kennedy stimulated by a severe epidemic, variolation was first employed in north america in 1721. the procedure had been known in boston since 1706, when preacher cotton mather learned it from onesimus, a man he held as a slave, who – like many of his peers – had been inoculated in africa before they were kidnapped. this practice was widely criticized at first. however, a limited trial showed six deaths occurred out of 244 who were variolated (2.5%), while 844 out of 5980 died of natural disease (14%), and the process was widely adopted throughout the colonies. the inoculation technique was documented as having a mortality rate of only one in a thousand. two years after kennedy's description appeared, march 1718, dr. charles maitland successfully inoculated the five-year-old son of the british ambassador to the turkish court under orders from the ambassador's wife lady mary wortley montagu, who four years later introduced the practice to england. an account from letter by lady mary wortley montagu to sarah chiswell, dated 1 april 1717, from the turkish embassy describes this treatment: the small-pox so fatal and so general amongst us is here entirely harmless by the invention of ingrafting (which is the term they give it). there is a set of old women who make it their business to perform the operation. every autumn in the month of september, when the great heat is abated, people send to one another to know if any of their family has a mind to have the small-pox. they make parties for this purpose, and when they are met (commonly fifteen or sixteen together) the old woman comes with a nutshell full of the matter of the best sort of small-pox and asks what veins you please to have opened. she immediately rips open that you offer to her with a large needle (which gives you no more pain than a common scratch) and puts into the vein as much venom as can lye upon the head of her needle, and after binds up the little wound with a hollow bit of shell, and in this manner opens four or five veins. … the children or young patients play together all the rest of the day and are in perfect health till the eighth. then the fever begins to seize them and they keep their beds two days, very seldom three. they have very rarely above twenty or thirty in their faces, which never mark, and in eight days time they are as well as before the illness. … there is no example of any one that has died in it, and you may believe i am very well satisfied of the safety of the experiment since i intend to try it on my dear little son. i am patriot enough to take pains to bring this useful invention into fashion in england, and i should not fail to write to some of our doctors very particularly about it if i knew any one of them that i thought had virtue enough to destroy such a considerable branch of their revenue for the good of mankind, but that distemper is too beneficial to them not to expose to all their resentment the hardy wight that should undertake to put an end to it. perhaps if i live to return i may, however, have courage to war with them. early vaccination dr edward jenner performing his first vaccination on james phipps, a boy of age 8. 14 may 1796. painting by ernest board (early 20th century). in the early empirical days of vaccination, before louis pasteur's work on establishing the germ theory and joseph lister's on antisepsis and asepsis, there was considerable cross-infection. william woodville, one of the early vaccinators and director of the london smallpox hospital is thought to have contaminated the cowpox matter – the vaccine – with smallpox matter and this essentially produced variolation. other vaccine material was not reliably derived from cowpox, but from other skin eruptions of cattle. during the earlier days of empirical experimentation in 1758, american calvinist jonathan edwards died from a smallpox inoculation. some of the earliest statistical and epidemiological studies were performed by james jurin in 1727 and daniel bernoulli in 1766. in 1768, dr john fewster reported that variolation induced no reaction in persons who had had cowpox. an 1802 caricature by james gillray depicting the early controversy surrounding jenner's vaccination theory edward jenner was born in berkeley, england as an orphan. as a young child, jenner was variolated with the other schoolboys through parish funds, but nearly died due to the seriousness of his infection. fed purgative medicine and going through the bloodletting process, jenner was put in one of the variolation stables until he recovered. at the age of 13, he was apprenticed to apothecary daniel ludlow and later surgeon george hardwick in nearby sodbury. he observed that people who caught cowpox while working with cattle were known not to catch smallpox. jenner assumed a causal connection but the idea was not taken up at that time. from 1770 to 1772 jenner received advanced training in london at st georges hospital and as the private pupil of john hunter, then returned to set up practice in berkeley. perhaps there was already an informal public understanding of some connection between disease resistance and working with cattle. the "beautiful milkmaid" seems to have been a frequent image in the art and literature of this period. but it is known for certain that in the years following 1770, at least six people in england and germany (sevel, jensen, jesty 1774, rendall, plett 1791) tested successfully the possibility of using the cowpox vaccine as an immunization for smallpox in humans. diagram a: exposure to the cowpox virus builds immunity to the smallpox virus. 1a. cowpox virus is injected into the bloodstream. 2a. the virus enters the cells and a mild fever develops. 3a. t-cells recognize the antigen as a threat. 4a. activated t-cells replicate, and their offspring become memory t-cells. 5a. antibodies are produced and destroy the virus. diagram b: when exposed to the smallpox virus, the immune system is resistant. 1b. smallpox virus is injected into the bloodstream. 2b. memory t cells recognize the virus. 3b. antibodies are produced and destroy the virus. the process above shows the steps taken by edward jenner to create vaccination. jenner did this by inoculating james phipps with cowpox, a similar virus to smallpox, to create immunity, unlike variolation, which used smallpox to create an immunity to itself. jenner sent a paper reporting his observations to the royal society in april 1797. it was not submitted formally and there is no mention of it in the society's records. jenner had sent the paper informally to sir joseph banks, the society's president, who asked everard home for his views. reviews of his rejected report, published for the first time in 1999, were skeptical and called for further vaccinations. additional vaccinations were performed and in 1798 jenner published his work entitled an inquiry into the causes and effects of the variolae vaccinae, a disease discovered in some of the western counties of england, particularly gloucestershire and known by the name of cow pox. it was an analysis of 23 cases including several individuals who had resisted natural exposure after previous cowpox. it is not known how many jenner vaccinated or challenged by inoculation with smallpox virus; e.g. case 21 included 'several children and adults'. crucially all of at least four whom jenner deliberately inoculated with smallpox virus resisted it. these included the first and last patients in a series of arm-to-arm transfers. he concluded that cowpox inoculation was a safe alternative to smallpox inoculation, but rashly claimed that the protective effect was lifelong. this last proved to be incorrect. jenner also tried to distinguish between 'true'