Smallpox vaccine

• 1. Introduction

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  The smallpox vaccine holds a distinction no other vaccine can claim: it is the first ever developed against a contagious disease. Long before laboratories existed, before germ theory had a name, a British physician named Edward Jenner noticed something that would change the course of human history. In 1796, he demonstrated that a mild infection with cowpox could make a person immune to smallpox, a disease that killed up to 35% of those it struck in its most severe form. What began as an observation about milkmaids and cattle became a global campaign that, by 1977, had wiped smallpox off the face of the earth. It is the only human disease ever to be eradicated. How did a nutshell full of matter passed between village women in Ottoman Turkey become the foundation for that achievement? And what does the word "vaccine" itself reveal about the animal at the center of this story?

• 2. Before Jenner: Variolation

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  Centuries before Jenner was born, people were deliberately infecting themselves with smallpox to avoid dying from it. The practice, called variolation or inoculation, involved introducing material from a mild smallpox case into a healthy person. The first clear written reference to it comes from the Chinese author Wan Quan, who described the technique in his Douzhen xinfa, published in 1549. In China, powdered smallpox scabs were blown up the noses of the healthy. The technique carried a mortality rate of 0.5-2.0%, a grim tradeoff that nonetheless looked attractive against the 20-30% mortality rate of the disease itself. Two reports on Chinese inoculation practice reached the Royal Society in London in 1700, one from a Dr. Martin Lister who received an account from an employee of the East India Company in China, and another from Clopton Havers. By 1714 and 1716, further reports arrived from Emmanuel Timoni and Giacomo Pylarini describing the Ottoman Turkish method. The practice spread to England through a remarkable woman named Lady Mary Wortley Montagu. While in the Ottoman Empire, she witnessed variolation firsthand. In 1718 she had her five-year-old son variolated; he recovered quickly. Back in London in 1721, she had her daughter variolated by Charles Maitland during a smallpox epidemic. Caroline of Ansbach, the Princess of Wales, allowed Maitland to vaccinate her own children in 1722 after a successful trial on prisoners in Newgate Prison. That same year of 1721, variolation first reached North America, introduced during a severe epidemic in Boston. The preacher Cotton Mather had learned the technique in 1706 from Onesimus, a man he held as a slave, who had been inoculated in Africa before being kidnapped. A limited trial in Boston found that six deaths occurred among 244 variolated people, compared with 844 deaths among 5,980 who contracted the disease naturally. The numbers made a compelling case.

• 3. Jenner and the Cowpox Leap

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  Edward Jenner was born in Berkeley, England, and nearly died from variolation as a child. He was variolated with the other schoolboys through parish funds, but the infection was so serious it almost killed him. He was fed purgative medicine, subjected to bloodletting, and kept in one of the variolation stables until he recovered. At the age of 13, he was apprenticed to apothecary Daniel Ludlow and later to surgeon George Hardwick in nearby Sodbury. There he observed what many people already sensed informally: those who caught cowpox while working with cattle did not seem to catch smallpox. From 1770 to 1772 he received advanced training in London at St. George's Hospital, studying under John Hunter before returning to Berkeley to practice. Jenner was not the first to act on the cowpox idea. Benjamin Jesty, a farmer of Yetminster in Dorset, inoculated his family with cowpox in 1774. Peter Plett, a teacher from Holstein, reported limited cowpox inoculation results to the University of Kiel during 1790-92. John Fewster, a surgeon friend of Jenner's from Thornbury, had discussed the possibility at meetings as early as 1765. What Jenner did that none of them had done was publish and distribute his findings freely. He sent a paper to the Royal Society in April 1797, informally, to its president Sir Joseph Banks, who passed it to Everard Home for review. The reviews were skeptical. After performing additional vaccinations, Jenner published his full work in 1798 under the title An Inquiry into the Causes and Effects of the Variolae Vaccinae. It analyzed 23 cases, including several individuals who had resisted natural smallpox exposure after prior cowpox. At least four people whom Jenner deliberately inoculated with smallpox virus afterwards showed resistance to it. By 1800, his work had been translated into all the major European languages. Benjamin Waterhouse in the United States had received a copy. The first smallpox vaccination in the United States was administered in 1799 by physician Valentine Seaman, who gave his own children a serum he had obtained from Jenner. The WHO's official account of the eradication effort would later conclude that Jenner deserved more credit than anyone else for the watershed that followed.

• 4. Spreading the Vaccine

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  In 1804 Spain mounted one of the most extraordinary public health expeditions in history. The Balmis Expedition, commanded by Francisco Javier de Balmis, sailed to spread the vaccine throughout the Spanish Empire. The vaccine was not carried in flasks. It was carried in the bodies of 22 orphaned boys, who served as living carriers of the live cowpox virus, passing it arm-to-arm across the Atlantic. Balmis reached the Canary Islands, then Spanish Central America. His deputy Jose Salvany took the vaccine down both coasts of Spanish South America. Balmis himself sailed on to Manila in the Philippines, then to Canton and Macao on the Chinese coast. He returned to Spain in 1806. Napoleon, meanwhile, ordered army recruits to be vaccinated and had his son Napoleon II vaccinated after his birth in 1811. By 1815, roughly half of French children had received the vaccine, and smallpox accounted for 1.8% of deaths in France, down from 4.8% at the time of the French Revolution. Governments began mandating vaccination. On the 26th of March 1806, the Swiss canton of Thurgau became the first state in the world to introduce compulsory smallpox vaccination, by order of cantonal councillor Jakob Christoph Scherb. Bavaria followed in 1807, Baden in 1809, Prussia in 1815, and England in 1867. Compulsory vaccination also provoked resistance. England's Vaccination Act 1853 introduced fines for non-compliance; by 1871, parents could be imprisoned for non-payment of those fines. The Vaccination Act 1898 introduced a conscience clause allowing exemption with a certificate signed by two magistrates. A further act in 1907 allowed exemption by statutory declaration, effectively ending compulsory infant vaccination in England. In the United States, Massachusetts was the first state to impose compulsory vaccination in 1809. The U.S. Supreme Court upheld mandatory vaccination in Jacobson v. Massachusetts in 1905, ruling that the public good could override personal freedom.

• 5. Making the Vaccine Safer

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  Early vaccines were crude. Scraped from the skin of infected calves, they contained bacteria along with the virus, and instances arose of contaminated vaccine transmitting erysipelas, tetanus, septicaemia, and tuberculosis. Arm-to-arm transfer of vaccine, practiced widely until the end of the 19th century, carried the risk of transmitting syphilis, estimated at roughly 750 cases in 100 million vaccinations. Sydney Arthur Monckton Copeman, an English government bacteriologist, found that suspending vaccine in 50% chemically pure glycerine and storing it under controlled conditions reduced bacterial contamination dramatically. In 1896 he was asked to supply this improved calf vaccine to vaccinate the future Edward VIII. By 1899 it was the only type issued free to public vaccinators by the British Government Vaccine Establishment. A 1900 survey found that government vaccine contained 5,000 bacteria per gram, while commercial vaccines ran as high as 100,000 per gram. The Therapeutic Substances Act 1925 set an upper limit of 5,000 bacteria per gram for all vaccine. A bigger problem was tropical heat. Glycerolated vaccine lost potency quickly at ambient temperatures, limiting its use in the places smallpox was hardest to fight. In the late 1940s and early 1950s, Leslie Collier, an English microbiologist working at the Lister Institute of Preventive Medicine, solved this. He developed a heat-stable freeze-dried vaccine by adding 0.5% phenol to reduce bacterial contamination and, crucially, 5% peptone to protect the virus during freeze-drying. The ampoules were sealed under nitrogen. The dried vaccine was 100% effective when reconstituted after six months of storage at 37 degrees Celsius, making it possible to transport and store the vaccine in remote tropical areas. With minor modifications, Collier's method became the WHO standard when the global eradication campaign began in 1967. Donald Henderson, who led the Smallpox Eradication Unit from 1967 to 1977, later wrote that Copeman and Collier made an enormous contribution for which neither ever received due credit. A further tool arrived in the 1960s, when Benjamin Rubin, an American microbiologist working for Wyeth Laboratories, developed the bifurcated needle. A two-pronged fork that held one dose of freeze-dried vaccine by capillarity, it cost $5 per thousand, used one quarter as much vaccine as other methods, and could be reused after flame sterilization. Rubin estimated that it was used for 200 million vaccinations per year during the final years of the eradication campaign.

• 6. Eradicating Smallpox

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  The WHO launched its global eradication campaign in 1967, organized and coordinated by a unit headed by Donald Henderson. The strategy combined an international search for outbreaks with targeted vaccination. Results came region by region. The last case in the Americas occurred in 1971 in Brazil. The last in south-east Asia occurred in Indonesia in 1972. The last on the Indian subcontinent occurred in Bangladesh in 1975. After two years of intensive searching, the last endemic case anywhere in the world was recorded in Somalia in October 1977. A Global Commission for the Certification of Smallpox Eradication, chaired by Frank Fenner, examined the evidence from every country where smallpox had been endemic. In December 1979 they concluded that smallpox had been eradicated. The WHO General Assembly endorsed that conclusion in May 1980. Laboratory safety remained a concern even after the disease was gone. An accidental containment breach at the University of Birmingham Medical School in 1978 caused two cases of smallpox, one of them fatal. The victim was Janet Parker. That incident accelerated the consolidation of remaining virus stocks. By 1979 only four laboratories were known to hold the virus. All English stocks held at St Mary's Hospital, London were transferred to Porton Down and then to the Centers for Disease Control and Prevention in Atlanta, Georgia, in 1982. All South African stocks were destroyed in 1983. By 1984, only the CDC in the United States and the State Research Center of Virology and Biotechnology, known as VECTOR, in Koltsovo, Russia, held the only known surviving samples.

• 7. Generations of Technology

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  Three generations of smallpox vaccine have been developed across nearly two and a half centuries of medical practice. First-generation vaccines, grown on the skin of live animals, were the workhorses of the eradication campaign in the 1950s-1970s. The development of freeze-dried vaccine in the 1950s made it possible to preserve vaccinia virus for long periods without refrigeration. One consequence: the U.S. stockpile of WetVax, manufactured in 1956-1957 and kept at -4 degrees Fahrenheit, was still effective when tested in 2004. First-generation vaccines contain live unattenuated vaccinia virus and can cause death in 1-10 people per million vaccinations. One third of first-time vaccinees develop side effects serious enough to miss school or work. Between 15% and 20% of children receiving the vaccine for the first time develop fevers above 102 degrees Fahrenheit. Second-generation vaccines, grown in chorioallantoic membrane or cell culture, offered greater purity by avoiding the skin bacteria present in animal-grown vaccine. Ernest William Goodpasture, Alice Miles Woodruff, and G. John Buddingh first grew vaccinia on the chorioallantoic membrane of chicken embryos in 1932. Vaccinia was first grown in cell culture in 1931 by Thomas Milton Rivers. ACAM2000, developed by Acambis and later acquired by Emergent Biosolutions in 2017, was approved for medical use in the United States in August 2007 and for mpox prevention in August 2024. The United States ordered over 200 million doses of ACAM2000 in 1999-2001. Third-generation vaccines use attenuated strains of vaccinia with a much milder side effect profile. Modified vaccinia Ankara, or MVA, was developed in West Germany through 572 serial passages of the Ankara strain at LMU Munich. After those passages, the virus had lost over 14% of its genome and could no longer replicate in human cells. MVA-BN, sold under the names Imvanex, Imvamune, and Jynneos, is manufactured by Bavarian Nordic. Unlike replicating vaccines, it is given by injection rather than scarification and does not produce a vaccine take. LC16m8, a replicating attenuated vaccine manufactured by Kaketsuken in Japan, was approved in Japan in 1975 after testing in over 50,000 children.

• 8. Stockpiles and the Ongoing Threat

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  When smallpox was declared eradicated, the WHO maintained a stockpile of 200 million doses as a precaution. By the late 1980s, with no reemergence of the disease, 99% of that stockpile was destroyed. Then came the 11th of September 2001. Fears of bioterrorism drove governments to rebuild their reserves. Several companies sold off vaccines manufactured in the 1970s, and production resumed. Aventis Pasteur discovered a stockpile from the 1950s and donated it to the U.S. government. By 2019, the United States had received 269 million doses of ACAM2000 and 28 million doses of MVA-BN. When the 2022-2023 mpox outbreak began, only 100 million doses of ACAM2000 and 65,000 doses of MVA-BN remained available in the U.S. stockpile. Canada, anticipating a similar threat, published a tender in April 2022 seeking 500,000 doses of smallpox vaccine. In May 2022 it awarded the contract to Bavarian Nordic for their Imvamune product, which was then deployed in response to the mpox outbreak. Replicating vaccines retain a useful property in a scarcity scenario: they remain effective even at a 1:10 dilution, meaning a limited number of doses can be stretched to cover a much larger population. First-generation vaccines, unlike their newer counterparts, carry no specified expiration date and remain viable indefinitely in deep freeze. The bifurcated needle that Benjamin Rubin designed for $5 per thousand, and which its users wore as a lapel badge shaped into the letter O for "Target Zero," remains a symbol of the campaign that turned the smallpox vaccine into the only instrument ever used to erase a human disease from existence.