EDWARD JENNER, COWPOX, AND VACCINATION

12 May

Edward Jenner (1749–1823) was 13 years old when he was appren- ticed to a physician. He obtained a respectable medical degree from St. Andrews, but preferred the life of country doctor to a fashionable London practice. Although he was often described as modest in both professional ambitions and intelligence, his mind was lively enough to maintain a lifelong friendship with the distinguished anatomist John Hunter (1728–1793). Thanks to a study of the rather nasty reproductive strategy of the cuckoo and Hunter’s sponsorship, Jenner became a mem- ber of the Royal Society. In their correspondence, Hunter and Jenner exchanged ideas about natural history and medicine. Thus, when Jenner became intrigued by local folk beliefs about smallpox and cowpox, he asked Hunter for his opinion of the hypothesis that inoculation with cowpox might eliminate the danger of smallpox. Hunter offered the advice that guided his own work: do not speculate, do the experiment. In 1793, the Royal Society rejected Jenner’s paper ‘‘Inquiry into the Natural History of a Disease known in Gloucestershire by the name of the ‘Cowpox.’’’ Five years later, Jenner published 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 the Cow Pox. Jenner named the infective cow- pox agent Variola vaccinae (Latin, vacca, meaning cow, and variola, the Latin name of smallpox). In view of the medical profession’s tendency to resist new ideas and methods, the fact that Jennerian vaccination spread throughout Europe and the Americas by 1800 is as remarkable as the rewards and honors heaped upon the modest country doctor who championed the new technique.

The Royal Jennerian Society was established in 1803 in order to provide free vaccinations for the impover- ished children of London. In the Inquiry, Jenner suggested that a disease of horses’ hooves, called ‘‘the grease,’’ was modified by passage through the cow and caused a disease in humans that was so similar to smallpox that it might be the primordial source of the disease. Because both men and women in Gloucestershire milked dairy cows, a man who had applied ointments to the hooves of horses suffering from the grease could transfer the infection to the udders of cows, where it appeared as an eruptive disease called cowpox. Infected milkmaids noted lesions on their hands, along with mild symptoms of generalized illness. While the cowpox was a minor inconvenience, people who contracted the infection seemed to be immune to natural and inoculated smallpox. Eighteenth century standards of proof, medical ethics, informed consent, and clinical trials were very different from those proclaimed by modern medicine. Jenner’s evidence would probably intrigue, but certainly not convince, a modern research review board. In addition to compiling case histories, Jenner performed experiments on the trans- mission and effect of cowpox.

For example, in May of 1796, Jenner inoculated eight-year-old James Phipps with fluid taken from a cowpox lesion on the hand of a milkmaid named Sara Nelmes. About a week later, the boy complained of mild generalized discomfort, but within a few days he had completely recovered. When Jenner performed a test inoculation, using pus taken from a patient with smallpox, Phipps appeared to be immune to inoculated smallpox. After a number of suc- cessful trials, Jenner concluded that a person previously affected by cowpox virus ‘‘is forever after secure from the infection of the small pox.’’ Jenner even inoculated his own son with cowpox fluid and later tested his immunity against smallpox pus. To distinguish between the old practice of inoculation with small- pox matter and his new method, Jenner coined the term vaccination (Latin vaccinus, relating to the cow). For the sake of convenience, and to distance his procedure from unwelcome associations with ‘‘brute animals,’’ Jenner proved that immunity could be transmitted directly from person to person.

Nevertheless, some of Jenner’s contemporaries denounced him as a fraud and a quack and raged against the use of vile animal matter in human beings, while others called vaccination the greatest discovery in the history of medicine. Physicians, surgeons, apothecaries, clergymen, and assorted opportunists vied for control of vaccination. But maintaining control was impossible because recipients of the vaccine could use their own vesicles to vaccinate family and friends. Critics of Jennerian vaccination warned that deliberately transmit- ting disease from animals to human beings was a loathsome, immoral, and dangerous act. Experience, however, substantiated Jenner’s major contention: vaccination was simple, safe, inexpensive, and effective. Vaccination, therefore, rapidly displaced inoculation despite inevitable religious, social, scientific, and pseudoscientific objections. Within one brief decade, enterprising practitioners had carried vaccination all around the world. Threads impregnated with cowpox lymph were gen- erally the medium of transmission, but on long voyages vaccine could be kept alive by a series of person-to-person transfers. A major difficulty in assuring the continuity of the chain of vaccination was finding individuals who had not previously contracted smallpox or cowpox. In 1802, Charles IV ordered the Council of the Indies to study ways of bringing vaccination to Spanish America.

An expedition was quickly organized and Francisco Xavier de Balmis (1753–1819) was appointed director. As the Spanish ship sailed around the world, de Balmis established vaccination boards in South America, the Philippines, and China. To maintain active vaccine on these long voyages, de Balmis selected about two dozen orphans and performed arm-to-arm passage every 9 or 10 days. When necessary, he replenished his supply of unvaccinated boys and continued with his mission. Because of the remarkable dispersal of Jennerian vaccine, de Balmis sometimes found that vaccine had gotten to some parts of the world before he did. The first vaccination in North America was probably performed by John Clinch, a physician and clergyman who had settled in the Newfoundland area. Clinch and Jenner became friends while they were students in England. In 1800, Jenner’s nephew, the Reverend Dr. George Jenner, sent ‘‘pox threads’’ to Clinch. Physicians in Cincinnati, Lexington, St. Louis, and other communities apparently obtained samples of cowpox vaccine during the first decade of the nine- teenth century. Dr. Antoine Franc¸ois Saugrain de Vigny (1763–1820), for example, introduced the vaccine to St. Louis in 1809, just eight years after a smallpox outbreak in the city. As early as 1800, Saugrain’s rela- tives in France had relayed reports about the vaccine and urged him to vaccinate his children. In June 1809, Saugrain put a notice in the Missouri Gazette to inform readers that he had obtained ‘‘the genuine vaccine infection.’’ Having successfully vaccinated his family and others, he felt compelled to ‘‘disseminate this blessing’’ and inform physicians and others about the availability of vaccine. He also offered free vaccinations for poor people and Indians. The best-known advocate of vaccination in America during the first part of the nineteenth century was Benjamin Waterhouse (1754– 1846). Born in Newport, Rhode Island, Waterhouse completed a medical apprenticeship with Newport’s leading physician, John Halliburton. Like many ambitious American doctors, Waterhouse pursued medical studies in London, Edinburgh, and Leiden. Having earned his medical degree, Waterhouse returned to Newport, where he estab- lished a private practice.

He also taught natural history and applied bot- any at the College of Rhode Island (later Brown University). Water- house later became the first professor of the Theory and Practice of Medicine at the newly established Harvard Medical School. In addition to his work on the cowpox, Waterhouse presented lectures in natural history, helped establish the Botanical Gardens in Cambridge, and pub- lished numerous books and essays, including The Rise, Progress and Present State of Medicine (1792), A Prospect of Exterminating Smallpox (Part I, 1800; Part II, 1802), and The Botanist (1811). Although Waterhouse was not the first person to perform vacci- nation in North America, he was the first vaccinator to capture the attention of the public and the medical profession. Indeed, William H. Welch (1850–1934), a prominent pathologist and one of the founders of the Johns Hopkins School of Medicine, called Waterhouse the ‘‘American Jenner.’’ Early in 1799, Waterhouse received a copy of Jenner’s Inquiry from a friend. Under the heading ‘‘Something Curious in the Medical Line,’’ Waterhouse published a brief note on vaccination in Boston’s Columbian Centinel and appealed to local dairy farmers for information about the existence of ‘‘kine-pox’’ in their herds. After sev- eral frustrating attempts to obtain active vaccine, Waterhouse secured a sample in July 1800 and began experimenting on his own children and servants. Although he was later criticized for trying to establish a monop- oly on vaccination in America, Waterhouse sent some of his vaccine to Thomas Jefferson, who vaccinated his entire household.

In a letter sent to Jenner in 1806, Jefferson predicted: ‘‘Future generations will know by history only that the loathsome smallpox existed and by you has been extirpated.’’ Although his prediction would not come true until the 1970s, Jefferson helped set the process in motion through his example and support. Debates about the safety and efficacy of preventive vaccines have raged ever since the first experiments on smallpox inoculation and vac- cination, long before the establishment of the sciences of microbiology and immunology. Many arguments about vaccination were more emotional than scientific: any interference with nature or the will of God is immoral; deliberately introducing disease matter into a healthy person is obscene; inoculations may appear to be beneficial, but the risks must ultimately outweigh the benefits. Other critics objected to the enactment of mandatory vaccination laws as an infringement on per- sonal liberty. For example, the British philosopher Herbert Spencer (1820–1903) wrote: ‘‘Compulsory vaccination I detest, and voluntary vaccination I disapprove.’’ On the other hand, Johann Peter Frank had no doubt that vaccination was ‘‘the greatest and most important dis- covery ever made for Medical Police.’’ Frank predicted that if all states adopted compulsory vaccination, smallpox would soon disappear. Early attempts to measure the impact of preventive immunizations lacked the rigorous controls that modern scientists demand. Indeed, results assembled from early clinical trials performed in hospitals, orphanages, and poorhouses were often little better than purely anecdotal evidence. When a disease is widespread, it is difficult to compare experimental and control groups because some people in both groups may have had the disease or, in the case of smallpox, may have contracted the disease just before the beginning of the experiment. Despite uncertainty and protests, during the 1850s, variolation was declared illegal and vaccination was made compulsory in the United Kingdom. The death rate from smallpox fell from the eighteenth century level of 3,000 to 4,000 per million to 90 per million after 1872, when enforcement of the vaccination laws became more common. Nevertheless, Alfred Russel Wallace (1823–1913), English naturalist and co-discover of evolution by natural selection, denounced vacci- nation as one of the major failures of the nineteenth century.

According to Wallace, the public health authorities were not only guilty of incompetence and dishonesty in their use of statistics, but had con- spired with the medical establishment to cover up numerous deaths caused by vaccination. Reflecting the views of many Englishmen, Wallace asserted that those who promulgated and enforced the vacci- nation statutes were guilty of a crime against liberty, health, and humanity. Many Americans must have agreed with Wallace, because in the 1910s epidemiologists were still complaining that the United States was the least vaccinated industrialized nation in the world. Individual states were almost as likely to pass laws prohibiting compulsory vacci- nation as laws mandating vaccination. Surveys conducted between 1928 and 1931 found that more than 40 percent of U.S. residents had never been vaccinated. Enforcement of vaccination laws improved dramat- ically after World War II, and the risk of contracting smallpox within the United States eventually became so small that in 1971 the Public Health Service recommended ending routine vaccination. At that point, although the United States had been smallpox-free for over 20 years, six to eight children died each year from vaccination-related complications. Hostility to compulsory vaccination never entirely disappeared. Indeed, in the 1980s, opponents of immunization claimed that the global campaign for the eradication of smallpox was responsible for the AIDS epidemic. Vaccinia virus made the eradication of smallpox possible, but the origin of vaccinia remains as great a puzzle as the nature of the relation- ships among smallpox, cowpox, and vaccinia viruses. As demonstrated in the 1930s, vaccinia is different from cowpox. Some virologists have defined vaccinia as a species of laboratory virus that has no natural reser- voir. Smallpox, cowpox, and vaccinia viruses are all members of the genus Orthopoxvirus, but they are distinct species and cannot be transformed into each other. Horsepox was extinct by the time immunological identification of particular strains was possible. Because cowpox and horsepox were rare and sporadic, virologists think that wild rodents were the natural reservoir of the ancestral poxvirus.

Since the 1960s, vaccines have been produced from three vaccinia strains maintained in England, America, and Russia. But the early trials of vaccination apparently involved an uncontrollable hodgepodge of viruses, with natural smallpox ever present. Inoculators took their material indiscriminately from cows and people, from primary pustules and secondary pustules of uncertain origin. The strength and duration of protection conferred by vaccination and inoculation were uncertain. Despite Jenner’s optimistic declaration that vaccination, if properly done, produced life-long immunity, later research proved that immunity from vaccination, inoculation, and natural smallpox falls off with time and is variable in any population. Thus, it is not surprising that different patterns of morbidity and mortality have been found among different populations. After World War II, smallpox was no longer considered endemic in Britain or the United States. Nevertheless, imported cases continued to touch off minor epidemics and major panics. Because the disease was so rarely seen in England, Europe, and the United States, smallpox patients often infected relatives, hospital personnel, and visitors before the proper diagnosis was made. Once a smallpox outbreak was identi- fied, some cities launched heroic vaccination campaigns. During small- pox panics in the 1940s, newspaper and radio messages exhorted young and old: ‘‘Be Sure, Be Safe, Get Vaccinated!’’ In New York City, William D. O’Dwyer (1890–1964), who served as Mayor from 1945 to 1950, set a good example by having himself vaccinated in the presence of reporters and photographers five times during his years in office. Although vaccination was supposedly required before admission to the city school system, public health officials estimated that at the outset of the 1947 outbreak only about two million of New York’s nearly eight million residents had any immunity to smallpox. Under the threat of an epidemic, five million New Yorkers were vaccinated within two weeks. This world record was achieved with the help of some 400 volunteers out of the city’s 13,000 private physicians.

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