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Science, “society”, and immunity
The evolution of vaccines and antitoxins was a collaboration between hard science and the social milieu.

By Christopher S. W. Koehler

Modern Drug Discover
October 2001
Vol. 4, No. 10, pp 59–60.



The earliest known attempts to produce artificial immunity to disease involved smallpox, one of the great diseases of history. It disfigured or killed people of all social classes, from kings to commoners; and many cultures tried to stop it by inducing immunity. In China, powdered smallpox scabs were blown into the sinuses, and a century before Edward Jenner, Chinese physicians prepared pills made from the fleas of cows in an effort to prevent the disease. In India, physicians conferred immunity by applying scabs to the scarified skin of the healthy. The technique spread west along the silk road to Istanbul, where it came to Western attention.

Speckled monster
The story of smallpox and inoculation is really two stories that converged. The first strand of the story is that of a British aristocrat, Lady Mary Wortley Montague (1689–1762), herself a survivor of smallpox. In 1717, Lady Montague’s husband was appointed British ambassador to Turkey, and it was there that she encountered a practice called “variolation”. An uninfected person would be exposed to material from smallpox pustules. In a letter to a friend, Lady Montague described seeing old women make a small number of scratches or punctures to introduce smallpox from someone who had suffered a light case. She called it “ingrafting”. Given her own experiences, she insisted that the embassy surgeon variolate her son.

On her return to London in 1721, Lady Montague had the surgeon, Charles Maitland, inoculate her daughter before the physicians of the royal court. This caught the attention of the Princess of Wales, who later had Maitland treat her own children. Because it was not just any mothers who had their children treated to prevent smallpox, but two aristocratic women, including the wife of the heir to the throne, this significantly publicized the new practice and its possibilities.

Maitland went on to perform experiments on orphans and on prisoners (who received full pardons for their risk) with the blessings of the English crown. Prisoners and orphans alike survived and proved immune to smallpox.

Cottoning to inoculations
According to historian James Cassedy, variolation or inoculation developed independently in the United States at the same time as in Europe. During a Boston smallpox epidemic in 1721, the Rev. Cotton Mather, who had learned of the practice from his slave, Onesimus, waged a successful campaign of the clergy against the medical establishment in favor of inoculation. Aided by a sympathetic physician, Zabdiel Boylston, who performed and monitored the treatments, Mather worked to make inoculations routine against the vehement protests of newspapers and the only Boston physician with an M.D. degree, William Douglass.
Despite the risks of infection from variolation, the number of cases of smallpox plummeted. The mortality rate in uninoculated children was 1:14, but 1:91 in children who had been inoculated. Thus variolation spread throughout Europe, spurred by the inoculation of many of Europe’s ruling dynasties. In the United States, although happening independently and without a clear-cut aristocracy, the role requirement for a famous and respected public figure was similar (see box, “Cottoning to inoculations”).

Enter Jenner
The second strand of the smallpox story likewise involved simple medical technology within a complicated social milieu. Later in the 18th century, the work of Edward Jenner (1749–1823) aroused controversy similar to that faced in the Americas. Had he not surmounted this debate, his breakthrough might have been relegated to footnotes and postponed by decades.

It was a staple of rural lore that milkmaids who had contracted cowpox from the cows they tended did not contract smallpox. Cowpox, to cows, is a relatively minor infection of the udder, leading to a slight decrease in milk production. It also led to a case of pox in humans that might scar, but not nearly to the extent of smallpox, and it was not fatal. That was a small price to pay for immunity to the “speckled monster”.

Over the years, observant people, from farmers to physicians, had noted that contraction of cowpox conferred smallpox immunity. Jenner, who had success with variolation, became obsessed with this connection between a minor disease in cows and the possibility of freedom from one of the great scourges of human health. By 1788, he was convinced that the folk belief was also scientific truth, and an outbreak of cowpox in 1796 allowed him to experiment. He extracted fluid from the milkmaid Sarah Nelmes’s hand and used it to inoculate 8-year-old James Phipps. Phipps later proved resistant to not only cowpox but also smallpox.

Yet Jenner’s paper detailing the experiment and its success was rejected for publication by the Royal Society. In fact, he was warned against publishing it anywhere out of concern for his reputation. Perhaps Lady Montague and the Princess of Wales had succeeded too well in publicizing variolation, for medical authorities were at first unwilling to credit Jenner’s technique, which he called vaccination (from the Latin for cow). After all, how could the reputation of a milkmaid compare with that of the Princess of Wales?

Nonetheless, Jenner’s findings were subsequently verified by other physicians, including William Woodville of London’s Smallpox and Inoculation Hospital. Just as with variolation, Jenner’s technique spread because it was rapidly espoused by Europe’s ruling families. By 1800, it had been adopted in most European countries.

“Active” vaccines
The late 19th century saw further development of the modern tools needed to induce “active” immunity. Active immunity is that developed by the body’s own immune system against a pathogenic organism. Obviously, the normal pathogen itself is inappropriate for a vaccine, because it would cause the very disease it was intended to treat; instead, a debilitated or dead pathogen, or only part of the pathogen, is used. Variolation and cowpox inoculation unwittingly took advantage of this technique, by using a natural debilitated strain in the first case and a related but “safe” virus in the second.

Louis Pasteur developed the first modern vaccine in 1885 in his attempt to prevent the onset of rabies. Rabies, a disease of the nervous system, is characterized by encephalitis and, in the absence of treatment, death. But how could Pasteur make a vaccine from a pathogen that was a sure death sentence in its native state?

The answer came to Pasteur through his work with chicken cholera. Healthy birds inoculated with cholera quickly contracted it. However, by accident he noted that although a given culture would lose its efficacy, a bird dosed with that culture would resist infections from fresh cultures. Pasteur thus found a way of producing resistance without the initial disease by using an attenuated, or weakened, form of a pathogen. But devising an experimental vaccine through a weakened form of a deadly pathogen is one thing, testing it quite another. On July 6, 1885, a boy, Joseph Meister, was bitten by a rabid dog. Pasteur tested his novel vaccine on a human for the first time, and Meister did not develop rabies.

Scientists, inspired by Pasteur’s success, realized that if other pathogens could be weakened through this strategy, an entirely new frontier of preventions would be available to medicine. This breakthrough and those that rapidly followed drove late-19th-century medical science in a grand quest for knowledge about microbiology.

Enter antitoxins
In 1890, five years after Pasteur’s breakthrough in vaccines, Emil von Behring and Shibasaburo Kitasato (who would later demonstrate that the bacillus Pasteurella pestis caused bubonic plague), isolated the first of the antitoxins. What these researchers called “antitoxins” were actually antibodies to specific disease substances—in this case the toxins produced by the pathogens.

The efficacy of antitoxins in disease therapeutics was discovered through work on diphtheria and tetanus. Startlingly, von Behring and Kitasato noted that blood from animals already immune to specific diseases could be used to heal other infected animals (Deutsche Medizinische Wochenschrift 1890, 16, 1113–1114). Between 1893 and 1895, antitoxin experiments were successfully conducted in humans; and in 1901, von Behring won the first Nobel Prize in Physiology or Medicine (such prizes would go far in creating a scientific social elite in the future) for his development of the first “reliable weapon” against diphtheria.

But this new technology was not embraced without controversy either. According to James H. Cassedy, organized protests flared up in the United States against the adoption of the diphtheria antitoxin in the 1890s, and violent reactions also occurred among immigrants of the same period who were forced to take smallpox vaccinations.

Old wine in new bottles?
Today, as in Pasteur’s era, the production of artificial immunity still involves the isolation of the infectious agent (or a part thereof) to spark an immune response without causing the disease. And as in Cotton Mather’s time (see box above, “Cottoning to inoculations”), distrust of inoculations, including vaccines given to military personnel against biological warfare agents (claimed by some to have caused various veterans’ ailments), is currently rampant among certain public sectors. Similarly, many parents recently have been upset by reports of possible correlations between multiple vaccinations and autism.

So perhaps a role still exists, at least in some cases, for trusted elites like Lady Montague, Mather, and Pasteur to help allay the public’s natural fears of a technology so intimately associated with deadly and terrible diseases. And as for the role of social elites, especially royalty, in the promulgation of medical science in the modern world—well, the King of Sweden still hands out the Nobels every year.

Suggested reading

  • Barquet, N.; Domingo, P. Smallpox: The Triumph over the Most Terrible of the Ministers of Death. Ann. Intern. Med. Oct 15, 1997, 127, 635–642. www.acponline.org./journals/annals/15oct97/smallpox.htm.
  • Cassedy, J. H. Medicine in America: A Short History; Johns Hopkins University Press: Baltimore, MD, 1991.


Christopher S. W. Koehler holds a Ph.D. in the history of science. He writes and teaches in northern California. Send your comments or questions regarding this article to mdd@acs.org or the Editorial Office by fax at 202-776-8166 or by post at 1155 16th Street, NW; Washington, DC 20036.


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