The observation of immunity inspired our ancestors to devise procedures to try and protect the healthy from smallpox. The Chinese began practicing a procedure to protect people from smallpox as early as AD 1500. The procedure involved collecting scabs from individuals who had a mild form of the disease. The scabs were then converted to a powder. About a month later, it was administered by inhaling powder nasally through a silver tube, left nostril for females and right for males. A week after this procedure pustules formed in the mouth and skin. It was hoped that these symptoms would not be as severe as the full-blown disease or cause death, but this was not always the outcome. Importantly, people who had successfully undergone the procedure did not get the disease when epidemics occurred.
Europeans encountered a similar procedure being used in India in the seventeenth century. Here, the fluid from smallpox sores and scabs was collected, stored for a while, and ultimately mixed with cooked rice to form a paste. Several punctures were made in the skin (arm or forehead) of a healthy person with a needle. These needle punctures were then covered with the paste made with rice. This method spread from India to other parts of Asia and the Balkans.
The methods developed by the Chinese and Indians came to be called variolation. The story of how variolation was brought to Europe is interesting, and many detailed accounts are available. Our story begins by noting the establishment of the British Royal Society in 1660. It is the oldest scientific academy in continuous existence. Because the Royal Society was a prominent entity, many scientists would send their important observations to the Fellows of this society. In 1700, the Royal Society received two letters from British subjects in China describing the Chinese variolation procedure. Neither communication led to any interest among the Fellows, perhaps because of the perceived risk in infecting an otherwise healthy person with diseased material. In December 1713, similar information about variolation was received in a letter from Emmanuel Timoni, a physician who practiced in Constantinople and whose patients included the British ambassadors there. Unlike in 1700, this letter did elicit interest in the variolation procedure.
Enter Mary Wortley Montagu. She was the wife of Edward Wortley Montagu, the British Ambassador in Constantinople. Her brother died of smallpox, and she herself was badly scarred by the disease. Mary Montagu witnessed variolation in Constantinople and given her personal encounters with smallpox developed a keen interest in the procedure. She decided to have her young son variolated by Dr. Charles Maitland, who was serving the British embassy in Constantinople. When she returned to England, she tried to champion the procedure. In 1721, a major smallpox epidemic broke out in London. Fearing for the life of her younger daughter, Montagu requested Maitland to carry out the procedure on her daughter. Maitland carried out the procedure. Members of the Royal College of Physicians were there to observe the procedure and its successful aftermath.
During the 1721 smallpox epidemic in England, a child of Caroline, the Princess of Wales, fell ill. Although it turned out that the child did not have smallpox, the princess got interested in variolation. While there is controversy as to who played the most prominent role, Montagu, Maitland, and Hans Sloane, Bart (the president of the Royal College of Physicians) all played important roles in promoting variolation among the royal family in England. Thus began what was likely the first “clinical trial.” The trial was to be carried out with six condemned prisoners in Newgate Prison in England. In exchange for participating in the trial, the prisoners were to be pardoned afterward. After being variolated in August 1721, five of the prisoners got symptoms of the disease but recovered. The sixth did not get symptoms, and it was then learned that this individual had recovered from smallpox the previous year. One of the women who had been successfully variolated was then sent to care for a child who was afflicted with smallpox. In spite of living in close quarters and tending to the patient, the variolated woman did not fall sick, further validating the efficacy of the procedure. All six prisoners were freed.
Despite the success of the variolation trial with prisoners, Princess Caroline still wondered whether the procedure was safe for her children. To further convince herself that the procedure was safe, the Princess then sponsored the variolation of five orphan children. Variolation did not harm these children. In April 1722, Princess Caroline, now convinced about the safety of the procedure, had two of her daughters variolated. This popularized the procedure among the upper classes of British society. Variolation was tried in Boston around the same time as the clinical trials in England. Benjamin Franklin became a strong proponent of the procedure.
The events of 1721 and 1722 were covered extensively by the press, which helped convince the public that variolation was a safe procedure. It is impossible to overstate the importance of clinical trials for establishing the safety and efficacy of any new vaccine even today. As we will describe in chapter 7, the time required to carry out proper clinical trials is one of many reasons why developing and deploying a new vaccine takes so long. Viewed from our modern perspective of ethics and morality, selecting prisoners and orphans as the subjects of the clinical trials seems highly unethical. Now, of course, participants in clinical trials of vaccines are healthy volunteers, who participate with full knowledge of the risks.
Variolation was practiced in a way that was traumatic for the person being inoculated. The individual was bled and given very little to eat before the procedure was carried out. Variolation involved the preparation of material taken from a person who was infected. We now know that this material contained the smallpox virus. So, even if the inoculum was prepared by an experienced practitioner, serious or lethal illness could ensue. Variolation also resulted in localized outbreaks of smallpox on occasion. Variolated people were therefore housed together after the procedure to prevent spread of the disease. The danger inherent in the variolation procedure and the trauma to the person being inoculated were reasons why variolation was not widely practiced, and most people remained unprotected from smallpox infections. All of this changed with the work of Edward Jenner, who incidentally had been variolated as a child.
Edward Jenner’s Paradigm Shift
Jenner was born on May 17, 1749, in the Gloucestershire town of Berkeley in England. After completing his early education and apprenticeship to an apothecary, Jenner became an early student of John Hunter, a Scottish surgeon and doctor. Hunter and Jenner shared many interests, including studying species that hibernated and the migration of birds.
After completing his work with Hunter, Jenner returned home to Berkeley in 1773. It is believed that a milkmaid told Jenner that she did not respond to variolation because she once had cowpox, a relatively harmless disease in cows and humans. He also heard about this phenomenon from John Fewster (1738–1824), a medical colleague in Gloucestershire who noticed that a young man who had previously been infected with cowpox did not react to variolation. Jenner began to study the connection between cowpox infection and protection from smallpox. These studies took time because cowpox outbreaks in dairies and farms were infrequent. Jenner’s studies led him to believe that the origin of cowpox was a disease called “grease heel,” which caused inflammation in the skin of horses, and he thought it was transmitted to cows by farmworkers who tended both horses and cows. In cows, the disease affected the nipples and it was passed to dairymaids while milking the cows. It is legend that dairy maids have fine complexions that were envied by noblewomen. The basis of this legend may be that because their exposure to cowpox left them immune to smallpox their faces were not pockmarked.
With his mentor Hunter’s encouragement, Jenner did an experiment to test whether cowpox inoculation could protect humans from smallpox. On May 14, 1796, Jenner used the variolation procedure to inoculate a boy called James Phipps with pus from a sore of a cowpox-infected milkmaid named Sarah Nelmes. Because this event was so momentous in medical history, we also know that the name of the cow that infected Nelmes was “Blossom.” Two months later, Jenner repeated the variolation procedure on Phip
ps, but now he used smallpox. When no symptoms appeared, his hypothesis that cowpox inoculation could protect a person from smallpox was validated. He would repeat the procedure with a small number of individuals two years later.
Jenner’s experiment represented a paradigm shift in the human endeavor to protect people from infectious diseases. His new paradigm was that one could protect an individual from a deadly illness by inoculating with a material derived from a relatively harmless (for humans) related disease. Thus, unlike variolation, the procedure was largely safe for healthy people.
Jenner described his work to the British Royal Society, and he tried to publish a paper based on his findings in the society’s prestigious journal, Philosophical Transactions, which still exists today. In spite of the fact that Jenner was a Fellow of the Royal Society, the Royal Society rejected his paper. They felt that Jenner did not have enough evidence for his claims, and he might do irreparable damage to his reputation by publishing the work before he had definitive proof. Jenner had his findings published by the private firm of Sampson Low. Presumably, he made money from the sales of this book, which would not have happened if he had published his findings in the Philosophical Transactions.
The popularity of Jenner’s procedure began to grow. Richard Dunning, an early supporter of the procedure in England, proposed that the procedure be called vaccination because the Latin name of cowpox is Vaccinia. Pasteur later promulgated the use of this term for an inoculation procedure that protected humans from any disease. Ultimately, vaccination replaced variolation, and the latter procedure was made illegal in 1840 in England. Vaccination was made mandatory shortly thereafter.
Jenner’s development of vaccination based on careful observation was a remarkable advance. It led to a safe procedure that protected millions of people from a disease that had caused frequent devastating epidemics over millennia. This huge advance in public health was recognized in Jenner’s lifetime with numerous honors from professional organizations in England and around the world. The French Emperor Napoleon was supposedly a big fan. Statues were built and poems were written to honor Jenner’s contribution to humankind. Jenner’s home is now a museum, as is the hut where Phipps was vaccinated. Remarkably, when Jenner did his work, we did not know that infectious microbes cause diseases or that we have an immune system. We will describe infectious microbes and how our immune system works in the next three chapters.
Eradication of Smallpox from the Planet
Throughout the twentieth century, Jenner’s smallpox vaccine was administered just like the variolation procedure. After applying the vaccine material, the surface of the skin was punctured repeatedly with a needle to induce a scab. The use of the smallpox vaccine spread around the globe with particularly strong efforts in the Western world. By the early twentieth century, smallpox had been eradicated in Northern Europe and only a small number of cases were reported in other European countries. In 1950, a group of health officials proposed an effort to eradicate smallpox in the Americas and largely succeeded within the decade. In 1958, the Soviet Union proposed that the World Health Organization (WHO) lead an international effort to eradicate smallpox worldwide. Efforts were mounted in almost every country using a novel strategy called ring vaccination. Following the identification of an infected person, every person who lived in the vicinity was vaccinated.
The last two countries with extensive caseloads were Ethiopia and Somalia. A stepped-up focus on these two countries finally succeeded in the eradication of smallpox from these countries in 1979. The last case of smallpox was the fatal infection of Janet Parker, a medical photographer, who contracted the virus from a laboratory that was doing research on smallpox. This resulted in the destruction of all known stocks of the virus except for two vials, one stored in the United States and the other in Russia. As the years passed by without any new smallpox cases, a raging controversy stormed through the scientific community about whether these last vials should be destroyed to literally eradicate smallpox completely from the planet. There was worry that if terrorists were to take control of these stocks and weaponize smallpox, without anyone in the world being immune, a devastating pandemic could take place. Others argued that for scientific purposes it might be necessary to draw on these stocks for some unknown future problem. This controversy was made moot in 2017, when researchers showed that it would be possible to recreate smallpox in the lab using existing methods.
What was the secret to eradicating smallpox, this centuries-old enemy of the human race? The first was the international cooperation of all countries of the world in understanding the horrific nature of smallpox infection and the importance of eradicating it from the earth. Can we now achieve a similar level of global coordination to create a more pandemic-resilient world? The other key was that the virus that causes smallpox did not infect animals. It infected only humans, and spread solely by human-to-human contact. As we will learn in a later chapter, the natural hosts for many viruses are animals, and that viruses can jump to humans when they change in a way that allows them to infect and/or reproduce in human cells. This is precisely what happened to cause the H1N1 influenza pandemic in 2009 and the COVID-19 pandemic. Eradication of a viral disease that infects animals would require the extermination of entire species of animals or finding a way to vaccinate them. Newer technologies have suggested approaches where genetically engineered insects or animals are released into the wild. These organisms are engineered to have the ability to breed with existing species and block the ability of specific pathogenic microbes to survive in their progeny. Whether this is a strategy that is worth trying or whether this may generate unexpected ecological changes is a difficult ethical issue with potentially dangerous environmental impact.
Early Opposition to Vaccination
The smallpox epidemics in Boston in the early twentieth century led the local board of health to start free vaccination programs. Much like flu shots today, one could get vaccinated for free in various locations around the city. In 1902, vaccination was made mandatory in Boston. Those who refused to be vaccinated were subject to a $5 fine or 15 days in prison. Henning Jacobson, a Swedish immigrant in Boston, refused to be vaccinated because he feared that it would make him sick. But, instead of paying the fine, he sued the state of Massachusetts on the basis that the mandatory vaccination program violated his rights. This case went all the way to the US Supreme Court, which ruled in favor of Massachusetts in 1905. The Court’s reasoning was that Jacobson’s refusal to be vaccinated endangered the health of others.
With improvements in vaccine quality, vaccination is now practiced widely. It is fair to say that vaccination has saved more lives than any other medical procedure. The sharp decrease in child mortality over the past century is primarily due to the success of vaccination programs. Polio, another disease caused by a virus, afflicted 60,000 people in the United States in 1952. Jonas Salk, and then Albert Sabin, developed vaccines that protected people from polio. Today, polio has been all but eradicated from the world.
But, the controversy over the use of vaccines still rages today in some quarters. As we will discuss later, when a significant fraction of the population is not vaccinated against specific diseases, outbreaks occur. Several parents choosing not to vaccinate their children against measles led to the recent outbreaks of this disease in California. High vaccination rates protect the public—in particular, vulnerable people like the elderly and the immunocompromised—by generating something called “herd immunity,” which we hear about so much during the COVID-19 pandemic. We will focus on these topics in later chapters.
2 Discovery of Infectious Disease-Causing Microbes and the Dawn of the Modern Era of Vaccines
The ancient Greek physician Hippocrates (460–370 BC) noted that miasmas and poisons in the environment caused diseases. But this was not a concrete concept that could suggest ways to protect humans from specific infectious diseases. In this chapter, we will describe how it became clear that microscopic organisms, or microbes, cause inf
ectious diseases, and how this knowledge led to the development of vaccines against cholera, anthrax, and other diseases in the nineteenth century.
Most of the work in the nineteenth century was done on microbes called bacteria, which are tiny organisms that are made up of a single cell. Bacteria cause devastating illnesses, such as tuberculosis, tetanus, typhoid, diphtheria, and syphilis. These infectious diseases still occur throughout the world. Viruses, which cause illnesses like COVID-19, influenza, and polio, were too small to be seen with the technology available during the nineteenth century. Thus, they were not characterized until the beginning of the twentieth century. We will focus almost exclusively on viruses starting with the next chapter. The knowledge gained by Koch, Pasteur, and others in the nineteenth century about disease-causing microbes and vaccines, described in this chapter, is important background for the chapters that follow.
“Animalcules” under a Microscope
Lenses were used in ancient times to convert sunlight into fire and later on to help with reading (reading stones). But, it was only in the seventeenth century that they were used for scientific exploration. Galileo constructed a telescope in 1609 with which he observed celestial objects, thus creating modern observational astronomy. Although the Assyrians seem to have developed a rudimentary form of a microscope as early as 700 BC, it was not until the seventeenth century that van Leeuwenhoek used such an instrument to reveal the fascinating world of microscopic organisms.
Antonie Philips van Leeuwenhoek (1632–1723) was an amateur Dutch inventor. He was a businessman and held important municipal positions in the city of Delft. Van Leeuwenhoek invented a new way to make lenses that he kept a trade secret. This advance enabled him to construct a microscope that was more powerful than others available at the time. His microscopes were delicately constructed and were tiny, measuring about two inches in length. Van Leeuwenhoek used his new microscope to describe details of the stinger of a bee, the shape of a louse, and mold growing on bread. At the urging of a physician friend, he started communicating his observations to the British Royal Society in letters with hand-drawn illustrations. Later, noting that the water in a nearby pond would become cloudy in the summer, he used his microscope to investigate. He not only saw what we now know as algae, but noticed unusually small organisms swimming about. He named them “animalcules.” From his drawings we can discern that van Leeuwenhoek was describing single-celled living organisms that would later be found to be the cause of diseases such as giardia. Observing bacteria for the first time, he estimated their size relative to a grain of sand. He found that more than 100 lined up to equal the length of a sand grain, and therefore, millions could be present in a single drop of water. The Royal Society did not initially believe these observations about tiny living organisms. In 1677, a number of experts were sent to visit van Leeuwenhoek, and he was able to convince them that his observations were valid. Thus, at the dawn of the eighteenth century, a new world of microscopic living organisms was discovered.
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