Historical context and the roots of Jenner's discovery

ABSTRACT

May 2016 marks the 220^th anniversary of Edward Jenner's first experimental vaccination using cowpox to protect against smallpox. Jenner's discovery, and its rapid adoption around the world, launched a medical revolution that continues to shape how we approach disease prevention. The historical roots of vaccination are found in the popularization of smallpox inoculation during the 18^th century, part of an Enlightenment culture that fostered scientific inquiry and the global circulation of knowledge. Jenner was part of that culture and his study of cowpox stemmed from his varied interests as a natural historian, his contacts with leading savants in London, and his medical practice in a flourishing dairy area of England. The amazingly quick spread of vaccination resulted from organized hospital trials in major cities, the severe smallpox epidemic at the turn of the century, disease environment, and policies of European colonial powers.

KEYWORDS:

• cowpox
• Edward Jenner
• smallpox inoculation
• vaccination

In May 1796, Edward Jenner (1749–1823) performed his first experimental vaccination on 8-year old James Phipps (1788–1853), a healthy boy who had had the good fortune to escape smallpox in his first years of life. Jenner selected young Phipps to test his observation that exposure to cowpox—a disease that produced ulcers on cows' udders—would protect him from a subsequent attack of smallpox. We do not know Phipps' reaction to being chosen as Jenner's first vaccination subject, but artists commemorating the event frequently portray the boy cringing and looking away from Jenner. We do know that later in life Jenner deeded a cottage to Phipps for his bravery.

Phipps' cottage is just down the street from Jenner's large house in the small village of Berkeley just miles from the Severn River that separates England from Wales. Jenner's house, flanked on one side by the 12^th-century Berkeley castle and its extensive grounds, and on the other by the village church and graveyard, stands atop a hill and is now a museum. Jenner spent many of his days on horseback, riding through the luxuriant countryside and farms of Gloucestershire to attend patients in their homes. His day-to-day practice provided the “experiments of nature” for his discovery.

The domestic setting of Edward Jenner's discovery of smallpox vaccine is as far from a modern pharmaceutical laboratory as one can get and his experiment so simple as compared to today's multiple-phase clinical trials. And yet important similarities and continuities exist between the vaccine work of Jenner and that of researchers and doctors today. Jenner envisioned the potential global impact of vaccination and he would be gratified to see the revolutionary changes vaccination has made to the world.

Looking for roots: Folk practices

Bio-prospecting is nothing new. The roots of vaccination are to be found in smallpox inoculation – a practice with a long history in many cultures around the world. In China, for example, doctors blew dried and pulverized smallpox scabs in patients' noses—a process known as insufflation. Greek women in Turkey inserted pus from smallpox pustules into small incisions they made with a needle on healthy children and adults. Welsh children “bought the pox” by rubbing smallpox scabs between their hands. Africans along the Gold Coast rubbed smallpox matter into scratches in the skin. The aim of all such practices was to induce a mild case of smallpox to protect a patient from full-blown smallpox later in life.^1-4 But there were risks: sometimes an individual contracted severe smallpox and could be left blind, scarred, or even dead. Mathematically-minded doctors calculated the risks of dying from inoculation—roughly 1 in 100 in the 1720s – and compared it to the much greater risk of dying from smallpox, about 1 in 7.⁵ (Today the case fatality rate for smallpox is estimated to be much higher, roughly 30%). Today we would consider such a gamble appalling, but the odds looked good at that time, because smallpox spread so quickly through communities; inoculation offered the best possibility to decrease its devastation.

Several features of smallpox made it an ideal target for inoculation. The disease was readily identifiable by its characteristic rash. Individuals who suffered and survived a bout of smallpox knew they were protected from any subsequent attacks. And finally, the poxy matter taken from pustules—easily harvested and preserved in nutshells, on threads, or in glass tubes—conveyed the disease from one person to the next.

In the half century before Jenner's birth, European doctors, scientists, and concerned parents, including mothers, learned about inoculation practices from reports circulating in new print media characteristic of the Enlightenment: newspapers, scientific and medical journals, and public letters. Thus, for instance, the Boston minister Cotton Mather shared the testimony of his African servant about inoculation practices to members of the Royal Society in London; the English aristocrat Lady Mary Wortley Montagu living abroad in Constantinople (Istanbul) penned letters to her friends in London about Turkish customs; and British officials from the East India Company described the techniques found in India.^1-4

By 1750, inoculation had become widely publicized and adopted by many doctors and surgeons. As a youth, Jenner himself underwent inoculation at one of the many houses used for isolating individuals. Since inoculated persons were just as contagious as someone suffering from natural smallpox, segregating patients helped prevent unintended outbreaks. For the young Jenner, inoculation had been a miserable experience: he was first fed a light diet, then purged and bled, and finally inoculated. Improvements to this protocol in the 1760s and 1770s—especially by the Sutton family in England who pioneered a less invasive technique without the depleting preparation Jenner had undergone – made inoculation safer and less costly.⁶

A prepared mind

We tend to think of Jenner as a country doctor at home among cows, horses, dairymaids, and farmhands. But he spent a couple of years (1770–72) studying in London with one of the most renowned surgeons and scientists of the time, the Scotsman John Hunter. Jenner learned anatomy, chemistry, botany, and medicine. His scientific skills gained him an invitation to serve as a naturalist on Captain James Cook's second voyage, which Jenner politely declined, preferring to return to Gloucestershire to set up his practice. But his interest in science continued to grow and he corresponded with John Hunter on scientific matters until Hunter's death in 1793. Jenner's observations on the behavior of the cuckoo led to his election as Fellow of the Royal Society. His attention to detail, coupled with his fascination and curiosity for natural history, provided fertile ground for his discovery of vaccination.⁷

Jenner learned about the virtues of cowpox from dairymaids and farmhands, and from failed inoculations. On some patients, the inoculation did not “take,” despite inserting smallpox matter in several incisions. And yet, these individuals did not come down with smallpox during periodic outbreaks. What they had in common was prior experience with cowpox. Intrigued, Jenner began to record their case histories. He was able to track cases of smallpox and cowpox because of Gloucestershire's low population density—in a bulging metropolis like London it would have been an impossible task—and thus confirm the reports and experiences of local inhabitants. These experiments of nature—collected over several years—prompted Jenner to perform his first vaccination on Phipps. Following that success, Jenner vaccinated many other men, women, and children and kept detailed notes about their experiences with cowpox. These case histories became the subjects and substance of his Inquiry into the Causes and Effects of Variolae Vaccinae (1798), his first publication on vaccination. The advantages of cowpox vaccination over smallpox inoculation were clear: cowpox was a mild disease in humans that did not cause death, and vaccinated individuals were not contagious, so there was no need to isolate them through the course of their illness. Jenner also believed that vaccination conferred lifelong immunity, but this proved untrue as instances of vaccinated individuals contracting smallpox began to emerge in the second decade of the 19^th century.

Jenner, of course, was not the first one to note the fact that prior exposure to cowpox protected persons from smallpox, nor was he the first to vaccinate with cowpox. John Fewster, a surgeon and friend of Jenner who ran an inoculation house in Gloucestershire, had noted that smallpox inoculation failed to take on persons who had suffered from cowpox. The Dorset farmer Benjamin Jesty took the additional step and vaccinated his wife and 2 sons in 1774 with cowpox.⁸ There are also scattered reports of doctors in Germany and France who noted the connection, and in at least one instance, performed a vaccination.⁴

But these men did not make their experiences widely known. Jenner, by contrast, sent his first account of Phipps' vaccination to the Royal Society for publication in their Philosophical Transactions. The Royal Society declined because they wanted additional evidence. In response, Jenner wrote a more substantial pamphlet, part of which focused on the origin and nature of cowpox and reflected his keen interest in natural history. In his rural practice, Jenner had observed that cowpox occurred in farms where both men and women worked with dairy cows, which led him to postulate that the origin of cowpox was in fact another disease that affected horse's hooves called horse grease (horsepox). This theory was and remains much disputed. We do know that contemporaries vaccinated successfully with horsepox, and in the 20^th century scientists discovered that the virus most commonly used in vaccination was vaccinia, a virus more closely related to horsepox than cowpox.⁹ The historical context of Jenner's practice provides support for a connection. Dairy was traditionally women's work, but by the late 18^th century cheese-making was becoming big business, and farms increasingly employed men and women to milk the cows.¹⁰ Jenner's medical practice just happened to be in one of the major cheese-making areas of England. Moreover, in the search for supplies of cowpox, contemporaries frequently relied upon Jenner's observation that cowpox would be found where men as well as women milked cows.

Jenner lays claim to the discovery of vaccination because of his publications that carefully documented the evidence he collected to support vaccination, his investigations into the nature of cowpox, his extensive correspondence with individuals around the world, and his efforts to establish a supply of cowpox vaccine and to distribute it freely. In essence, he acted more like a modern scientist than a private doctor, and this desire to make his ideas known is what made him the father of vaccination.

Clinical trials

Vaccines have been associated with clinical trials ever since Jenner's discovery. Within five years of his publication, doctors in Europe and North America conducted trials both in hospitals and in communities to test the safety and efficacy of cowpox vaccine. These trials – initially exploratory in nature and later primarily for purposes of demonstration – proved enormously influential and set the model for evaluations of subsequent vaccines.

The first clinical trial took place in 1799 in the London Smallpox and Inoculation Hospital located in St. Pancras, now the site of King's Cross railway station in north central London. Dr. William Woodville, head of the Smallpox Hospital, vaccinated over 600 patients and just a few days later inoculated many of them with smallpox to test their immunity. The results were confusing: patients exhibited symptoms of both cowpox and smallpox. Many contemporaries concluded that a smallpox hospital was not the ideal setting for testing vaccination; patients there ran the risk of contracting smallpox before getting vaccinated.¹¹ So, later that year, doctors in Geneva, Switzerland, and Hanover, Germany conducted trials by vaccinating individuals in their homes. And the results were much clearer: patients exhibited the symptoms described by Jenner (a large pustule at the vaccination site; minor fever) without the pocks characteristic of smallpox.

In France, a special committee formed in 1800 to test the vaccine. Given permission by the Revolutionary government to try it on orphans at the foundling hospital in Paris, leading French doctors conducted carefully planned trials designed to explore the characteristics, risks, and benefits of vaccination. Children were vaccinated and then inoculated with smallpox or sent to live with a family experiencing an outbreak of natural smallpox. Different techniques were tested and evaluated. An official report issued in 1803 approved and recommended vaccination.¹² In the wake of these trials, French officials implemented an ambitious vaccination program at home and for revolutionary soldiers in the field.^13,14

Further trials in Vienna, Austria and in Boston, Massachusetts in 1802 took place in hospitals set up specifically for the occasion. Doctors vaccinated children and then after 2 weeks, inoculated them with smallpox. Government officials, surgeons, and other doctors attended these trials, which were primarily demonstrative in purpose.^15,16 Their success led to official support of the adoption of vaccination and in the first 2 decades of the 19^th century, several governments made vaccination compulsory: Bavaria (1807), Denmark (1810), Sweden (1815), Germany (1818), and Egypt (1819).⁴

Disease environment

One of the key factors to vaccine hesitancy today is the current disease environment. Thankfully most Americans will not see their children suffer from polio, measles, mumps, or whooping cough because of routine vaccination. And yet, paradoxically, this success has encouraged parents to become more skeptical about the necessity of vaccination. Around 1800, the reverse situation worked as a catalyst to the rapid acceptance and expansion of vaccination.

Smallpox, of course, is the first disease to be eradicated—one of the triumphs of human history. But before its eradication in the 1970s, smallpox reigned as the most dreaded disease causing great suffering. European expansion beginning in the late 15^th century brought smallpox to the New World resulting in catastrophic mortality. After the decline of bubonic plague in the early 1700s, populations around the world experienced more virulent smallpox epidemics, and smallpox became the leading cause of death in many communities. Fear of smallpox encouraged the adoption of smallpox inoculation and the threat of an outbreak often led to general inoculations of the population: an occasion where all inhabitants of a village who had not had smallpox were inoculated on the same day.

The upheavals caused by the French revolutionary wars contributed to a deadly smallpox epidemic beginning in 1799 and lasting through 1800. As news of Jenner's discovery spread, demand for the new vaccination rose as the epidemic threatened more and more populations. The British and French vaccinated their soldiers, parents sought out medical practitioners willing to try the new vaccination, and doctors corresponded continuously about the best ways to ship, store, and preserve vaccine. The felicitous timing of Jenner's publication in 1798– on the threshold of a major epidemic – propelled vaccination to public attention and accelerated its adoption around the world.

Vaccine supply

One of the main obstacles to the rapid adoption of vaccination was supply. Cowpox was quite rare: it appeared sporadically in only a few counties in England, northern Italy, France, and Germany. Getting cowpox to vaccinators around the globe presented enduring challenges, especially since vaccine production remained decentralized and haphazard through much of the 19th century. Vaccinators borrowed some techniques already refined by inoculators. They placed threads across the vaccination pustule to absorb the fluid and then let them dry. These threads were sent in letters to new vaccinators around the world who inserted them into an incision made on a patient's arm. They tried storing vaccine fluid in glass tubes or between plates of glass that were sealed in wax. The most successful method was to harvest vaccine lymph directly from the vaccine site and insert it into the arm of a healthy individual, a process referred to as arm-to-arm transmission. This technique was used to get vaccine across oceans and into tropical climates where the heat frequently destroyed the active qualities of vaccine.

Despite these efforts, an efficacious supply of cowpox often disappeared. In response, charities, local governments, and entrepreneurial medical practitioners established clinics or dispensaries to maintain a continuous chain of vaccination. In London, the Royal Jennerian Society (later the National Vaccine Institution) created vaccination houses across London where children were vaccinated and then asked to return 6 to 10 days later in order to harvest vaccine. The lymph collected from London's children supplied the world with vaccine: in 1810, the National Vaccine Institution reported that 2,087 individuals had been vaccinated in London, and that 19,685 charges of vaccine matter had been sent to 3,973 applicants.¹⁷ Similar institutes were created in Paris and in French provincial towns. The Spanish colonial government, for its part, mandated the establishment of vaccination houses throughout its empire. Local practitioners maintained their own supply through arm-to-arm transmission and other storage techniques, and when their supply disappeared they sent for new vaccine from London, Paris, or other vaccination centers.¹⁸

Humans continued as the primary medium for cultivating vaccine until the mid-19^th century, when calves and later sheep and water buffaloes were used to cultivate vaccine by inserting cowpox in long scratches on the animals' sides. Approximately four days after insertion, lymph was harvested from the animals. By 1900, it became common to add glycerol to prevent bacterial infections in the vaccinating lymph.¹⁹ The shift to animal production and the addition of an anti-bacterial agent decreased the occurrence of the transmission of syphilis through vaccine—a horrendous side effect that fueled opposition to vaccination.

Ever since Jenner's first publication, vaccination had provoked a strong backlash, especially in countries like England where smallpox inoculation had been well established. Jenner became the butt of satire and anger: cartoonists depicted vaccinated patients sprouting bovine features, and publicists decried the practice of inserting an animal disease into a human. Some of the religious arguments against smallpox inoculation—that it went against divine providence—resurfaced, and the reservations about whether it was moral to infect a healthy individual continued to haunt medical ethicists. The introduction of compulsory vaccination beginning in the first decades of the 19^th century further fueled anti-vaccination movements and remains a strongly divisive issue as shown in the recent debates about school mandates for HPV vaccine.

Global visions

The Smallpox Eradication Campaign (SEP) was a high point of idealism in the gloom of the Cold War, but the idea of using vaccination to rid the world of a dread disease stems from Jenner and his contemporaries. They saw the potential for vaccination to eliminate smallpox completely – from communities, countries, and eventually the entire world. Many shared their optimism and in the early 1800s, vaccination became interwoven with European colonial ambitions.

Jenner himself strove to get cowpox to India and other British colonies, and the British Navy strongly encouraged vaccination of its sailors by providing vaccine to its far-flung naval hospitals. King Charles IV of Spain commissioned an ambitious expedition to vaccinate populations across the global Spanish empire, sending the surgeon Francisco Javier de Balmis with a group of 40 orphans to keep the vaccine alive across the Atlantic ocean, through Central and South America, and eventually to the Philippines.²⁰ And beginning in 1803, the Central Vaccine Committee in Paris furnished glass tubes containing vaccine to ships bound for French colonies, a practice made mandatory by the Minister of Sea in March 1819.¹³

The adoption of vaccination, of course, is a much more complicated story than the imposition of a medical practice by colonial powers. Local leaders, mothers and midwives, and indigenous healers all contributed to the spread of vaccination and their stories are only beginning to be told. And yet, Jenner's optimism about the potential of vaccination to improve the human condition continues to this day. “The numbers who have partaken of its benefits throughout Europe and other parts of the globe are incalculable,” Jenner wrote in 1801, “ and it now becomes too manifest to admit of controversy, that the annihilation of the Small Pox, the most dreadful scourge of the human species, must be the final result of this practice.”²¹

Disclosure of potential conflicts of interest

The author reports no conflicts of interest.

Acknowledgments

I would like to thank Paul Lucier for his insightful comments on an earlier draft.

Funding

This work was supported by National Library of Medicine grant 5 G13 LM 011206-02.