Heading almost due west from London, the train passes city outskirts and urban fringe housing before the landscape becomes progressively more suburban, replete with upscale homes for those commuting between Bristol and the capital. Travel slightly farther north, and the surroundings quickly become quite rural. Here, within Gloucestershire County, approximately 150 kilometers from London, lying in the valley formed by the east bank of the River Severn, is the 1,200-year-old, bucolic town of Berkeley. Being there, one feels immediately transported back to an earlier time—the eighteenth century—in which local medical practitioners like Edward Jenner rode on horseback to their appointed rounds, gathering afterwards for informal discussions of their cases at The Ship tavern—itself already 200 years old at the time—over lunch and beer.

Although he was not the most famous resident of Berkeley when he returned there in 1773—King Edward II was murdered at Berkeley Castle in 1327—Jenner would later become the town’s favorite son. As was customary for aspiring physicians in the early eighteenth century, Jenner apprenticed with rural practitioners throughout his teenage years before going to London in 1770 to study for three years under John Hunter, the master surgeon and physiologist, at St. George’s Hospital.¹ That Hunter placed high value on experimental science—so much so that he acquired both gonorrhea and syphilis in the course of self-experimentation—was illustrated in his mentorship of Jenner.² Based on Hunter’s sage advice—“why think, why not trie [sic] the Expt.”—Jenner pursued a number of interests in natural science in addition to medicine; he was elected to Fellowship in the Royal Society in 1789—not for medical research—but for his observations involving the nesting behaviors of the hatchling cuckoo.³

Smallpox—“variola”—the most historically significant infectious disease in terms of overall human deaths and social impact—was a major source of morbidity and mortality in Jenner’s time. Variolation—the deliberate inoculation of pus or scabs from smallpox-infected individuals into healthy ones in order to produce a localized form of infection—appeared to afford some protection against full-blown disease and had been practiced sporadically for more than a century in various parts of the world including Egypt, Africa, India, and China.⁴ It was introduced into the West—England—by Lady Mary Wortley Montagu, the wife of the British Ambassador to the Ottoman Court, in 1721.

However, acceptance of variolation was limited in England due its high rate of complications, substantial death rate—albeit significantly lower than that of naturally acquired smallpox, cost, and risk of contagion. Although variolation was used to quell a smallpox epidemic in colonial Boston and later to prevent outbreaks in General Washington’s Continental Army, there remained an urgent need for a safe, broadly applicable method of smallpox prevention. Enter Jenner—then living in a rural, farming town with more cows than people.

The dairy cow was of critical economic import in eighteenth century English agricultural communities. The “Old Gloucester” breed, reddish mahogany in color with variable white markings and a white stripe on its back was built for dairy work—yielding an average of 500 gallons of milk per day in Jenner’s time.⁵ Although the Gloucester had probably grazed in Berkeley for half a millennium, the animal was on the verge of achieving fame for something only peripherally related to its primary use—the lesions, due to the disease cowpox, that affected its udder and teats, would be the future basis of immune protection against smallpox. For this feat, Pasteur suggested that the term “vaccination,” derived from vacca—Latin for cow, be used to describe immunization against any infection, nearly a century after that animal played a pivotal role in the development of smallpox vaccine.

The potential protective effect of cowpox against smallpox was the stuff of well-known, popular lore among English farmers. Milkmaids generally had unblemished complexions, presumably protected from the scarring caused by smallpox blisters by virtue of a previous bout with cowpox on their hands—acquired from milking infected cows. Benjamin Jesty, a tenant farmer in Yetminster, turned such anecdotes into action in 1774, inoculating his wife and two children with material acquired from cowpox lesions using stocking needles during a local smallpox outbreak; his act—although controversial in the small town—may have protected the trio and eventually led to Jesty being credited as the “pioneer vaccinator against smallpox”.⁶ Jenner would have known about the folklore surrounding the preventive properties of cowpox, and his “Hunterian” training in the scientific method may have influenced him to experimentally study the concept.⁷

With this background, Jenner prepared a systematic study of the issue. He published his findings—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—at his own expense in 1798, after an initial paper had been rejected by the Royal Society.⁸ The work contains a series of twenty-three case histories—some involving more than one individual and others based solely on second-hand knowledge—detailing epidemiological as well as experimental evidence of the protective effect of cowpox against smallpox.⁹ Natural cowpox infection of seventeen individuals prevented their subsequent ­successful variolation—in one case more than forty years later; two individuals with previous cowpox infection resisted smallpox upon exposure to active cases of the disease.

The remaining case histories in the Inquiry comprised Jenner’s uncontrolled inoculation experiments using cowpox. These involved some of the most memorable characters—human and bovine—in vaccine history. Using material obtained from a “large pustulous sore” on the hand of dairymaid Sarah Nelmes, who had been infected by milking “Blossom,” an Old Gloucester breed of cow, he inoculated James Phipps, a healthy 8-year-old neighborhood boy via two superficial incisions on the arm in May 1796. Six weeks later—a month after the boy had recovered from the acute cowpox infection—Jenner variolated him in standard fashion and noted a stereotypical lesion on the arm, but no systemic response.

In 1798, after a hiatus necessitated by a lack of infected animals in the community and following a fortuitous outbreak of cowpox among the local dairy farms that provided more material for study, Jenner again carried out a series of similar vaccinations in children. In these ‘experiments,’ he not only demonstrated resistance to subsequent variolation in some cases but also showed that cowpox—the immunizing agent—could be successfully transmitted from arm to arm through successive generations. This latter finding raised the possibility—still years away from reality—of vaccination without the continuous need for an animal intermediary.

Jenner’s Inquiry provided the first experimental data to support the popular belief that cowpox infection represented a potentially viable and safer alternative to variolation for the prevention of smallpox. Perhaps most significantly, it represented the first scientific study of the use of an altered form of an infectious agent of animals to provide cross-protection against a related, human pathogen. Jenner’s observations were subsequently confirmed and extended by a variety of investigators and by the early part of the nineteenth century, the concept had disseminated throughout Europe and into the United States—with millions vaccinated. Jenner had opened the door to vaccination; 85 years later, Pasteur would step through it.

While Jenner exploited observations from nature to develop a means of vaccine prevention, Pasteur extrapolated observations from the laboratory towards the same end. In an ironic nod to his own axiom concerning chance favoring the prepared mind, Pasteur serendipitously discovered the phenomenon of attenuation—weakening of microorganisms through laboratory manipulation—and envisioned this as a vaccine strategy.

In 1879, he observed that after successive generations of serial passage in culture—in the presence of elevated temperatures and oxygen—the chicken cholera bacillus—now known as Pasteurella spp.—lost its capacity to cause death when injected into chickens. Because chickens were a scarce laboratory resource, Pasteur was forced to recycle the same animals in subsequent experiments using freshly passed and highly virulent strains of bacteria. Remarkably, the chickens that had previously been exposed to and survived injection with the weakened—attenuated—bacilli also survived infection with virulent strains; however, naïve chickens—those that had not been previously exposed to the weaker bacilli—rapidly died upon challenge.¹⁰ He surmised that the attenuated bacteria induced protection in the animal, allowing it to survive a challenge from virulent forms of the same bacteria.

Pasteur, always prescient, recognized that such laboratory-induced “artificial attenuation” could replace the difficult task of identifying naturally attenuated microorganisms, such as Jenner’s cowpox. He also understood that this phenomenon would revolutionize vaccine science, and this it did, initiating a new epoch in the battle against communicable diseases—one in which the microbiology laboratory performed a pivotal function. Armed with such knowledge, Pasteur rapidly developed effective, attenuated vaccines against anthrax—a zoonotic disease of immense economic importance at the time—in 1881 and rabies—a frightening and otherwise uniformly lethal disease acquired from the bite of an infected—rabid—animal in 1885. A quarter of a century later, Albert Calmette and Camille Guérin, working at the Institute Pasteur in Lille, returned to the cow as a source for another microbe—a bovine strain of tuberculosis—that could be “artificially attenuated” in the laboratory and developed as a vaccine11 Bacille Calmette–Guérin—BCG—is still in use today in many parts of the world as a relatively effective vaccine against human tuberculosis.