When assessing scientific evidence, I always recommend to my students that they be mindful of the hierarchy of evidence. That hierarchy places scientific level in different levels, beginning with the lowest or most subjective all the way to the highest or most objective. At the top of that hierarchy is evidence found in scientific studies such as systematic reviews or meta-analyses of randomized controlled trials (RCT). At the bottom is expert opinion, or even some case series (not to be confused with cohort studies). A case series is a report from an investigator — or team of investigators — describing in detail a series of cases of a disease or condition including any observations made when the case-patients received an intervention. While case series are toward the bottom of the hierarchy, they are usually the “canary in the coalmine” when it comes to identifying some new disease or even a new treatment.
That is exactly what Edward Jenner was aiming for when he published his observations of 23 case-patients in 1798, all of whom received inoculations with cowpox in an attempt to immunize them against smallpox. At the time, smallpox was known as a disease that would travel the world in periodic epidemics, causing up to 30% of those who acquired to die. Those who did not die would be immune for life, leading to the practice of inoculation with smallpox under the supervision of a physician to acquire immunity, though not without some consequences of the disease. Jenner changed the paradigm by inoculating patients with cowpox, a disease that caused mild symptoms and virtually no deaths but still provided protection against smallpox.
The first case is identified as Joseph Merret. Of him, Jenner writes:
“Joseph Merret, now an under gardener to the Earl of Berkeley, lived as a servant with a farmer near this place in the year 1770, and occasionally assisted in milking his master’s cows. Several horses belonging to the farm began to have sore heels, which Merret frequently attended. The cows soon became affected with the cow-pox, and soon after several sores appeared on his hands. Swellings and stiffness in each axilla followed, and he was so much indisposed for several days as to be incapable of pursuing his ordinary employment. Previously to the appearance of the distemper among the cows there was no fresh cow brought into the farm, nor any servant employed who was affected with the cow-pox.
In April, 1795, a general inoculation taking place here, Merret was inoculated with his family; so that a period of twenty-five years had elapsed from his having the cow-pox to this time. However, though the variolous matter was repeatedly inserted into his arm, I found it impracticable to infect him with it; an efflorescence only, taking on an erysipelatous look about the centre, appearing on the skin near the punctured parts. During the whole time that his family had the smallpox, one of whom had it very full, he remained in the house with them, but received no injury from exposure to the contagion.
It is necessary to observe that the utmost care was taken to ascertain, with the most scrupulous precision, that no one whose case is here adduced had gone through the smallpox previous to these attempts to produce that disease.
Had these experiments been conducted in a large city, or in a populous neighbourhood, some doubts might have been entertained; but here, where population is thin, and where such an event as a person’s having had the smallpox is always faithfully recorded, as risk of inaccuracy in this particular can arise.”
At the time, nothing was known about viruses. Theories were discussed in scientific circles on what caused smallpox and other similar diseases, but no one had solidified Germ Theory. No one had even seen a bacterium through a microscope yet. (That would happen in the 1800s.) But those same observant people who had documented how smallpox was transmitted came to include Jenner, and his observations on milkmaids who acquired cowpox but not smallpox led to his experimentation, first with James Phipps, and then with other people, as he wrote in his first treatise on the subject. With Joseph Merret and the other case-patients, Jenner’s experimentation with James Phipps was confirmed.
Case #17 is James Phipps:
“The more accurately to observe the progress of the infection I selected a healthy boy, about eight years old, for the purpose of inoculation for the cow-pox. The matter was taken from a sore on the hand of a dairymaid [Footnote: From the sore on the hand of Sarah Nelmes. See the preceding case.], who was infected by her master’s cows, and it was inserted, on the 14th of May, 1796, into the arm of the boy by means of two superficial incisions, barely penetrating the cutis, each about half an inch long.
On the seventh day he complained of uneasiness in the axilla, and on the ninth he became a little chilly, lost his appetite, and had a slight headache. During the whole of this day he was perceptibly indisposed, and spent the night with some degree of restlessness, but on the day following he was perfectly well.
The appearance of the incisions in their progress to a state of maturation were much the same as when produced in a similar manner by variolous matter. The only difference which I perceived was in the state of the limpid fluid arising from the action of the virus, which assumed rather a darker hue, and in that of the efflorescence spreading round the incisions, which had more of an erysipelatous look than we commonly perceive when variolous matter has been made use of in the same manner; but the whole died away (leaving on the inoculated parts scabs and subsequent eschars) without giving me or my patient the least trouble.
In order to ascertain whether the boy, after feeling so slight an affection of the system from the cow–pox virus, was secure from the contagion of the smallpox, he was inoculated the 1st of July following with variolous matter, immediately taken from a pustule. Several slight punctures and incisions were made on both his arms, and the matter was carefully inserted, but no disease followed. The same appearances were observable on the arms as we commonly see when a patient has had variolous matter applied, after having either the cow–pox or smallpox. Several months afterwards he was again inoculated with variolous matter, but no sensible effect was produced on the constitution.
Here my researches were interrupted till the spring of the year 1798, when, from the wetness of the early part of the season, many of the farmers’ horses in this neighbourhood were affected with sore heels, in consequence of which the cow–pox broke out among several of our dairies, which afforded me an opportunity of making further observations upon this curious disease.
A mare, the property of a person who keeps a dairy in a neighbouring parish, began to have sore heels the latter end of the month of February, 1798, which were occasionally washed by the servant men of the farm, Thomas Virgoe, William Wherret, and William Haynes, who in consequence became affected with sores in their hands, followed by inflamed lymphatic glands in the arms and axillae, shiverings succeeded by heat, lassitude, and general pains in the limbs. A single paroxysm terminated the disease; for within twenty–four hours they were free from general indisposition, nothing remaining but the sores on their hands. Haynes and Virgoe, who had gone through the smallpox from inoculation, described their feelings as very similar to those which affected them on sickening with that malady. Wherret never had had the smallpox. Haynes was daily employed as one of the milkers at the farm, and the disease began to shew itself among the cows about ten days after he first assisted in washing the mare’s heels. Their nipples became sore in the usual way, with bluish pustules; but as remedies were early applied, they did not ulcerate to any extent.”
Edward Jenner would go on to write two more treatises on cowpox inoculation as immunization against smallpox, and his theories would gain traction all over the world, leading to widespread use of cowpox as immunization by the Spanish and the British, and then other world governments. In the United States, the government of Massachusetts would require smallpox vaccination for school admissions beginning in the 1850s. By 1979, smallpox was eradicated as a disease. Today, very few people get the vaccine, including scientists studying other pox viruses and national defense personnel getting it just in case there is an accidental release from the two known stockpiles held by the United States and Russia.
You can read Jenner’s treatises here: https://biotech.law.lsu.edu/cphl/history/articles/jenner.htm