Epidemiologic Reviews Copyright © 1992 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved

Vol. 14, 1992 Printed in U.S.A.

Not Just a Country Doctor: Edward Jenner, Scientist

Warren Winkelstein, Jr.

INTRODUCTION

In Somalia, East Africa, in October 1977, the last naturally occurring case of smallpox was registered (1). This ended a 10-year effort based on an epidemiologic strategy and implemented by the World Health Organization. Two years later, a Commission of the World Health Organization declared the worldwide eradication of smallpox accomplished (1, p. ix). This had been predicted in 1801 by Edward Jenner, the discoverer of vaccination, when he wrote, " . . . 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" (2, p. 8). In the foreword to the World Health Organization documentation of the history of smallpox and its eradication, the Secretary General described Jenner as, Received for publication April 2, 1991, and in final form August 13, 1991. From the Epidemiology Program, Department of Biomedical and Environmental Health Sciences, School of Public Health, University of California at Berkeley, Berkeley, CA. Reprint requests to Dr. Warren Winkelstein, Jr., School of Public Health, University of California at Berkeley, Berkeley, CA 94720. This review was prepared during the author's sabbatical leave in the Department of Epidemiology and Population Statistics of the London School of Hygiene and Tropical Medicine, London, England. Many of the references were obtained from the Reece Collection housed in the library of the London School. Additional material was obtained from the Hunterian Museum and the libraries of the Royal College of Surgeons of England and the Royal College of Physicians. Special thanks are given to Mary Gibson and John Eyers of the library staff of the London School of Hygiene and Tropical Medicine, Elizabeth Allen, curator of the Hunterian Museum, and Terry Parker, archivist of the Wellcome Library of the Royal College of Physicians, all of whom provided valuable guidance, assistance, and advice in the preparation of this review.

" . . . an English country doctor . . . " (1, p. vii). Most epidemiologists, and students of the field, look upon Jenner as a clever country doctor who, having observed that milkmaids who had suffered from cowpox didn't get smallpox, got the bright idea to artificially infect persons with cowpox to protect them from subsequent infection with smallpox. However, Jenner was much more than a clever country doctor, and it was those other attributes and accomplishments that made possible the establishment of vaccination on a scientific basis at the end of the 18th century. In fact, there is substantial evidence that at least five other practitioners recognized the protective effect of prior cowpox infection, and some of them even performed vaccination before Jenner's classic publication (3, p. 37). However, these practitioners worked on a pragmatic basis rather than as the result of a thorough scientific inquiry and did not record their observations in the scientific literature of the day. Because of Jenner's importance in the history of public health and epidemiology, it seems desirable that epidemiologists and students of the field be acquainted with the larger scope of his scientific background and achievements. It is the purpose of this communication to provide some of that information. Jenner's investigations of the protective effect of natural and artificial cowpox infection were first published in 1798 when he was 49 years of age (4). However, he had already been a member of the prestigious Royal Society of London for 9 years. His election to the Society in 1789 resulted from investigations far afield from the accomplishment for which he is usually remembered. His work on the anatomy and nest

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behavior of baby cuckoos is a remarkable example of an observational field study in the discipline of natural science. Nor was this the only important investigation which Jenner conducted before his most renowned work. It may be said that the publication of An Inquiry into the Causes and Effects ofthe Variolae Vaccinae, a Disease Discovered in Some of the Western Counties of England, Particularly Gloucestershire, and Known by the Name of the Cow Pox (4) was the culminating accomplishment of a thoroughly trained and experienced scientist. In support of this assertion, let us first examine Jenner's career prior to the publication of the "Inquiry" and then consider his investigation of cowpox vaccination. TRAINING AND EARLY ACCOMPLISHMENTS

Jenner was the son of a clergyman and grew up in Gloucestershire, a rural county in the west of England bordering Wales. We are told by his contemporary, friend, and biographer, Dr. John Baron, that even as a child he showed an interest in nature, collecting the nests of field mice and searching the area for fossils (5, p. 3). After completing grammar school he studied medicine with an eminent Gloucestershire surgeon. In 1770, at the age of 21 years, he went to London to study surgery under the tutelage of John Hunter. He stayed in London a little more than 2 years, living in Hunter's home. It is apparent that his contact with Hunter, and the subsequent relationship that lasted throughout Hunter's life, had a profound impact on Jenner.

ogy. Hunter's curiosity was insatiable. He studied such disparate species as whales and honey bees; such varying functions as color blindness in humans and the hibernation of hedgehogs; and he created a museum in which the exhibits illustrated his theories of adaptation of structure to function (6). This museum, at Hunter's death, comprised more than 14,000 exhibits, a substantial portion of which still exist despite considerable bomb damage during World War II. The Hunterian Museum may be visited today at the Royal College of Surgeons of England in Lincoln's Inn Fields. Jenner was certainly employed in the preparation of specimens for the museum. An example of Jenner's expertise is demonstrated in specimen 3376A in the Hunterian Museum (figure 1), a gift from Jenner to Hunter subsequent to his student period. This specimen shows, in section, the ovary and oviduct of a cuckoo containing a partially developed egg (6, p. 31). When Captain James Cook returned from his first voyage of exploration in 1771, the expedition's naturalist, Sir Joseph Banks, brought the specimens which he had collected to Hunter for sorting and classification. Hunter assigned Jenner to the task. Both Hunter and Banks were sufficiently satisfied with the results to recommend that Jenner be appointed naturalist for Cook's subsequent expedition. Although Jenner refused the offer and returned to Gloucestershire to take up a country medical practice, he retained the interest of Banks, an important and influential contact, and carried on a scientific collaboration with Hunter as well as maintaining a close personal friendship (5, pp. 6-7).

Study with John Hunter

When Jenner became his student, Hunter had already received recognition for substantial scientific accomplishments by election to the Royal Society in 1767. Although he is sometimes referred to as the father of scientific surgery and was recognized during his lifetime, and long afterwards, for his outstanding contributions to this field, he was also renowned and is remembered for his contributions to what would now be termed comparative anatomy and physiol-

Hunter's letters to Jenner

The evidence for Jenner's relationship with Hunter is based on the series of letters which Hunter addressed to him from shortly after his departure from London in 1772 until 2 months before Hunter's death in 1793. Jenner kept these letters and many have come down to us as original autographs (7). These, and others, have been extensively cited by Baron. Unfortunately, almost all of Jenner's letters to Hunter have disappeared.

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2nd, but probably written in the mid-1770s, Hunter wrote: Dear Jenner I received yours in answer to mine, which I should have answered . . . . I thank you for your experiment on the hedge-hog; but why do you ask me a question, by the way of solving it. I think your solution is just; but why think, -why not try the experiment. Repeat all the experiments upon a hedge-hog as soon as you receive this, and they will give you the solution . . . (5, P. 33).

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Apparently Hunter was an inspiring teacher who numbered among his more prominent pupils three Americans, P. S. Physic, W. Shippen, and J. Morgan, all of whom played an important role in the promotion of medical education in the United States (6, p. 1). According to Baron: Mr. Hunter never damped the ardour of a pupil, by suggesting doubts or difficulties: on the contrary, as was usual with him on all occasions when the matter in hand admitted of being brought to the test of experiment; he advised that trial should be made, and that accuracy and faithfulness should guide the investigation . . . (5, p. 124).

FIGURE 1. Specimen 3376A, Hunterian Museum. The catalogue description is as follows: "The posterior half of a hen Cuckoo (Cuculus canorus), showing the single left ovary and oviduct at the period of full functional activity. One ovum has already been shed from the ovary and has reached the terminal or uterine segment of the oviduct within which it is coated by the calcareous egg-shell. Part of the wall of this region of the duct has been cut away to expose the egg, from which a small portion of the calcareous egg-shell has been removed to show the putamen or parchment-like membrane that envelops the egg between the calcareous shell and the white. Prepared for Hunter by Edward Jenner."

That there were many and that they contained important observations is attested to by Hunter's frequent reference to them. For example, in an early letter dated only August

Most of Hunter's letters to Jenner contained requests for specimens or specific directions for particular investigations along with personal matters, such as the acquisition of paintings for their respective collections. Sometimes the ideas were jumbled together as though Hunter's mind was running far ahead of the fingers holding the pen. Thus, in an undated letter probably written not long after Jenner had returned to Gloucestershire, Hunter wrote: Dear Jenner I received your salmon and very fresh and just examined enough to want another, but wait till another season, if I was to have another, it should be one that had just spawned I will take a cock salmon when you please. If you catch any bats, let me have some of them, and those you try yourself, open a hole in the belly just size enough to admit the ball; put the ball down towards the pelvis and observe the heat there, then up towards the diaphragm and observe the

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heat there, observe the fluidity of the blood, do all this in a cold place. Extraneous fossils are all vegetable and animal productions found in a fossil state, see if you can catch the number of pulsations, and the frequency of breathing in the bat without torture. If the frost is hard, see what vegetables freese, bore holes in large trees, and see whether the sap runs out, which will show it is not frose. I am afraid you have not a proper thermometer I will send you o n e . . . (5, pp. 30-31). Investigations of the hibernation of hedgehogs

During the years immediately after Jenner's departure from London, Hunter was engaged in intensive investigations of hibernation and temperature control. Jenner played a role in carrying out the field investigations which focused on the hedgehog, an animal easily available in rural Gloucestershire and one that overwintered by hibernation. In these investigations, Jenner sharpened his observational and analytical skills. Although Jenner never published any papers on the hibernation studies, Hunter recognized his contributions to the research and included Jenner's descriptions of certain of the experiments in his own papers on this subject published between 1775 and 1786: . . . As I was unable to procure hedgehogs in the torpid state, to ascertain their heat during that period, I got my friend Mr. Jenner, surgeon at Berkeley, to make the same experiments on that animal, that I might compare them with those in the doormouse; and his account is as follows: Experiment I. In the winter, the atmosphere at 44°, the heat of a torpid hedgehog, in the pelvis, was 45°, at the diaphragm 48°. Experiment II. The atmosphere 26°, the heat of a torpid hedgehog, in the cavity of the abdomen, was reduced as low as 30°. Experiment III. The same hedgehog was exposed to the cold atmosphere at 26° for two d a y s . . . . The hedgehog, while the heat of the stomach was at 30°, had neither desire for food, or power of digesting it; but when increased by inflammation in the abdomen to 93°, the animal siezed a toad which happened to be in the room, and upon being offered some bread and milk, it immediately ate it. The heat roused up

the actions of the animal oeconomy; and . . . the stomach was stimulated to digest. A comparative experiment was made with a puppy, the atmosphere at 50°; the heat in the pelvis, as also at the diaphragm, was 102°. In summer, the atmosphere at 78°, the heat of the hedgehog, in an active state, in the cavity of the abdomen, towards the pelvis 95°; at the diaphragm 97° (8, IV, pp. 8788, 142-143). Jenner's first independent publication was an anonymous pamphlet bearing on the preparation of tartar emetic and privately

printed in the fall of 1783. Signed copies in Jenner's handwriting are extant in the British and Manchester Museum libraries. Hunter urged Jenner to exploit this work for its financial benefits, but there is no evidence that Jenner followed this advice (9, pp. 9, 10). Investigations of the nest behavior of baby cuckoos and election to the Royal Society

In what may have been Hunter's first letter to Jenner, he wrote: Dear Jenner ... I am oblig'd to you for thinking of me especially in my Natural History. I shall be glad of your observations on the cuckow and upon the breeding of toads, be as particular as you possibly can;... (5, p. 28). Presumably, Jenner had referred to cuckoos in his previous letter to Hunter or, while Jenner was resident in Hunter's home as a student, they may have discussed the cuckoos' remarkable habit of laying its eggs in other birds' nests for nurture. At any rate, it is apparent that Jenner had a lifelong interest in birds. (Jenner's last work was on the migration of birds and was published posthumously (10).) In subsequent letters, Hunter repeatedly urged Jenner to complete his observations of these interesting birds which were then so common in Gloucestershire. The problem to be solved was why and how the foster parents' eggs and fledglings disappeared from the nest after the birth of the imposter cuckoo chick. In 1787,

Edward Jenner, Scientist

Jenner sent a paper to the Royal Society concluding that the foster parent was responsible for the exodus (9, p. 16). However, this paper was withdrawn for good reason as indicated in a letter from Sir Joseph Banks dated July 7th 1787: Sir, . . . In consequence of you having discovered that the young cuckoo, and not the parent bird, removes the eggs and young from the nest in which it is depositied, the council thought it best to give you a full scope for altering it as you choose. Another year we shall be glad to receive it again and print it. Your other papers I hope you will proceed with when your leisure allows you opportunity . . . (5, p. 77).

Jenner's revised paper, in the form of a letter to Hunter, was read to the Royal Society on March 13, 1788, and published in the Transactions for that year (11). The key passage follows: June 18, 1787, I examined the nest of a Hedge-sparrow, which then contained a Cuckoo's and three Hedge-sparrow's eggs. On inspecting it the day following, I found the bird had hatched, but that the nest now contained only a young cuckoo and one Hedge-sparrow. The nest was placed so near the extremity of the hedge, that I could distinctly see what was going forward in it; and, to my astonishment, saw the young Cuckoo, though so newly hatched, in the act of turning out the young Hedgesparrow. The mode of accomplishing this was curious. The little animal, with the assistance of its rump and wings, contrived to get the bird upon its back, and making a lodgement for the burden by elevating its elbows, clambered backward with it up the side of the nest till it reached the top, where resting for a moment, it threw off its load with a jerk, and quite disengaged it from the nest. It remained in this situation a short time, feeling about with the extremities of its wings, as if to be convinced whether the business was properly executed, and then dropped into the nest again . . . (11, p. 225).

In addition to the description of the cuckoo chicks removing eggs and fledglings from their foster parents' nests, Jenner described the expulsion of a sibling cuckoo resulting from the accidental deposition of two

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cuckoo eggs in the nest of a single foster parent as well as the anatomic peculiarity which allowed the baby cuckoo to carry the egg of its foster sibling on its back to the edge of the nest. He also speculated regarding the reasons for the complex egg laying and nest behavior of cuckoos. Hunter wrote to Jenner regarding the presentation as follows: Dear Jenner, . . . Your paper has been read, passed the council and is in print,... Sir Joseph Banks . . . will give us all his assistance; but he thinks the paper had better be first printed and delivered, and let the people rest a little upon it, -for he says there are many who cannot believe it wholly: this will put off the certificate till the beginning of the next winter, when we shall hang you up . . . (5, p. 78).

Jenner was, indeed, elected to the Royal Society on February 25, 1789. We can only infer that without the support of such prominent friends as Banks and Hunter, Jenner might not have achieved this objective. Jenner's observations on the nest behavior of cuckoos were not definitively confirmed until more than a century had passed (12, p. 25). Investigations of coronary and rheumatic heart diseases—the "Fleece" Medical Society

Jenner's observational talents were not only directed to the natural science investigations stimulated by Hunter, but also to clinical matters. In 1772, William Heberden published a clinical description of angina pectoris, and in 1773, Hunter performed an autopsy on a patient of Heberden's who had been diagnosed with the condition. Jenner was present at the dissection (9, p. 24). In 1778, Jenner reportedly wrote to Heberden regarding Hunter's medical condition which he had observed while visiting the latter in Bath in the previous year. The letter reads, in part, as follows: Sir, ... When I had the pleasure of seeing him at Bath last Autumn, I thought he was

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affected with many symptoms of Angina Pectoris. The dissections (as far as I have seen) of those who have died of it, throw but little light upon the subject . . . I have only had two opportunities of an examination after death. In the first of these I found no material disease of the heart, except that the coronary artery appeared thickened . . . : but about three weeks ago, Mr. Paytherus, . . . desired me to examine with him the heart of a person who had died of Angina Pectoris.... Here we found the same appearance of the coronary arteries as in the former case. But, what I had taken to be an ossification of the vessel itself, Mr. P. discovered to be a kind of firm fleshy t u b e , . . . , with a considerable quantity of ossific matter dispersed through it . . . . The importance of the coronary arteries, and how much the heart must suffer from their not being able to perform their functions, (we cannot be surprised at the painful spasms)... it is possible that all the symptoms may arise from this one circumstance . . . (5, pp. 39-40).

After Hunter's sudden death in 1793, Everard Home, Jenner's brother-in-law and an eminent surgeon who was present at Hunter's autopsy, confirmed Jenner's diagnosis in a letter to Jenner in which he wrote: " . . . the coronary arteries of the heart were considerably ossified . . . " (5, p. 105). Jenner never published a paper on the pathology of coronary artery disease. Baron erroneously reported that he delivered a paper on this subject to the Gloucestershire Medical Society, which he had helped organize, in 1788 (5, p. 45). This Society, which has come to be known as the "Fleece" Society because of the inn where the meetings were held, was a very unusual organization. The membership and the subjects presented and discussed have been described by Proudfit (13). The Society had a membership of just five practitioners and met only five or six times during the 5 years of its existence. The minutes of the meetings and fragments of the presentations, in a manuscript folio, are extant in the library of the Royal College of Physicians (14). At the first meeting, Caleb H. Parry discussed the pathology of angina pectoris and Jenner gave the first description in the English language of mitral stenosis (14, folio 5). At the July meeting in 1789, Jenner read a paper on the

relationship of rheumatic fever to rheumatic heart disease which included pathologic observations (14, folio 6). Unfortunately, this paper has been lost. At the September 9, 1789, meeting, Thomas Paytherus reported, " . . . a case and dissection of a patient who died of the Angina Pectoris . . . " (14, folio 7). Presumably, this was the case described by Jenner in his letter to Heberden cited above. Baron's 1778 dating of that letter is thought to be 10 years premature (9, p. 18). At the June 1790 meeting, Parry presented a paper in which he described the effect of carotid sinus pressure for the control of paroxysmal tachycardia (14, folio 8). At the next meeting, held on July 28, 1790, Daniel Ludlow presented a confirmatory case of rheumatic heart disease with a postmortem examination (14, folio 9). After the scientific meetings were concluded, the members had dinner together. Jenner was reported to have contributed substantially to the entertainment. According to Baron, Jenner called the "Fleece" Society medico-convivial to distinguish it from another society to which he belonged, which he termed conviviomedical (5, pp. 45, 47). Although Jenner's most important presentation to the "Fleece" Society, his paper on rheumatic heart disease, has been lost, all or a major part of his presentation on mitral stenosis has survived in a manuscript included in the Folio at the Royal College of Physicians. The full text follows: When the Heart becomes diseased from obstructions formed within its cavities, the symptoms arising appear to be very different from those which shew themselves in the Angina Pectoris. In both Cases there is a very painful sensation about the Chest upon an excitation, but in the former the brain becomes affected and not in the latter as I have ever seen. This may easily be accounted for from the appearance on the dissection. The outlines of the following Cases will probably serve to point out this difference. A young woman for some years was afflicted with a complaint about her chest—on motion her breathing became very laborious, her countenance as livid as if the vessels of the Neck had been compressed with a cord. I have often seen her reel in passing along a room after she had

Edward Jenner, Scientist

taken a few paces, her senses, suffer a momentary suspension. She died. Another young woman became affected in a manner similar to the former. She died and I was fortunate enough to gain an inspection of the Body. The chief disease was found about the chest. The passage for the blood from the left Auricle to the left Ventricle was so contracted from ossification of the Valvula Mitrales and surrounding parts that it was with some difficulty my little finger would pass from one cavity to the other. If the blood be impeded in its progress from the left Auricle to the left Ventricle, it must, of course, when its motion becomes accelerated be accumulated in the vessels of the Head so as to compress the Brain—The check will first be given to the circulation thro' the pulmonary Veins, then the Pulmon' arteries and thus be communicated to the Vessels which pour their contents into the right (sic) Ventricle . . . (14, folio 11). The first paper delivered to the Society was later expanded by Parry into his book, An Inquiry into the Symptoms and Causes of the Syncope Anginosa, Commonly Called Angina Pectoris; Illustrated by Dissections, in which he attributes the symptoms of angina pectoris to disease of the coronary arteries (15). In the first pages of his book, he mentions his earlier presentation to the Gloucestershire ("Fleece") Medical Society and Jenner's ideas regarding the structural changes in the heart accompanying the disease. He then quotes, in its entirety, a letter from Jenner, which he had solicited, describing these views. In that letter Jenner summarizes the conclusions described previously in the quotation from his letter to William Heberden in 1778 and adds further observations and conclusions: . . . Another case of a Mr. CARTER, at Dursley, fell under my care. After having examined the more important parts of the heart, without finding any things by means of which I could account for his sudden death, or the symptoms preceeding it, I was making a transverse section of the heart pretty near its base, when my knife struck against something so hard and gritty, as to notch it. I well remember looking up to the ceiling, which was old and crumbling, conceiving that some plaster had fallen down. But on a further scrutiny the real cause appeared: The coronaries were become

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bony canals. Then I began to suspect . . . . The appearance in Mr. BELLAMY'S case gave me the idea that the disease arose from a determination to the vasa vasorum, and that the concretions were deposits from the coagulable lymph, or other fluids, which had oozed out on the surface of the artery (l,p.4). Parry is very generous in his attribution of Jenner's influence on his thinking with regard to the subject matter of his book: With these ideas of Dr. JENNER we were well acquainted in the society. Many of them were communicated to me as they arose. During their course I witnessed the remarkable case of Rev. Mr. S****, whose body after death exhibited appearances so coincident with those which from the symptoms I had expected, and relying on the accuracy of Dr. JENNER, had predicted, that I was induced to relate it to the society, with a variety of pathological remarks intended to illustrate Dr. JENNER'S position, that the Angina Pectoris was a disease of the heart, connected with malorganization of the coronary arteries (14, P-5). Clearly, by the time of Hunter's death in 1793, Jenner had achieved independent status as a scientist. Although he had only published two papers, those on tartar emetic and on the nest behavior of cuckoos, he had made substantial contributions to Hunter's research on hibernation and had provided the conceptual base for Parry's work on heart disease. Both investigators had recognized Jenner's role in their efforts. Had his lost paper on rheumatic heart disease, which presumably included his observations of mitral stenosis, been published, and had he produced a paper on his observations of the pathologic changes in the coronary arteries accompanying angina pectoris, his place in medical history would already have been established. This was, however, to result from his demonstration of the protective effect of cowpox vaccination. THE INVESTIGATION OF COWPOX AND VACCINATION Background According to Baron, Jenner's interest in the protective effect of cowpox infection was

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aroused during his medical apprenticeship before going to London to study with John Hunter. In Baron's words: -He was pursuing his professional education in the house of his master in Sodbury: a young country-woman came to seek advice; the subject of smallpox was mentioned in her presence; she immediately observed, "I cannot take that disease, for I have had the cow-pox." This incident riveted the attention of Jenner. It was the first time that the popular notion, which was not at all uncommon in the district, had been brought home to him with force and influence . . . (5, p. 121). Although Baron asserts that Jenner discussed the prophylactic effect of cowpox with Hunter during his stay in the latter's house as a student, the issue is never mentioned in any of Hunter's letters to Jenner, cited by Baron. Certainly, they discussed variolation, the practice of inoculating with material from a pustule of a smallpox case or previously inoculated person, to produce a mild case of smallpox and consequent immunity against reinfection. In Hunter's "case book", 53 of the 419 case reports are entitled "inoculation" (15). It is not clear when Jenner actually began the serious investigation of the prophylactic effects of cowpox infection. However, the critical observations appear to have been made after 1790. Before discussing these observations, a brief description of the "Inquiry" will be provided. Plan of the cowpox investigation

The 1798 publication, which was privately published by Jenner, can be considered as having three parts. The first part presents Jenner's views regarding the origin of cowpox as a disease of horses transmitted to cows. This theory was discredited during Jenner's lifetime and, reluctantly, accepted by him. It also presents the hypothesis that infection with the cowpox protects against subsequent infection by smallpox (4, pp. 18). The second part contains the critical observations relevant to testing the hypothesis. This part of the "Inquiry" is presented in the form of 23 "case reports" (4, pp. 9-

45). The third part consists of a lengthy discussion, partly polemical, of the findings and a variety of related issues (4, pp. 45-75). It may be dismissed from further consideration here as it contains nothing particularly relevant to validation of Jenner's central hypothesis. The "case reports" comprise two sequential studies. The first 16 "cases", which actually include observations on 23 persons (three of whom were reported to have been infected with the hoof disease of horses, called "grease", which Jenner mistakenly believed to be the source of cowpox), are presented to show the protective effect of cowpox. Jenner evaluated immunity to smallpox by whether or not a person could be successfully variolated or whether exposure to naturally occurring cases of smallpox resulted in disease. The last seven case reports, Cases XVII through XXIII, record the results of inoculation of cowpox into individuals who had no history of previous infection by cowpox or smallpox. The validity of Jenner's inferences depended on the accuracy with which it was determined that individuals had not had smallpox before having been either naturally or artificially infected with cowpox as well as the effectiveness of the variolation. Jenner was aware of both of these requirements. He pointed out that smallpox was relatively uncommon in the sparsely populated rural area of Gloucestershire, was readily recognized by local medical practitioners, and, therefore, unlikely to be missed (4, p. 10). Despite the fact that Jenner was an experienced variolator, he specifically reported, in Case XXIII, the simultaneous successful variolation, from the same source, of a person who had neither had smallpox or cowpox as a "control" (4, p. 43). In Case XI, he noted that, "A large party were inoculated at the same time, some of whom had the disease in a more violent degree than is commonly seen from inoculation," suggesting that Case XI had been particularly severely challenged (4, p. ?.5). It is also interesting to note that, in a footnote to Case IV, Jenner described the characteristic accelerated reaction which occurred in those immune to variolation and

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which was subsequently associated with immunity to cowpox vaccination (4, p. 13).

Observations on the protective effect of cowpox inoculation

Observations on the protective effect of natural cowpox infection

The twentieth case of cowpox in Jenner's series, numbered Case XVI in the "Inquiry", was reported to have been infected in May 1796. Jenner describes the case as follows:

Apparently, cowpox in humans was not a common occurrence. Of the 20 cases of naturally occurring cowpox reported by Jenner before the first vaccination, the earliest was reported to have occurred in 1743, and three occurred before he began his medical training in Sodbury. Clearly, Jenner did not personally diagnose many of the reported cases of cowpox. However, he explicitly reports attending seven of the 14 cases reported after 1790. Similarly, Jenner did not perform all of the validations upon which he concluded that infection by cowpox produced immunity. Presumably, he variolated, at the least, the seven cases which he personally observed after 1790. Of the 20 reported cases of cowpox included in the first 16 case reports, 18 were reported to have been immune to variolation (all validations were reported to have been performed after 1790), and one, Case V, was reported to have resisted infection by smallpox on exposure. Case XVI was neither variolated nor exposed to smallpox. Jenner also variolated or observed the results of exposure to smallpox of a number of persons, family members or close associates of persons who were included in his cowpox case series, who had no history of prior cowpox. Many of these were subsequently infected by smallpox either artificially by variolation or naturally. The exact numbers are impossible to ascertain as he frequently reported these observations collectively, as described above in Case XI, viz., "A large party were inoculated at the same time, some of whom had the disease . . . , " by which he means that they developed inoculation smallpox (4, p. 26), or, as in Case I, " . . . during the whole time that his family (i.e., the family of the under-gardner) had the Small Pox,... he remained in the house with them but received no injury from exposure to the contagion" (4, p. 10).

SARAH NELMES, a dairymaid at a Farmer's near this place, was infected with the Cow Pox from her master's cows in May, 1796. She received the infection on a part of the hand which had been previously in a slight degree injured by a scratch from a thorn. A large pustulous sore and the usual symptoms accompanying the disease were produced in consequence . . . (4, p. 31,32). Figure 2, drawn by Jenner, shows the lesion on the milkmaid's, Sarah Nelmes', hand (4, facing p. 32). The diagnosis of cowpox having been quite definitive in Case XVI and the skin lesion very typical, Jenner decided to artificially infect a person with material from the pustule on Sarah Nelmes' hand. Jenner described the procedure in Case XVII as follows: THE more accurately to observe the progress of the infection, I selected a healthy boy, about eight years old, for the purpose of the inoculation for the Cow Pox. The matter was taken from a sore on the hand of a dairymaid*, 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 (4, pp. 32-34). Jenner described the results of this, his first vaccination, as being the same as that produced by variolation except that the subject, James Phipps, complained of only mild discomfort from the seventh to the ninth day after the event. Phipps was variolated in July at which time he resisted the infection, presumably giving an immune or accelerated reaction (4, p. 34). Jenner described the event enthusiastically to his friend Edward Gardner in a letter dated July 19, 1796. Jenner wrote, in part: . . . Having never seen the disease but in its casual way before; that is, when com-

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FIGURE 2. Photocopy of the drawing, by Jenner, of the cowpox pustule on the hand of Sarah Nelmes, Case XVI, from which the first vaccination was derived.

municated from the cow to the hand of the milker, I was astonished at the close resemblance of the pustules, in some of their stages, to the variolous pustules. But now listen to the most delightful part of my story. The boy has since been inoculated for the small pox which, as I ventured to predict, produced no effect. I shall now pursue my experiments with redoubled ardour (5, p. 138).

Jenner's letter to Gardner, in part, is reproduced in figure 3. The initial and first subsequent vaccinations were from persons naturally infected with cowpox. The third vaccination, Case XIX, was performed with material obtained directly from a cow infected with cowpox. All subsequent vaccinations, reported in the "Inquiry", were serially derived from Case XIX. A total of at least 12 vaccinations were

reported. The indefinite number derives from the fact that Jenner reported in Case XXI that, " . . . several children and adults were inoculated from the arm of William Pead", who was Case XX (4, p. 39). In one case, that of his son Robert, the vaccination did not succeed in producing the typical cowpox pustule. Unfortunately, only four of those vaccinated in this series were challenged by variolation, Case XVII, James Phipps (vaccinated from the hand of Sarah Nelmes), Case XIX (vaccinated directly from a cow), Case XX (serially vaccinated from Case XIX), and Case XXIII (the last in the series). All four were reported to be immune to variolation. Successful vaccinations of the others were judged by their symptomatology and the characteristic lesions produced by the vaccinations.

Edward Jenner, Scientist

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FIGURE 3. Photocopy of part of the letter from Jenner to his friend Edward Gardner describing the results of his first cowpox vaccination.

Reaction to publication of the "Inquiry"

doubtful of the validity of the findings. They

Publication of the "Inquiry" was met with a mixed reaction in medical circles. On the one hand, there were those critical and

cited instances in which prior infection by cowpox did not protect from subsequent successful validation or acquisition of naturally occurring smallpox. Some of these

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critics were prominent physicians with extensive experience with validation (3, pp. 70, 71). On the other hand, there was considerable interest shown by other prominent variolators and important confirmation was not long in appearing. Replication of Jenner's findings regarding the prophylactic effect of cowpox infection

In 1799, George Pearson, a prominent London physician and variolator, published observations which confirmed Jenner's basic hypothesis concerning the effect of cowpox infection on the subsequent susceptibility to artificial smallpox infection (16, pp. 14-26). Pearson identified three men who were believed to have had cowpox but not smallpox and two volunteers who had never had either smallpox or cowpox. These five men were then variolated. The three who had histories of cowpox infection responded with the typical immune or accelerated reaction previously described by Jenner (4, p. 13), and the two "controls" developed typical inoculation smallpox. This may have been the first controlled clinical trial in medical history. The confirmation of the ability of inoculation (vaccination) of material from the cowpox lesion of the cow to prevent subsequent smallpox infection produced by variolation was provided by William Woodville, physician in charge of the London Smallpox and Inoculation Hospital (17, pp. 13-113). Early in 1799, Woodville observed an outbreak of cowpox in a London dairy. The affected animals, as well as a related case in a dairymaid, were shown to Sir Joseph Banks, George Pearson, and others. The lesions were compared with those described and portrayed by Jenner in the "Inquiry" and it was agreed that they conformed very closely to them (17, pp. 9-12). Woodville then vaccinated upwards of 500 persons from material obtained directly from cows in this outbreak or serially from previously vaccinated persons in the series. Details of the results of the vaccinations of the first 200 persons in this series were pro-

vided by Woodville as individual case reports and in a table. Unfortunately, the table does not indicate the results of subsequent challenge by variolation or exposure to natural infection. However, a review of the case reports reveals that of the first 22 persons vaccinated (seven from a single cow), 10 were vaccinated and variolated simultaneously or the variolation was performed within 5 days after vaccination, eight were variolated on the eleventh to the fifteenth day after vaccination, and four were exposed to active cases of smallpox during the first 15 days after vaccination. None of these individuals developed smallpox. After the twenty-second case, Woodville's report is more systematic, and he explicitly indicates that validations were carried out subsequent to vaccination on all but three persons in the series. One of these, an infant, was nursed by its smallpox-infected mother throughout her illness but did not become infected. Two persons did not develop the lesions of cowpox after vaccination, one of whom was subsequently infected by smallpox after variolation while the other reacted to neither cowpox nor smallpox inoculation. Woodville also demonstrated that cowpox could be successfully transmitted from a vaccinated person (case 10) to an uninfected cow and then back to humans to provide the source for a further series of human vaccinations (17, p. 64). Incidentally, it was Woodville who showed that "grease" could not be transmitted from horses to cows to produce cowpox as thought by Jenner (17, PP. 6, 7). The publications of both Pearson and Woodville provided substantial confirmation of Jenner's findings and established the acceptability of cowpox vaccination. Furthermore, as early as March 1799, Pearson distributed vaccine on impregnated threads to over 200 people, and later in the same year organized an "Institution for the Inoculation of the Vaccine-Pox" (3, pp. 118, 119). Woodville also became active in distributing vaccine. His initial study had clearly demonstrated the feasibility of serial vaccination on a large scale.

Edward Jenner, Scientist

Jenner's solution to certain important objections

Jenner published three sequels to the "Inquiry" (2, 18, 19). In the final paper of the series (2), in addition to the prediction of the eventual eradication of smallpox already referred to, he provides a concise explanation for the major criticisms of his findings. With respect to the observation that some persons who reported having had cowpox had subsequently suffered from naturally occurring smallpox or had acquired inoculation smallpox, he pointed out: . . . I had the satisfaction to learn that the Cow was subject to some varieties of spontaneous eruptions upon her teats; that were capable of communicating sores to the hands of the milkers; and that whatever sore was derived from the animal, was called in the dairy the Cow Pox. Thus I surmounted a great obstacle, and, in consequence was led to form a distinction between these diseases, one of which only I have denominated the true, the other the spurious, Cow Pox, as they posses no specific power over the constitution (2, p. 3). With respect to the problem that some persons who had been exposed to and acquired the "true" cowpox and subsequently developed natural or inoculation smallpox, Jenner observed: . . . I now discovered that the Virus of Cow Pox was liable to undergo progressive changes, from the same causes precisely as that of Small Pox; and that when it is applied to the human skin in its degenerate state, it would produce the ulcerative effects in as great a degree as when it was not decomposed, and sometimes far greater; but having lost its specific properties, it was incapable of producing that change upon the human frame which is requisite to render it unsusceptible of the variolous contagion: . . . (2, p. 4). Today's interpretation of Jenner's observation would be different than his, but the

conclusion would be the same, i.e., that material obtained from the cowpox lesion in the stage of resolution may not consistently generate an immune response. Throughout the subsequent history of vaccination, the

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inconsistency of response to the insertion of vaccine virus was a problem. Thus, it was common practice in modern times to "read" the results of vaccination on the fourth to seventh day to ascertain whether a "take" had occurred, i.e., whether the vaccination had resulted in a primary, immune, or no response at all, in which case vaccination was repeated (20, p. 353). DISCUSSION

Jenner's major scientific contributions, the observations of the nest behavior of cuckoos, and the prophylactic effect of cowpox infection drew doubt and criticism during his lifetime and long thereafter. Charles Creighton, author of the prestigious A History of Epidemics in England, writing in the 1880s, summarized the cuckoo paper, in a separate book on Jenner, as follows: "Jenner's cuckoo paper contains a few credible and prosaic facts; but the greater part of it, and all that part of it which is best remembered, is a tissue of inconsistancies and absurdities" (21, p. 17). Regarding inoculation of cowpox, Creighton had this to say: "We may now sum up the contents of the famous Inquiry . . . . The proofs that there existed a genuine and a spurious cowpox, were both disingenuous in motive and puerile in effect. The proof of the main thesis, the protection from smallpox, was disgracefully scamped, even assuming that experiments were valid for proof. The average experiences of Gloucestershire milkers were ignored only such cases as supported the notion were adduced, and these were set forth in such loose and meagre fashion as to be worthless according to any strict standard of evidence . . . . Jenner's contemporaries had not the means which we now have of detecting all this laxity and dishonesty . . . " (21, pp. 7577). As late as 1935, Major Greenwood, distinguished professor of epidemiology and biostatistics at the London School of Hygiene and Tropical Medicine, described the "Inquiry" as follows: "I think that anybody . . . would have no difficulty in reaching the conclusion that it was not a 'masterpiece of

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medical induction' but just the sort of rambling, discursive essay, containing acute observations mixed up with mere conjectures, which an unsystematic field naturalist might be expected to produce . . . " (22, p. 254). Greenwood's characterization of Jenner was contradictory and not very complementary, viz., " . . . the vain imaginative, loosethinking person had, blunderingly and rashly, reached a true conclusion" (22, p. 273). Nevertheless, Greenwood concludes his 45 page discussion of Jenner and vaccination with the statements that " . . . Jenner was, directly or indirectly, the means of saving many hundreds of thousands of lives" and " . . . quite enough to entitle Englishmen to take pride in the recollection that Jenner was their countryman" (22, p. 287). The first 15 "case" reports of Jenner's "Inquiry" can be considered analogous to an historic cohort study. Jenner identified a series of persons who had been infected with the cowpox (exposed) and were, thereby, hypothesized to be resistant to infection by smallpox. Concurrently, he identified persons associated with each case who had not been infected with cowpox (unexposed). He then compared the exposed, presumed immune, to the unexposed, presumed susceptible, with respect to the subsequent development of smallpox as a result of either natural exposure or variolation. From his observations, he inferred that artificial infection with cowpox would be safe and would effectively prevent subsequent infection by smallpox. The last seven "case" reports, which then follow, and which demonstrated that inoculation with cowpox protects against inoculated smallpox, are analogous to a "phase I" clinical trial in which the safety and limited efficacy of the prophylactic procedure is evaluated. It is impossible to determine whether Jenner selectively omitted from his series cases of cowpox which subsequently developed smallpox by natural or artificial exposure. He did, however, recognize that the occurrence of such cases was inconsistent with his theory and he provided an explanation for them (2, p. 3). Furthermore, his rejection of such cases as a refutation of his

hypothesis and his search for an explanation for them was based on the following observation: ... but reflecting that the operations of nature are generally uniform, and that it was improbable that the human constitution (having undergone the Cow Pox) should in some instances be shielded from the Small Pox, and in many others remain unprotected, I resumed my labours with redoubled ardour (2, p. 3). Jenner's findings were promptly replicated by Pearson and Woodville. Within 5 years of the publication of the "Inquiry", it had been translated and published in German, French, Dutch, Italian, and Latin versions. In Germany alone it was reported that 17,000 vaccinations were performed in 1803, of which 8,000 were tested by variolation and judged to have produced immunity (23, p. 277). Cowpox vaccination for the prevention of smallpox infection was, of course, never evaluated by anything close to a rigorous field trial. But then, it was almost 100 years after Jenner's publication of the "Inquiry" before another vaccine was developed (Pasteur's antirabies vaccine) and 52 years more before the first effective live attenuated viral vaccine was discovered (chick embryo attenuated yellow fever vaccine) (24). It was only after the field trial of inactivated poliovirus vaccine, in 1954, that rigorous double-blind field trials became the desired standard for evaluating vaccine efficacy (25). CONCLUSIONS

This brief review of Jenner's career reveals a series of scientific accomplishments unlikely to be attributable to a person without a thorough scientific training and a long experience in the observation and interpretation of natural phenomena. His observations of the nest behavior of baby cuckoos and his largely unrecognized role in the early elucidation of the pathophysiology of coronary and rheumatic heart diseases are further indications of the breadth of his interests and his astute observational power. That he had detractors in his own lifetime and

Edward Jenner, Scientist

long thereafter is not a particularly unusual phenomenon. Were Jenner's scientific accomplishments epidemiologic and, therefore, deserving of review here? His observations of the nest behavior offledglingcuckoos and his limited observations of the pathology of coronary and rheumatic heart disease do not qualify as epidemiologic, although they were certainly rigorous and scientific. However, his observations of the protective effect of prior cowpox infection against subsequent smallpox infection are clearly population based, even though the numbers of observations were limited. The purpose of this review is to provide epidemiologists with a new appreciation of the background for the accomplishments of Edward Jenner which have had such a profound and worldwide impact on public health. Finally, it is hoped that you will agree that Edward Jenner was not just an "English country doctor", but, indeed, was a true "scientist".

8. 9. 10. 11. 12. 13. 14.

15.

16.

17. 18.

REFERENCES 1. Fenner F, Henderson DA, Arita I, et al. Smallpox and its eradication. Geneva, Switzerland: World Health Organization, 1988. 2. Jenner E. The origin of the vaccine inoculation. London, England: D. N. Shury, 1801. 3. Baxby D. Jenner's smallpox vaccine: the riddle of vaccinia virus and its origin. London, England: Heinemann Educational, 1981. 4. Jenner E. 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. London, England: Sampson Low, 1798. 5. Baron J. The life of Edward Jenner. London, England: Henry Colburn, 1827-1838. 6. Allen E. Hunterian Museum. London, England: Royal College of Surgeons of England, 1974. 7. Cornelius EH, Rains AJH, eds. Letters from the past: from John Hunter to Edward Jenner. London,

19. 20. 21. 22. 23. 24. 25.

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England: Royal College of Surgeons of England, 1976. Palmer JF, ed. The works of John Hunter. London, England: Longman, Rees, Orme, Brown, Green, and Longman, 1835. LeFanu WR. A bio-bibliography of Edward Jenner, 1749-1823. London, England: Harvey and Blythe, 1951. Jenner E. Some observations on the migration of birds. London, England: William Nicoll, 1824. Jenner E. Observations on the natural history of the cuckoo. Philos Trans R Soc Lond 1788;78: 219-37. Lancum FH. Photographs illustrating the various stages of the eviction process. Proc Linnean Soc 1929-1930,142:25. Proudfit WL. The Fleece Medical Society. Br Heart J 1981;46:589-94. Parry CH. An inquiry into the symptoms and causes of the syncope anginosa, commonly called angina pectoris; illustrated by dissections. London, England: Cadell and Davies, 1799. Turk JL, Allen E. The influence of John Hunter's inoculation practice on Edward Jenner's discovery of vaccination against smallpox. J R Soc Med 1990; 83:266-7. Pearson G. An inquiry concerning the history of the cow pox principally with a view to supercede and extinguish the smallpox. London, England: Johnson, 1798. Woodville W. Reports of a series of inoculations for the variolae vaccinae or cow-pox. London, England: Phillipps, 1799. Jenner E. Further observations on the variolae vaccinae. London, England: Sampson Low, 1799. Jenner E. A continuation of facts and observations relative to the variolae vaccinae or cow pox. London, England: Sampson Low, 1799. Benenson AS, ed. Control of communicable diseases in man. 14th ed. Washington, DC: American Public Health Association, 1985. Creighton C. Jenner and vaccination: a strange chapter of medical history. London, England: Sonnenschein, 1889. Greenwood M. Epidemics and crowd-diseases; an introduction to the study of epidemiology. London, England: Williams & Norgate, 1935. Dixon CW. Smallpox. London, England: J and A Churchill, 1962. Smith HH, Penna HA, Paoliello A. Yellow fever vaccination with cultured virus (17D) without immune serum. Am J Trop Med 1938; 18:437-68. Francis T Jr, Napier JA, Voight RB, et al. Evaluation of the 1954 field trial of poliomyelitis vaccine; final report. Ann Arbor, MI: National Foundation for Infantile Paralysis, 1957.