The Jenner bicentenary; still uses for smallpox vaccine

Edward Jenner performed his first vaccination, on James Phipps, on 14 May 1796 [1,2]. The centenary of that event was celebrated [3] rather than that of the publication of Jenner's famous Inquiry of 1798 [1], and that precedent is generally being followed for the bicentenary [4]. We are marking the bicentenary by publishing two Special Articles which describe how progress with poxvirus recombinant vaccines is leading to significant advances in the control of infection [5,6]. In fact the vaccination of Phipps was the second, and perhaps least important, link in a series of four related events. These, taken together, represent Jenner's seminal contribution to preventive medicine, and fortuitously reflect the title of our Journal. First was the series of circumstantial epidemiological observations carried out from the late 1770s which led Jenner to conclude that individuals who had acquired natural cowpox were subsequently resistant to natural and/or inoculated smallpox (variolation) [1,7]. Then came the vaccination of Phipps with material taken from the hand of Sarah Nelmes; Phipps resisted variolation. At this stage Jenner submitted a paper to the Royal Society, of which he was a Fellow, but was advised to collect more data [2]. This he did, and in May 1798 started the small but crucial series of vaccinations, the third link in the chain (Fig. 1). These showed that vaccine could be passed arm-to-arm and that those few who were tested resisted variolation. Jenner concluded that his cowpox vaccine was a safe, effective alternative to variolation, which could be maintained by arm-to-arm transfer. More controversially he concluded that the origin of his vaccine was an equine infection (grease) which was stabilized by passage through the cow, and also that his vaccine induced lifelong immunity to smallpox. At this stage he published his Inquiry [1,7]. The fourth and final link was provided in 1799 when Jenner provided guidance for those wanting to make use of vaccination. In his Further Observations [8], he compared 'true' cowpox which gave the expected result, i.e., a mild localized lesion which induced immunity to smallpox, with 'spurious' cowpox which did not produce the desired effect. In fact he recognized four varieties of spurious cowpox. In modern terms the first three corresponded to: (A) other bovine zoonoses, e.g., Milker's Nodes, which could be mistaken for cowpox; (B) abscesses caused by contaminating bacteria in cowpox material which had itself been inactivated during inappropriate storage; (C) abscesses produced by material similarly stored but which did not originally come from a cowpox lesion. The fourth variety was another reference to inconsistent results produced by material direct from horses [7]. Jenner's concept of true and spurious cowpox was essential for any realistic appreciation of the value of vaccination, and his clear differentiation of the first three varieties, many years before the discovery of pathogenic microorganisms has rightly been described as 'masterful' [9]. The introduction of smallpox vaccination in general was opposed by variolators who feared the end of a lucrative monopoly. Jenner's claims in particular were variously opposed, and well into the 20th Century, by those who believed others had 'discovered' vaccination earlier, that his cowpox vaccine was merely attenuated smallpox virus, and that the more extensive work of others established the true worth of vaccination. This last is true, but such trials could only build on Jenner's foundations, and claims to have discovered vaccination only came to light after 1798. Vaccine strains were soon to be developed from both cowpox and horsepox in circumstances where smallpox virus could not have been involved and there is no doubt that Jenner's introduction of vaccination with an animal virus marked a distinct break with previous practice and experience and laid the foundations for the effective control of smallpox [7,10]. Jenner's initial claims were based on only few vaccinations and he erred in his belief that his vaccine