Based on a general 18th century observation that farm maids in England, France, Germany, Holland, Italy and Mexico who came in contact and got infected with cowpox appeared resistant to smallpox (1), cowpox, the original smallpox vaccine, was intended to prevent, not cure, smallpox.
Smallpox vaccine in the form of cowpox was first introduced in the mid-to-late 18th – early 19th centuries when little was known about the causes of infectious diseases, certainly long before the discovery of micro-organisms. Since then a variety of vaccines have been used against smallpox including horsepox, and in the 20th century, attentuated (weakened) vaccinia virus and inactivated vaccines. Thus the biggest obstacle in the quest for smallpox vaccine efficacy data is it was eradicated from Europe and North America by mid-20th century and the world over by 1977 without the kind of controlled clinical trial that would now be mandated to evaluate the efficacy of a new vaccine (2), and proof of its efficacy is perforce largely based on historical records. Also important to bear in mind that even in the 18th century, vaccination wasn’t the only game in town.
This answer outlines
- Historical smallpox prevention measures included not just cowpox vaccination but also smallpox inoculation (variolation), strict case isolation and contact quarantine, all of which contributed to its decline and eventual eradication.
- Historical smallpox vaccination efforts began long before micro-organisms were discovered, its causative agent identified, and standardized vaccine manufacture, quality control and distribution methods developed.
- Some historical data on smallpox vaccine efficacy.
Historical Smallpox Prevention Measures Were Many: Not just Cowpox Vaccination But Also Smallpox Inoculation (Variolation), Case Isolation & Contact Quarantine
Inoculation (Variolation – Wikipedia) was the competing approach to try and prevent smallpox outbreaks.
Inoculation is reported to have been long practiced in China, India (see below from 3) and the Ottoman empire.
Consisting of exposure to a mild dose of the disease itself by placing a small piece of infective smallpox material, typically under the skin (2), inoculation was obviously a double-edged sword since it might itself cause disease. Vaccination, OTOH, was based on an entirely different principle, exposure to a related, less dangerous animal disease, cowpox. Though common credit for the cowpox vaccination is usually ascribed to Edward Jenner – Wikipedia, it was apparently first innovated by the English farmer Benjamin Jesty – Wikipedia (4, 5, 6).
Thus, at the time cowpox vaccination appeared on the scene, smallpox inoculation was already being practiced, for example by roving bands of ‘itinerant inoculators‘ (7) in England, Scottish Highlands and Ireland (8). However, historical data suggests vaccination soon overtook inoculation in popularity. The WHO treatise on the subject (2) states,
‘Jenner stated that by 1801 over 100 000 persons had been vaccinated in Great Britain, whereas by 1730, 8 years after the introduction of variolation, less than 1000 people had been variolated in Great Britain and North America’
Cowpox vaccination had several advantages over smallpox variolation (9; see below from 3)
- Produced a less severe, local inoculation site lesion.
- Was not communicable to contacts.
- Greatly reduced risk of disease from vaccination itself unlike inoculation (variolation).
However, all through its history, vaccination wasn’t whole-heartedly accepted by the population at large. For example, a review (10) notes the Medical Officer of Health for Whitechapel in London (11) recorded all the way back in 1859 that**
‘a “deep-rooted” prejudice against vaccination “strongly manifested” in poor neighbourhoods wherever a child had suffered some eruptive disease “syphilitic, eczematous, etc., commonly associated with teething” after vaccination.’
Since smallpox started causing cyclical epidemics from the 16th-17th century onward throughout Europe, some as frequent as every 2 years, with death rates ranging in the tens of thousands during each cycle, affected communities evolved rigorous preventive measures, consisting of prompt detection and expedient isolation of cases and quarantine of their contacts, efforts based on the pioneering insights of British physician John Haygarth – Wikipedia in 1793.
Haygarth’s original insight for exterminating smallpox from Great Britain consisted of ‘isolation of cases, variolation and a system of rewards and punishments‘ (9). It was so spot-on that almost 200 years later the WHO’s smallpox eradication program consisting of surveillance and containment only slightly altered from it by switching from variolation to limited vaccination and including strict isolation of contacts. This also means smallpox eradication ensued from not just vaccination but also from breaking transmission through strict quarantine.
Inoculation, vaccination, isolation of cases, and quarantine of contacts were thus preventive public health measures brought to bear on smallpox for centuries before it was even known what caused the disease and how it spread (see below from 3).
Historical Smallpox Vaccination Efforts Began Long Before Micro-organisms Were Discovered, Its Causative Agent Identified, And Standardized Vaccine Manufacture, Quality Control & Distribution Methods Developed
After the discovery of micro-organisms in the 19th century, bacteria, bacterial spores, protozoa, many organisms were historically suspected of causing smallpox. Not knowing what precisely caused the disease obviously hobbled rigorous assessment of how inoculation or vaccination prevented it even as smallpox vaccination itself became embedded as a widespread public health measure long before modern good manufacturing, clinical and regulatory practices came into existence.
Today it would be unthinkable to inject a vaccine into humans without rigorous quality control. Consider then that smallpox vaccination had already been in place >100 years before a potency assay was even established for it in the beginning of the 20th century (12). Thus even though smallpox vaccination had been in theory compulsory in the UK for decades by that point* (7, 10, 13), ‘the vaccinator had at best a very rough idea of the quantity of active material in the vaccine‘ (12) One reviewer estimates that 19th century smallpox vaccines may have been cowpox, horsepox or even attentuated smallpox (9).
So many caveats notwithstanding, smallpox vaccination as popularized by Jenner was so successful at bringing down smallpox mortality for several decades that many countries soon made smallpox vaccination, usually of infants, compulsory: Bavaria in 1807, Denmark in 1810, Norway in 1811, Bohemia and Russia in 1812, Sweden in 1816, Hanover in 1821, Great Britain in 1853 and France in 1902 (2). Enforcing such laws was however decidedly problematic since standardized methods for large-scale production and distribution of vaccine were then non-existent.
Thus, even though untold numbers of people got inoculated (variolated) or vaccinated against smallpox the world over for > a century, this complicated history means it isn’t possible to perform meta-analyses of well-controlled, rigorously collected scientific clinical trials on smallpox vaccine efficacy. Such data simply doesn’t exist.
- Historical records of groups of vaccinated and unvaccinated individuals aren’t easy to interpret.
- What did the vaccinated individuals actually get? Cowpox, smallpox itself, a mix of the two, a mix containing some cowpox with all kinds of other microbes, mainly bacteria, mixed in it? Were they vaccinated or variolated?
- Lack of standardized vaccination method and doses meant different individuals got different kinds of injections and material, i.e., different routes and doses, two important variables we now know greatly influence the strength and quality of ensuing immunity.
Some Compelling Historical Data On Smallpox Vaccine Efficacy
Even with the many caveats to historical smallpox vaccination data, several compelling examples demonstrate its unmistakable efficacy.
Some of the most robust historical statistical data for smallpox comes from Sweden which began smallpox vaccination late in 1801, making it compulsory in 1816. In the 18th century, Sweden used to have major smallpox epidemics with 3 to 7000 smallpox deaths per million every 5 years or so. The disease was also endemic meaning an average of 6 to 800 smallpox deaths per million as a matter of course. However, from about 1810, mortality rates declined steeply. In 1822, 6 years after smallpox vaccination was made compulsory, smallpox deaths per million had declined to single digits, i.e., a 100-fold reduction. Even though death rates rose slightly and epidemics recurred in later decades of the 19th century, they occurred at much lower frequency and at a fraction of pre-vaccination amplitude (see below from 2).
Lymph that the Empress of Russia obtained from Jenner in 1801 was maintained by arm-to-arm vaccination for >60 years. Infants aged 7 to 8 days at the St. Petersburg Foundling Hospital were vaccinated with this lymph until 1867 when the state switched to vaccines from cows. Compulsory registration of these infants until the age of 25 years meant another historical record with which to assess vaccine efficacy. St. Petersburg had 17 smallpox epidemics between 1826 and 1846. However, out of 15000 foundlings, only 34 (0.23%) got smallpox with only 1 fatality (2).
After Prussia instituted compulsory smallpox vaccination of military recruits in 1833, smallpox deaths fell from 88 per year in 1831 to 1834 to <2 per year for the next 30 years (2).
Prussia, Bavaria and Wurttemberg made smallpox vaccination and revaccination compulsory in 1874. Smallpox mortality rates declined more steeply in those German states compared to those in Austria which only practiced primary vaccination during the same time period (see below from 2).
A 1902 comparison study in Glasgow, Scotland, provides one of the clearest data sets attesting to smallpox vaccine efficacy (see below from 14).
* ~42000 deaths between 1837 and 1840 after a smallpox epidemic swept across England and Wales resulted in its first Vaccination Act in 1840. This made the vaccine freely available though not mandatory, even as it made inoculation an imprisonable offense.
** Plus ca change, plus c’est la meme chose.
1. Barquet, Nicolau, and Pere Domingo. “Smallpox: the triumph over the most terrible of the ministers of death.” Annals of internal medicine 127.8_Part_1 (1997): 635-642. https://www.researchgate.net/pro…
2. Fenner, Frank, et al. “Smallpox and its eradication.” (1988). http://apps.who.int/iris/bitstre…
3. Fenner, F., et al. “Early efforts at control: variolation, vaccination, and isolation and quarantine.” History of International Public Health 6 (1988): 245-276. http://www.leighainslie.com/bigr…
4. Crookshank, Edgar March. History and pathology of vaccination. Vol. 2. P. Blackiston, 1889.
5. Smith, John R. The speckled monster: smallpox in England, 1670-1970, with particular reference to Essex. Vol. 95. Essex Record Office, 1987.
6. Pead, Patrick J. “Benjamin Jesty: new light in the dawn of vaccination.” The Lancet 362.9401 (2003): 2104-2109. http://www.jesty.org/no_pead_lan…
7. Oxley, Deborah. “‘The seat of death and terror’: urbanization, stunting, and smallpox.” The Economic History Review 56.4 (2003): 623-656.
8. Brunton, Deborah. “Smallpox inoculation and demographic trends in eighteenth-century Scotland.” Medical history 36.04 (1992): 403-429. https://www.ncbi.nlm.nih.gov/pmc…
9. Baxby, Derrick. “Smallpox vaccine: ahead of its time.” Interdisciplinary Science Reviews 26.2 (2001): 125-138.
10. Hardy, Anne. “Smallpox in London: Factors in the Decline of the Disease in the Nineteenth Century.” Medical History 27.02 (1983): 111-138. https://www.ncbi.nlm.nih.gov/pmc…
12. Minor, Philip D. “Live attenuated vaccines: historical successes and current challenges.” Virology 479 (2015): 379-392. https://www.researchgate.net/pro…
13. Smith, John R. The speckled monster: smallpox in England, 1670-1970, with particular reference to Essex. Vol. 95. Essex Record Office, 1987.
14. McVail, J. C. “Small-Pox in Glasgow—1900-1902.” British medical journal 2.2166 (1902): 40. https://www.ncbi.nlm.nih.gov/pmc…