Conquering a Virus
A 200-year vaccination campaign and the final eradication of smallpox.
“The person who has been thus affected is for ever after secure from the infection of the Small Pox.” - Edward Jenner (1798)¹
This is the story of one of the greatest achievements in human history. It is a story about remarkable people and the remarkable things our species can accomplish. It is a happy and supremely encouraging story, but it also a story of warning. It is the story of the very first vaccine ever produced and the horrible virus it ultimately defeated. It is a story we must remember today. Only a single human disease has ever been wiped from the face of the earth, and it was one of the most destructive diseases we have ever known.
In 1980, a decades-long vaccination and containment campaign concluded and the World Health Organization (WHO) announced that smallpox, “the most terrible of all the ministers of death,”² had finally been globally eradicated. The virus no longer existed in the wild. No case had been found for years. After millennia of misery and devastation, going back, it seems, as far as recorded history itself, the human population was finally free from a truly terrible disease.
This virus, according to the WHO’s report, had “swept across the world, decimating populations and altering the course of history.” Our past is intricately linked with it. “It killed emperors of China and Japan… In Europe smallpox killed five reigning monarchs in the eighteenth century alone, ended the English royal House of Stuart, shifted the Austrian Habsburg line of succession four times in as many generations, and caused a violent pandemic after the Franco-Prussian War of 1871… It also prevented an American army from capturing Canada in 1776.”² American civilizations were decimated at an unprecedented scale when Europeans (and their African slaves) introduced smallpox into populations that had never before felt its wrath, and so held no immunity.
Eradicating this disease was an accomplishment unlike any other in human history. Amazingly, an effective vaccine against smallpox had been invented nearly 200 years earlier, and had been widely in use throughout the world. Eradication had been a stated goal of the WHO for decades, but previous efforts had been unsuccessful. So what had changed? As we consider the possibility of eradication of COVID, we will face many decisions that others have faced before us. The past is a window into the future. There is much to be learned.
Smallpox occupies a unique place in human history. It has been ravaging populations for so long we are not even sure where or when it first emerged. Devastating epidemics recorded in India and China as early as 1122 BC, and in Athens in 430 BC, have been attributed to smallpox based on descriptions of symptoms, but this has never been confirmed. The mummy of Pharaoh Rameses V, who died in 1145 BC, is covered with blisters consistent with the disease.³ Genetic dating suggests that it may have emerged 4000 years ago in the east of the African continent.⁴ Smallpox has been plaguing the populations of Africa, Asia and Europe for as long as history has been recorded.
Researchers have given the name “Columbian exchange” to the transfer across the Atlantic ocean of plants, animals, people and disease following the voyages of Christopher Columbus. Plants and animals moved both ways. People and disease moved west. The WHO’s report on eradication notes that “in the Americas smallpox facilitated the European conquest and colonization by decimating native American populations,”² but to say that it “facilitated” this conquest is rather an understatement. Smallpox, in reality, was the conqueror. Cultures and civilizations fell in its wake. Once introduced, disease spread so quickly over extensive trade networks that many American populations were obliterated without ever knowing the source of their misery. Early Europeans were struck by the vast empty territories and abandoned cities. They did not realize that waves of disease had fanned out in front of them, a ruthless vanguard more effective than any army. But the savage destruction that smallpox and other infections wrought on the populations of the Americas deserves its own story, and is a story for another time.
Smallpox is caused by the Variola virus and is easily one of the deadliest diseases to ever plague our species. Case fatality rates of 20%² have been recorded, with estimates as high as 45%³ for some outbreaks. Illness starts with prostration, fever, aching, nausea and vomiting. A pronounced rash of sharply raised lesions develops, giving the disease its name. Extreme cases can include bleeding from the mouth, gums, eyes and other orifices. Sometimes the fever does not subside for days. Death often occurs suddenly. Children are particularly susceptible and survivors can be left badly disfigured from scars.² This is a horrendous disease for which no treatment has ever been found.
It is also the only human disease to ever be fully eradicated from the planet. The only known specimens of Variola are now held in research laboratories, and no natural cases have been identified for decades.⁵ A massive, years long global eradication campaign finally freed our species from this scourge and it is hard to overstate the significance of this accomplishment. But eradication did not come easily. Our species fought smallpox for millennia and we must learn from these battles.
By the eighteenth century, smallpox was so common in Europe that inhabitants of towns and cities could be nearly certain they would contract the disease at some point in their lives. Early immunization research had to be done in rural areas so that doctors could actually find subjects who had never been infected.¹ Children suffered most, so when an outbreak hit, parents were desperate for protection.
For centuries it had been well-known that those who survived smallpox became immune to reinfection. The natural route of transmission was by respiratory inhalation and close contact with patients.² Some communities discovered that by deliberately infecting themselves via less common transmission channels they would (hopefully) suffer a less severe infection, yet still acquire the same immunity. This technique of direct inoculation often meant cutting the patient and inserting viral matter directly into the wound. It had been practiced for generations in Africa and Asia before making its way to Europe and ultimately North America.³
During a typical eighteenth-century inoculation of one patient, “variolous matter was inserted into both his arms; in the right by means of superficial incisions, and into the left by slight punctures into the cutis.”¹ This was not a safe procedure, and it was not a vaccination. This was simply a less deadly way for people to get infected with smallpox, something they saw as inevitable anyway. Some 2%-3% of recipients died, either directly from the smallpox infection or from other diseases transferred from the host or on unclean instruments. Many still became very ill and were permanently disfigured by scars. In some cases the inoculation itself triggered an outbreak. But, 2%-3% was a huge improvement over the more than 20% case fatality for patients who contracted the disease naturally, so the procedure was not uncommon.²
Edward Jenner (1749-1823) was one of many physicians carrying out routine smallpox inoculations at the end of the eighteenth century. At the time, the disease was killing an estimated 400,000 Europeans a year.² Jenner and others observed a connection between smallpox and a much less deadly disease that often passed from cows to the farm workers who milked them. “It is a fact so well known among our Dairy Farmers, that those who have had the Small Pox either escape the Cow Pox or are disposed to have it slightly,”¹ Jenner wrote in 1798. He found that workers inoculated with smallpox virus were also immune to infection from cowpox. He decided to test the reverse.
Jenner had previously treated one Sarah Nelmes, a local dairymaid, for cowpox. On May 14th, 1796 he took viral matter from a sore on Nelmes’s hand and inserted it into the arm of eight year old James Phipps “by means of two superficial incisions, barely penetrating the cutis, each about half an inch long.”¹ Phipps suffered mild symptoms for eight days and on the ninth day was “perceptibly indisposed,” but on the tenth day was perfectly fine. Six weeks later, and again after several months, Phipps was inoculated with smallpox virus, but “no sensible effect was produced on the constitution.”¹ He had become immune. This was not the world’s first vaccination. Other doctors in Europe, unknown to Jenner, had already been using cowpox to protect their patients from smallpox. Jenner’s chief contribution was to record his observations and to share them with the world. In 1798 he published his findings under the extensive title An Inquiry into the Causes and Effects of Variolae Vaccinae, a Disease Discovered in some of the Western Counties of England, Particularly Gloucestershire, and Known by the Name of The Cow Pox. The Latin word for cow is ‘vacca’ and Jenner called the cowpox virus Variolae Vaccinae, or ‘smallpox of the cow.’ The process became known as vaccination, so to get vaccinated literally means to get ‘cowpoxified.’
While inoculation (with smallpox virus) was risky and dangerous, vaccination (with cowpox virus) was much safer. Not only was cowpox less deadly, but recipients were also unlikely to infect others, “so that a single individual in a family might at any time receive it without the risk of infecting the rest, or of spreading a distemper that fills a country with terror.”¹ Jenner had realized one of the big differences between achieving immunity through vaccination and achieving it through infection: infections spread. Infections risk growing out of control and overwhelming whole cities, countries, continents. The risks from vaccination are borne by the recipient. Some people have needed reminding of this fact during our current “distemper.”
Medical practice in Jenner’s time was not advanced and much of the work was trial and error, but vaccination was a clear improvement over direct inoculation, and many physicians took up the practice. Acceptance, however, was not universal, as may come as no surprise to us today. Many absurd and outrageous claims were made about these new vaccines, often involving the development of horns or other bovine features. But smallpox was terrible enough that people were often willing to accept the vaccine, and to accept a little trial and error from their doctor. This was good, because early methods were crude to say the least. Fresh and active vaccine material could only be obtained from an existing host, either human or bovine, which meant vaccination looked a lot like direct inoculation, but instead of coming from a sore on another patient’s arm, the vaccine could also be taken from a sore on a sick cow’s udder. We should be thankful that medicine has come so far.
In 1803, Charles IV of Spain dispatched the Royal Philanthropic Expedition of the Vaccine (La Real Expedición Filantrópica de la Vacuna). The Maria Pita carried the newly-discovered vaccine from Europe to South and Central America and then on to the Philippines and China. The vaccine was preserved during its voyage across the Atlantic and beyond by successively infecting, arm to arm, a sequence of 22 orphan boys. Every few days, a new pair of boys was vaccinated from the sores and pustules of the last infected pair, thereby keeping the infection alive. Homes for the newly-immune orphans were found in ports along the way, and more children were brought on board.⁶
The expedition was successful; immunity was boosted in populations along its route, and those populations grew. But these efforts neither eradicated smallpox locally nor could stop it from being re-imported from elsewhere.⁶ Smallpox would continue to ravage Asia and South America for another century and a half.
Jenner never used his discovery to enrich himself. He shared his ideas widely, and continued to advocate for widespread vaccination. He had a small hut built on a corner of his property, from which he administered vaccines to the poor, free of charge. He named it the Temple of Vaccinia. Alas, the world is a tremendously unfair place, and later life was not kind to poor Jenner. Within a span of just a few years he lost his wife and eldest son to tuberculosis, as well as two of his sisters; he withdrew from public life.⁷ Tuberculosis is a different story, perhaps even more frightening than the story of smallpox.
By the time of Jenner’s death in 1823, many European nations had made vaccination legally mandatory for all citizens.² Methods for preserving vaccine material were eventually developed and the primitive technique of transferring virus from patient (or cow) to patient was replaced by more modern and familiar ones. By the 1950s large-scale production of freeze-dried vaccines became a possibility, finally bringing the global eradication of smallpox within reach. But a goal within reach is not a goal accomplished. In 1801 Jenner had written about vaccination that “the annihilation of smallpox — the most dreadful scourge of the human race — will be the final result of this practice.”⁸ A century and a half would pass before the world finally decided it was finished with smallpox. The time for annihilation had come.
Mass vaccination campaigns and border screening had achieved eradication from the world’s wealthier nations by the middle of the twentieth century, but smallpox still remained endemic in Africa, Asia and South America. When the Eleventh World Health Assembly convened in 1958 it noted that smallpox was still widespread throughout the world, and that “endemic foci existed constituting a permanent threat of propagation.”² As long as smallpox existed anywhere, it was a threat everywhere. Early eradication attempts had been localized and insufficient. Populations lost immunity over time and again became susceptible through new births and immigration. The virus persisted by passing between these groups. As late as 1967 smallpox killed an estimated 2 million people globally. Full global eradication became a stated goal.²
Initially the eradication campaign was simple: vaccinate, vaccinate, vaccinate. Vaccines were produced in huge numbers, incubated inside fertilized chicken eggs. Staff were trained and deployed around the world. A goal of 80% population coverage was set for affected areas. Wealthy countries donated supplies. After nearly a decade of this, however, the virus was still winning. In 1967, “the situation in many endemic countries was not encouraging.”² Incidence remained high in Africa, Brazil and Asia. In India case numbers had actually increased since the start of the campaign. “Eradication campaigns based entirely or primarily on mass vaccination succeeded in some countries but failed in most.”² Something more was needed.
Starting in 1967, the strategy shifted to incorporate more careful reporting, investigation and containment of outbreaks. Blindly vaccinating huge numbers of people and then moving on was simply not enough. The virus found pockets of susceptible people, laying low and biding its time before moving on again.
India in particular, with its population of 600 million, densely packed into cities and scattered widely into far-flung villages, demonstrated the need for investigation and containment. “Primary vaccination was performed on a very large scale, but there always remained a large pool of unvaccinated persons and it was constantly added to by the large number of newborn children. Even when vaccination coverage reached 85% to 90%, a goal difficult to achieve, there consequently remained in the endemic states a population numbered in tens of millions among whom smallpox transmission was readily perpetuated. On the other hand, when active surveillance and effective containment programmes were fully developed, India, with its great number of trained health personnel, was able to complete eradication within a relatively short period.”² Eradication was ultimately an achievement of patience, diligence and cooperation.
Cases were regularly exported from affected countries and proof of vaccination was required for travel. Ten outbreaks were recorded in Europe between 1962 and 1974. Within endemic countries, the problem was even worse. “One community in Bihar was the source for nearly 300 outbreaks involving almost every other Indian state.”²
Vaccine hesitancy has been a problem since Edward Jenner’s time and complicated eradication efforts throughout the campaign. The WHO noted that it “played a role in impeding the success of a number of programmes,” identifying religious beliefs, superstitions, and hostility of different minority groups as among its sources. “Great ingenuity and persistence were required to overcome these obstacles.”² Jenner faced opposition from an especially irrational segment of the populace who held the fantastical belief that his vaccine would turn its recipients into cows. A satirical political cartoon of the day by James Gillray mocks these earliest of anti-vaxxers.
Despite all of this, care, diligence and persistence paid off in the end; one by one the world’s nations became smallpox-free. By 1971 Brazil had recorded South America’s last infection. India identified its last case in 1975. The world’s very last known case of smallpox was reported in Somalia on October 26, 1977. Two years of intense searching followed, with no cases found. Finally, on May 8th, 1980, the WHO officially concluded that “smallpox eradication has been achieved throughout the world.”² Vaccination and other measures were no longer needed and the world could finally move on. A momentous achievement indeed.
Smallpox is not COVID. The fight against smallpox required solutions to problems that today have been solved. Sterilization and refrigeration mean vaccines can be deployed safely and quickly around the globe. Smallpox was a well-studied and familiar disease at the time of its eradication, while COVID is new and poorly understood. The viruses and their effects on our bodies are very different. It was well-known that vaccination against smallpox gave long-term protection. This is not yet clear of COVID vaccines. Thankfully, COVID is much less deadly than smallpox. Still, those who fought smallpox fought battles familiar to us today.
As vaccination became common in Europe and elsewhere, a new variant of smallpox rose to prominence. Fortunately, and unfortunately, this variant was less severe. Patients were less sick and died much less often, but this meant they were less incapacitated and spread the virus much more widely. Edward Jenner had noted the presence of one such “variety of the Small-pox” in his Inquiry in 1798. It was, he wrote, “so little dreaded by the lower orders of the community, that they scrupled not to hold the same intercourse with each other as if no infectious disease had been present among them.”¹ Sadly, this rings all too true today. Jenner would understand our consternation at young spring-breakers packing together in bars and on beaches, or at selfish conspiracy theorists resisting masks and gathering in crowds. Some things will never change.
Transmission of this variant was more difficult to trace and “the lack of concern many communities felt for this mild disease increased the difficulty of containment and eradication” during the WHO’s campaign. The virus was figuring out, quite ingeniously, how to fight back. The variant spread through Europe and North America, greatly complicating vaccination efforts.²
Viruses, possessing the mighty intelligence of evolution, learn to take advantage of human ignorance, and to resist our efforts to contain them. During the eradication campaign, case fatality rates as high as 20% (India, 1974) and as low as 0.2% (Botswana, 1972) were recorded. This wide range led the WHO to conclude that many variants of “differing pathogenicity” had likely been in circulation.² These variants act as a reserve arsenal, waiting for a time when their particular set of features might be the right weapon the virus needs in its fight for survival. Thankfully our smallpox vaccines held out.
We have reached a decision point in our current pandemic and there are only two choices. We can choose to eradicate COVID completely, or we can choose to live with it. Vaccines will play a role in either scenario. They are a weapon in our arsenal, but they alone will not win our fight. Identification and careful containment of outbreaks will remain crucial for years to come. This is not appealing but the alternative is worse.
The H3N2 flu strain in common circulation today started its life as a mutation that caused the so-called Hong Kong flu pandemic of 1968 and 1969, in which 4 million people died.⁹ Since then it has circulated through the world’s population, gradually becoming less deadly as we develop more immunity by getting sick or dying. We lost that fight but we do not need to lose our current one. Once before we came together and eradicated a virus from the face of the Earth. We know we can do it again. Careful policies with strong, clear messaging can reduce cases to zero, and contain and eliminate outbreaks as they occur. Australia, New Zealand, Taiwan and others have shown that this is possible. Vaccination can help reduce cases, but it alone will never eliminate them, and it certainly cannot identify them.
We need to remember that the virus will react to everything we throw at it because it is fighting for its very existence. It will use the power of vast, vast numbers of small random experiments to find a successful path to survival. As we develop vaccines, the virus develops variants. If the young gather in groups, these variants will learn to target the young. As vaccinated people interact with others, the virus will learn to overcome these vaccines. It is naive to think that our attempts will work perfectly and that the virus will simply accept its demise.
There are many good reasons to pursue eradication of COVID. The long-term effects of the disease are not yet fully clear, with many patients apparently suffering from worrisome “Long COVID” symptoms. Eliminating the virus is safer in terms of avoiding potentially dangerous future mutations, and also sets a good precedent for future generations and the pandemics they will inevitably face. And maybe the best reason for pursuing global eradication of COVID is, in fact, spite. SARS-CoV-2 has been a major son-of-bitch and it deserves to go. It has spent more than a year turning our lives upside down, filling us with fear and uncertainty and hatred, not to mention killing a bunch of us and making us sick. So let’s show this stupid little virus what we humans are capable of. We’ve done it before. We can do it again.
Notes
- Rinderpest, a viral disease related to measles and affecting livestock only, was also eradicated in a coordinated global vaccination campaign during the latter half of the 20th century.
Sources
[1] Jenner, Edward. An Inquiry Into the Causes and Effects of the Variolae Vaccinae, a Disease Discovered in Some of the Western Counties of England,… and Known by the Name of the Cow Pox. By Edward Jenner, MDFRS &c. printed, for the author, by Sampson Low: and sold by Law; and Murray and Highley, 1798. https://collections.nlm.nih.gov/catalog/nlm:nlmuid-2559001R-bk
[2] World Health Organization. “Final Report of the Global Commission for the Certification of Smallpox Eradication.” Geneva: World Health Organization (1980). https://biotech.law.lsu.edu/blaw/bt/smallpox/smallpox-a41438.pdf
[3] Behbehani, Abbas M. “The smallpox story: life and death of an old disease.” Microbiological reviews 47.4 (1983): 455. https://mmbr.asm.org/content/mmbr/47/4/455.full.pdf
[4] Babkin, Igor V., and Irina N. Babkina. “The origin of the variola virus.” Viruses 7.3 (2015): 1100–1112. https://www.mdpi.com/1999-4915/7/3/1100
[5] CDC. “History of smallpox.” www.cdc.gov/smallpox/history/history.html
[6] Franco-Paredes, Carlos, Lorena Lammoglia, and José Ignacio Santos-Preciado. “The Spanish royal philanthropic expedition to bring smallpox vaccination to the New World and Asia in the 19th century.” Clinical Infectious Diseases 41.9 (2005): 1285–1289. https://academic.oup.com/cid/article/41/9/1285/278013?login=true
[7] Riedel, Stefan. “Edward Jenner and the history of smallpox and vaccination.” Baylor University Medical Center Proceedings. Vol. 18. №1. Taylor & Francis, 2005. https://www.tandfonline.com/doi/pdf/10.1080/08998280.2005.11928028
[8] Jenner, Edward. “On the origin of the vaccine inoculation.” The Medical and physical journal 5.28 (1801): 505. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5598692/
[9] Rogers, Kara. “1968 flu pandemic”. Encyclopedia Britannica, 25 Mar. 2020, https://www.britannica.com/event/1968-flu-pandemic. Accessed 18 April 2021.
Images
Growing vaccines-
https://commons.wikimedia.org/wiki/File:Researcher_injecting_smallpox_into_chicken_eggs--Bangledesh.jpg. This image is a work of the Centers for Disease Control and Prevention, part of the United States Department of Health and Human Services, taken or made as part of an employee’s official duties. As a work of the U.S. federal government, the image is in the public domain.
Aztec smallpox victims-
https://commons.wikimedia.org/wiki/File:FlorentineCodex_BK12_F54_smallpox.jpg. Public Domain.
Jenner vaccinates Phipps-
https://commons.wikimedia.org/wiki/File:Melingue_Jenner_peint.jpg. This work is in the public domain in its country of origin and other countries and areas where the copyright term is the author’s life plus 100 years or fewer.
Inquiry title page-
https://commons.wikimedia.org/wiki/File:Edward_Jenner_book.jpg. This work is in the public domain in its country of origin and other countries and areas where the copyright term is the author’s life plus 70 years or fewer.
Temple of Vaccinia-
https://commons.wikimedia.org/wiki/File:Edward_Jenner_House_-_Vaccine_temple.jpg. This file is licensed under the Creative Commons Attribution-Share Alike 4.0 International license. https://creativecommons.org/licenses/by-sa/4.0/deed.en
Amsterdam vaccination-
https://commons.wikimedia.org/wiki/File:Inenting_te_Amsterdam_tegen_pokken,_Bestanddeelnr_903-5386.jpg. This file is made available under the Creative Commons CC0 1.0 Universal Public Domain Dedication. https://creativecommons.org/publicdomain/zero/1.0/deed.en
Final years of eradication-
See [2]. https://biotech.law.lsu.edu/blaw/bt/smallpox/smallpox-a41438.pdf.
The Cow Pock-
https://commons.wikimedia.org/wiki/File:The_cow_pock.jpg. This work is in the public domain in its country of origin and other countries and areas where the copyright term is the author’s life plus 100 years or fewer.
Jenner Vaccine-
https://commons.wikimedia.org/wiki/File:Vaccination_set,_London,_England,_1925-1928_Wellcome_L0058079.jpg. This file comes from Science Museum Group, in the United Kingdom. https://wellcome.org/press-release/thousands-years-visual-culture-made-free-through-wellcome-images. This file is licensed under the Creative Commons Attribution 4.0 International license. https://creativecommons.org/licenses/by/4.0/deed.en
Eradication-
https://xkcd.com/2448/. This work is licensed under a Creative Commons Attribution-NonCommercial 2.5 License. https://creativecommons.org/licenses/by-nc/2.5/
