Episode 30: The Orphan Vaccine

Two hundred years ago, a few doctors, a matron, and 22 orphans set sail in a gutsy attempt to spread the new invention of vaccination across three continents in the world’s first attempt to eliminate smallpox. Learn about their epic journey, the Balmis-Salvany Expedition, as well as the medical context surrounding the invention of vaccination in “The Orphan Vaccine”. Plus, a new #AdamAnswers about why you always get sick when you first go on vacation. You can find all this and more in the latest episode of Bedside Rounds, a tiny podcast about fascinating stories in clinical medicine!



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  • Franco-Paredes C, et al. “The Spanish Royal Philanthropic Expedition to Bring Smallpox Vaccination to the New World and Asia in the 19th Century”, Clinical Infectious Diseases, Volume 41, Issue 9, 1 November 2005, Pages 1285–1289
  • Hammarsten JF et al, “Who discovered smallpox vaccination? Edward Jenner or Benjamin Jesty?” Trans Am Clin Climatol Assoc. 1979;90:44-55.
  • Lipton RB et al, “Reduction in perceived stress as a migraine trigger: testing the ‘let-down headache’ hypothesis,” Neurology. 2014 Apr 22; 82(16): 1395–1401.
  • Mark C and Rigau-Peres JG, “The World’s First Immunization Campaign: The Spanish Smallpox Vaccine Expedition, 1803-1813,” Bulletin of the History of Medicine, Volume 83, Number 1, Spring 2009, pp 63-94.
  • Morgan AJ and Poland GA, “The Jenner Society and the Edward Jenner Museum: Tributes to a physician-scientist,” Vaccine, 295 (2011) D152-D154.
  • Tuells J. “Francisco Xavier Balmis (1753–1819), a pioneer of international vaccination,” Journal of Epidemiology and Community Health, 2002, 56:11.


This is Adam Rodman, and you’re listening to Bedside Rounds, a tiny podcast about fascinating stories in clinical medicine. This episode is called the Orphan Vaccine. In Episode 28: Smallpox Blankets I talked about how our medical understanding of smallpox, and especially variolation, that is, directly injecting smallpox into a wound to protect an individual, likely led to the virus being used as a weapon of war and genocide. That was a little dark, so in this episode, I’m going to talk about how Edward Jenner’s discovery of vaccination led to the dream of eliminating the illness once and for all, and about how this spurred the first vaccination campaign in history, with a small group of doctors and orphans journeying across the ocean and the wilds of South and North America, the Pacific Islands, and even China to try and stop smallpox for good.


So it’s basically a rule that every episode about smallpox has to start with Edward Jenner. Apparently I can’t say enough about the man, since this will be the third time I’ve talked about him on Bedside Rounds. So let’s start with the context for his discovery of vaccination. Variolation is the introduction of smallpox scabs or pus into a skin wound to cause a localized reaction. It would protect the variolated individual from future smallpox infection and had been introduced to European medicine sometime in the beginning of the 1700s. It had considerable drawbacks — mostly its mortality rate of up to 2%, but also the propensity to “go rogue” and cause small outbreaks, and only in the United Kingdom and its colonies did it really catch on. By the middle of the 18th century, any man, woman, or child could be variolated for free by the British government, and the process was routinely practiced throughout the Isles, though in typical European medical fashion, it involved a lengthy process of preparation, including taking various herbs, and of course, bloodletting to balance the four humors so variolation would take.


It is in this context that Edward Jenner was born in 1749, variolated himself at a young age, and trained as both a surgeon and physician, returning to his native Gloucestershire to work as a country doctor. He was a student of the Enlightenment and the scientific method, and his mentor was the famous surgeon John Hunter. So, a budding scientist but also intimately familiar with rural life, Jenner was perfectly positioned for what happened next.


The traditional story is that Jenner realized that milkmaids were immune to smallpox by noticing that they didn’t have pockmarks, and then realizing  that this was due to another mild infection that they got from cows, the cowpox. But this probably isn’t true. It was apparently common knowledge among rural doctors in southwest England. And in fact, a series of other doctors had already practiced vaccination before Jenner. We know now that Benjamin Jesty deserves the credit for the first vaccination; he inoculated his family with cowpox as smallpox burned throughout the countryside.


The actual story, I think, is much more interesting, because it’s not a “Eureka!” moment that led to vaccination, but his desire to methodically experiment and challenge himself. Jenner himself said he was inspired by the fact that milkmaids would not take to variolation; he likely witnessed this himself, trying to treat young women and noting in frustration that no matter how much smallpox material he inserted in their skin, they would not have a local reaction. And despite this, they were still immune to smallpox. 


Like others, he theorized that the cowpox somehow protected the milkmaids. But this time, Jenner designed an experiment to test his theory. In 1791, he found a young milkmaid who had just developed cox pox, named Sarah Nelmes. There are no pictures of her that I could find, but I did find an engraving of her poxed hands, which I posted to twitter. From her he took samples from the insides of her pox. He then he inoculated them into his neighbor, an 8 year-old named James Phipps. Phipps developed a mild febrile illness with pox of his own at the inoculation site, and after the boy recovered Jenner performed a standard variolation, inoculating him with smallpox material. This seems particularly horrific by modern standards, but remember that the standard of care at the time would have been variolation for all children in England. Phipps, like the milkmaids that had inspired him, did not take to variolation. Jenner then tried to variolate the boy one more time, but the boy was immune. Taking detailed notes, Jenner repeated his methodology on 23 more subjects, before concluding that in every one of them, inoculation with cowpox protected from smallpox. He named this new procedure “vaccination” — and yes, the root word for vaccine is “vaca”, or cow, since it’s named after the scientific name for cowpox, variola vaccinae.


I want to stop and appreciate how impressive this discovery was. Jenner didn’t know about evolution. Darwin’s “Origin of Species” was still 63 years away. He didn’t know about microorganisms or viruses. Germ theory was almost a century away. He didn’t have any mathematical tools to suss out trends in his data. Statistics wouldn’t exist for a few more decades.  But this country doctor, by using principles from the Enlightenment, discovered a way to prevent probably the greatest killer of humanity.


And Jenner immediately realized the impact of his discovery. At the end of his groundbreaking paper An Inquiry into the Causes and Effects of the Variolæ Vaccinæ, he takes vaccination to its logical conclusion, writing:


“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.” 


Within weeks of being published in 1798, Jenner’s inquiry was translated into almost a dozen different languages, and repeat cowpox inoculation and variolation challenge experiments were held across the globe, all confirming his findings. Which led to a collective consideration of, now what? Now that vaccination existed, how could it be used to stop smallpox?


Again, this is 1798. Public health didn’t exist yet. Some of the concepts were floating out there — quarantine dates back to the ancients, and the idea that you could fight plague by controlling noxious odors was largely accepted, but any interventions beyond a single city had never been carried out. It would take the great cholera outbreaks that would ravage Europe in the middle in the 19th century to spur modern public health, which I touched on briefly in Episode 25 about the invention of saline. And now a few dreamers were calling for the elimination of smallpox around the globe? Who would be crazy enough to attempt that?


The answer came from a very unlikely quarter — King Carlos IV of Spain. And to understand why, we need a very brief foray into the political situation at the time. At the turn of the nineteenth century, Carlos rules over the massive Spanish Empire, which stretched from  modern day Chile and Argentina in South America, through Central America, and well-into the lands that are now part of the United States and Canada, including California and Louisiana, as well as the archipelago of the Philippines in the Pacific. It covered a large portion of the Earth, but the political situation was precarious. Revolution had toppled the French monarchy, and Napoleon had just come to power. The Napoleonic Wars would soon subsume Europe, and Carlos himself would be forced to abdicate just a few years later. By all accounts, Carlos was not the monarch you’d want for this time of crisis; he was roundly considered simple minded, preferring hunting and sporting to actual governing.  


But Carlos was also an advocate for treating and eliminating smallpox. The royal family had been struck by a smallpox outbreak a few years before that had killed his brother and sister-in-law, and almost killed his beloved daughter. In the aftermath of this, Carlos became interested in variolation, and by 1798 ordered that the entire civilian population of his massive empire be variolated. This was the same year that Jenner’s inquiry was published, mind you, and the King pivoted almost immediately to vaccination. 


But how to accomplish this for the subjects of his massive Empire? At the same time Carlos started to dream of eliminating smallpox, a massive outbreak started in the territory of New Granada (modern day Colombia) and spread throughout New Spain. Carlos conferred with his Council of the Indies. Even in the 1700s, doctors realized the effect that smallpox had on their New World territories, brought over by the first conquistadores. An attempt to vaccinate the New World would be the most expensive health undertaking in history. The Council argued that the cost would be recouped in time with increased tax revenue from non-dead subjects. Whether from this financial argument, or from a genuine concern for his subjects, Carlos was swayed, and he authorized what was then called the Royal Philanthropic Expedition of Vaccination.


The Council of the Indies realized early on that they would never be able to vaccinate enough people to stop smallpox. Therefore, a major goal of the expedition was to establish vaccine boards and local stocks of the vaccine, and to train local physicians. For this task they chose the physician Francisco Xavier de Balmis to lead this expedition. At age 49, he had experience in New Spain, living in Mexico City studying indigenous medicinal plants. But the main reason he was chosen was his experience with vaccination. He was one of the earliest vaccinators in Spain, and was aware of the latest research on how to transport the vaccine.


Which was good, because it was an open question on how the expedition would get the vaccine to New Spain. It turned out that outside of southwest England, cowpox was relatively rare, though doctors quickly realized they could use the related horsepox virus as well, which they called equinization (the name didn’t catch on). Early attempts were made to dry the lymph on strings, or between glass plates, like smallpox had been for variolation. However, when cowpox was prepared in this manner, it would often fail to take. Therefore, de Balmis settled on most proven and reliable method of vaccination — arm to arm. Just as Jenner had used Sarah Nelmes’ pox to vaccinate James Phipps, Balmis would transfer the cowpox from person to person to make the months-long journey across the Atlantic. But the incubation of the disease was far shorter than this, and there would be multiple stops along the way. Balmis settled on a creative — though ethically murky — method; chain vaccination. Balmis recruited 22 non-immune orphans ranging in ages from 3 to 9. They would be infected, one after another, along the journey, providing a fresh supply of cowpox on the entire trip. He also recruited Isabel Zendala y Gomez, a rectoress at their orphanage, who would care for the orphans along the way. She was the only woman on the expedition. The vulnerability of the children was recognized; the King provided that the children be adopted by wealthy families in Mexico City, and that they would receive a state-sponsored education, almost certainly a better fate than they would have had they remained in Spain.


With that, the expedition set sail in November 1803 on the corvette Maria Pita, with the captain, an unknown number of sailors, five doctors including de Balmis and Jose Salvany, who was named vice-director, Isabel, and the 22 orphans.


At first, the Expedition received a heroes welcome; they stopped over in the Canary Islands to perform mass vaccinations, form a vaccine board, and attend parades in their honor. But by the time they reached Puerto Rico in New Spain in February of 1804, many of the challenges the expedition would face became apparent. Puerto Rico had already established a vaccination program, receiving cowpox from the Dutch at St. Thomas. De Balmis was a stubborn perfectionist, and he clashed with local authorities and doctors over how to properly proceed. A month later, he left for Caracas without setting up a formal vaccination board.


In Venezuela, it went considerably better — there was a carriage procession, fireworks, and a Thanksgiving mass, and the local authorities set up a central vaccine board — more than 12,000 people were vaccinated within a month! But having reached the mainland, de Balmis realized the enormity of his task, trying to spread vaccination over two continents with an expedition of only about a dozen people. Therefore, he split his group into two — one, lead by Jose Salvany, would travel overland into New Grenada and Peru, in the lands of the old Inca Empire in South America. De Balmis would continue by sea throughout New Spain, heading into North America, and then continue towards the Philippines. 


De Balmis continued to Cuba, then overland to Mexico City, vaccinating almost 100,000 people along the way and setting up a number of vaccine boards. He deposited the orphans, and recruited 26 Mexican boys for the next stretch of the journey to Asia; the children were from prominent families, and had a promise of payment and return to Mexico. They booked a passenger ship called the Magallanes and traveled West across the Pacific. The ship was rat-infested and just generally terrible. The expedition would have failed here were it not for the kindness of the other passengers, who provided food and money to the boys and the expedition. In the Philippines, de Balmis and the boys traveled throughout the islands, vaccinating about 20,000 people, but his determination and pride earned the annoyance of the governor, who disparagingly  called him “quijote,” after another famous Spaniard who tilted at windmills. De Balmis later said that the only request the governor granted him was a passport to leave for Macau and mainland China.


And when De Balmis arrived in Macau and Guangzhou he found an unusual situation — his own government refused to help him. But he found assistance from the enemies of his nation — the British East India Company, who helped de Balmis set up vaccination boards that would vaccinate countless people on the Chinese coast for decades to come. And to be clear from the context — the British and Spanish were at war at this point, and in fact the very day de Balmis met with representatives of the British East India Company was the Battle of Trafalgar, where the British fleet defeated the combined Spanish and French navies. In any event, from Guangzhou, de Balmis set sail back to Spain, and was received as a hero in August 1806, almost three years after he left. 


Jose Salvany encountered significantly more trouble. He and his expedition traveled overland through the Andes, establishing vaccination boards in cities as he went. By the time he reached Buenos Aires, he had vaccinated almost 200,000 people! By the difficult conditions took their toll on Salvany, and he died of a heart condition in Bolivia in 1810. His expedition would continue for another two years without him. 


From our modern, post-smallpox world, the Balmis-Salvany expedition, the name most scholars prefer, stands out for being the first vaccination campaign in history. And as such, the challenges it ran into predicted future challenges to vaccination programs. First and foremost, it was incredibly expensive, and de Balmis had difficulty convincing local officials to pay for vaccination. This remains a major problem in public health, where local leaders may not see value in the upfront costs of vaccination programs. The quality of vaccine stocks was a constant problem, and arm-to-arm vaccination had significant disadvantages, most notably that they transmitted a number of other diseases, including erysipelas, syphilis, and hepatitis. There was also considerable pushback and skepticism from the local population, who were distrustful out outsiders jabbing needles in their children. The vaccination was voluntary, but occasionally to continue arm-to-arm transmission, children were forced or compelled to be vaccinated. More optimistically, the cooperation of enemies at war to fight smallpox — the British East India Company lending funds and support — would foreshadow US-Soviet cooperation 150 years later when smallpox was finally eliminated. And it pioneered the pattern of vaccination that would be followed by basically every vaccination program to follow — vaccinating as many people as possible in the short term,while establishing vaccine boards to get the stragglers.


The expedition was considered a success in its own day — over 400,000 people were vaccinated across the globe during the expedition, and in New Spain the coverage was dense enough to provide herd immunity to an estimated 20% of the population. De Balmis and his compatriots were hailed as “conquistadores”, but instead of conquering the indigenous people in the Americas, they were conquering disease, with the obvious ironic caveat that they were fighting a disease that they themselves had introduced. Edward Jenner himself considered the expedition the logical conclusion of his dream, writing “I don’t imagine the annals of history furnish an example of philanthropy so noble, so extensive as this.”


But I’m willing to bet that before this, you had never heard of de Balmis, Salvany, or the orphans. I know I hadn’t. Their memory has faded from our collective consciousness for various reasons; Spain’s Empire fractured in a series of revolutions and wars, Carlos was forced to abdicate, important historical documents were spread throughout a dozen new countries, and of course science kept marching forward, culminating with Jenner’s true dream: final eradication of smallpox in 1979 by the World Health organization. The last few decades, especially in the Spanish-speaking world, have seen renewed appreciation and interest in the Expedition. Notes have been published, old monuments have been restored, and there’s even a fictional account of the expedition from the point of view of Isabel, the lone woman and caretaker of the orphans, which was developed into a TV series. But not much has been published in English yet.  For now, I think it’s enough to remember that Jenner’s dream of eliminating smallpox started with a philanthropic king, a few foolhardy doctors, one brave rectoress, and 22 orphans. 


Well, that’s it for the show! But what — it’s time for #AdamAnswers, the segment where I answer every and all questions about medicine, no matter how trivial or ridiculous. This month’s question comes from Dr. David Neal. I’ll let him ask his own question:


So you’re not alone Dr. Neal. I’ve noticed this happening to myself; especially in residency, I would have a very stressful block on wards or the ICU, and immediately after during my “golden weekend,” or even worse, a vacation, I’d get a URI. And I’ve noticed it multiple times through my life, that after periods of stress, I seemed to be more vulnerable to illness.


Well, Dr. Neal, we are not the only ones! It’s a commonly recognized phenomena, called either alternatively “post-stress illness,” or more commonly the “let-down” effect. Classically, it presents as either a flare of a chronic disease, or development of a mild viral illness, after a period of great stress passes. I should mention in advance that the vast majority of what has been written about the let-down effect on the internet is basically pop-psychology. The explanation is straightforward enough, and involves cytokines, stress hormones, the immune system yadda yadda. 


But we have actual data when it comes to the phenomenon of let-down migraines. Migraine headaches can be debilitating. One of the first line treatments is actually to keep a diary of everything that happens, and try to correlate that with headaches. There have now been multiple studies were people with migraines have tracked their stress level throughout the day, and noted that stress ENDING is a strong trigger for a migraine 6-24 hours later. There’s, of course, an alternative explanation, which might be that the stress itself leads to a reduction in self-care (lack of sleep, more caffeine, maybe even missing medications), therefore leading to a migraine immediately after, but given the predictability of let-down migraines within 24 hours of stress — regardless of the duration of the stress — the authors find this less likely. 

No study has attempted to identify the pathophysiological cause, but the purported mechanism involves the upregulation of the hypothalamic-pituitary axis, glucocorticoid production, and steroid withdrawal. Or basically, cytokines, stress hormones, and the immune system, yadda yadda. 


So to answer your question, your illness very likely could have been due to the let-down effect, which is reasonably well-documented in migraines, but appears to be widely experienced and involves a number of self-limited conditions. We don’t really know the reason, but, sure, it likely involves the relationship between our stress response and our immune system. And how do you prevent it from happening? Well, basically stress reduction, especially in the last 24 hours ending the stressor, and leading up to the first day. At least for migraines, this includes cognitive behavioral therapy, biofeedback, mindfulness, and just generally exercising and sleeping well. 


Thank you very much for the question Dr. Neal, and I hope your next vacation is pulled off illness free! And to you, dear listeners, if anyone has a pressing question about medicine they wanted answered for the next #AdamAnswers, tweet it to me @AdamRodmanMD, or on facebook at /BedsideRounds!


I hope you enjoyed that episode! It comes at a time that I’m trying to improve my Spanish, but unfortunately I’m not quite at the level where I can read medical texts from the 19th century, so I had to mostly rely on English review articles based off of Spanish sources. Before researching this episode, I had never heard of De Balmis myself, and I have to admit, I was pretty ignorant of New Spain as a whole, so I had a great time working on this. Let me know what you think! All of these smallpox episodes started because I wanted to update my episode on Dark Winter. Then I started reading the excellent “Smallpox and Its Eradication,” a WHO textbook by the architects of the eradication. There’s just too many rabbit holes in there. So this was originally going to be a two parter on smallpox. But now, well, let’s just say we’ll see. There may be more parts.


You can listen to all my episodes on the website at www.bedside-rounds.org, or on Apple Podcasts, Stitcher, or the podcast retrieval method of your choice. I’m on facebook at /BedsideRounds, or on Twitter @AdamRodmanMD, so come say hi! I often tweet about medical ephemera or evidence-based medicine.