Most of us are familiar with the story of the milkmaids who inspired Edward Jenner to develop the first vaccine. But even I, with a doctorate in public health, was unfamiliar with the brave little orphan boys who carried the inoculation fluid within their bodies on a humanitarian expedition to bring the smallpox vaccine from Spain to Mexico, Central and South America.

Smallpox epidemics ravaged the people of Asia, Africa, and Europe for centuries before arriving in the Americas aboard a slave ship of a Spanish expedition of the early 1500s. The introduction was devastating. At the time, there were about 26 million Aztec Indians. One hundred years later, only 1.6 million remained, with smallpox a leading cause of human death and cultural destruction.

Ironically, it was another Spanish expedition that would bring smallpox immunization to the Americas.

King Charles IV

For King Charles IV of Spain, smallpox was both personal and professional. He had lost his brother and sister-in-law to the disease and his daughter survived but her face was significantly scarred. At the same, his Spanish holdings in the Americas were being decimated by repeated smallpox outbreaks. After providing the new smallpox vaccine to his subjects in Spain, the King decided to send an expedition to the colonies with the smallpox vaccine on board. The only problem was that the vaccine would spoil by the time it got there.

For centuries prior to the development of the smallpox vaccine, variolation was practiced in Asia, Africa and the Middle East. It saved many lives before being adopted in Europe. It worked by collecting the fluid from a few active blisters, called vesicles, on a smallpox victim and scraping it under the skin of a healthy person. If everything went well, the person would develop a mild case of smallpox and acquire antibodies that bestowed immunity. Inoculation of the skin with the smallpox virus caused a less virulent reaction than inhaling it into your lungs. Yes, smallpox was a respiratory infection. However, in about 5% of applications, it would kill you (as opposed to the 30% to 60% rate of death from the natural disease). Still, that’s a pretty big risk for a healthy person who might never be exposed, so the practice was controversial.

The Milkmaids

Edward Jenner was a country doctor who was curious about the reason behind milkmaids’ peculiar immunity to smallpox. Cowpox used to be a common but mild disease that caused vesicles (large blisters) to break out on cow udders. Milkmaids sometimes got vesicles on their hands from the vesicles on the udders. Jenner knew that cows and milkmaids got cowpox but didn’t get smallpox. Could something in cowpox protect the cows and the maids from smallpox?

Instead of using the liquid from smallpox vesicles, could the liquid from cowpox vesicles be used to variolate people against smallpox? Jenner knew that the people and the church would object to the transfer of anything from an animal into a human. But what if he used the liquid from a milkmaid’s blisters for the variolation? It was a bit of a stretch but he decided to try it out. He thought he should test the theory on someone who had never been exposed to smallpox because he was aware that if you’d had smallpox once you were immune.

Dr. Jenner spoke to his gardener about the current smallpox epidemic that was infecting the community. He wondered if the gardener would like Dr. Jenner to try to protect his 9-year-old son, James, from the disease in a procedure similar to, but safer than, variolation. It was an offer the gardener couldn’t refuse. So, the doctor took some liquid from a milkmaid’s cowpox vesicle and inoculated James’ arm. The child got sick – he had a fever and aches and broke out with a few vesicles. But after about nine days he recovered. I’m not sure how Dr. Jenner convinced James’ dad to proceed with the second step but six weeks or so later, and several times after that, Dr. Jenner variolated the boy with actual smallpox. To, I’m sure, the great relief of the father, the son, and the doctor, the child did not develop smallpox.

Dr. Jenner called his method ‘vaccination.’ It was much safer, easier, and just as effective, as variolation. Although other medically inclined scientists had also attempted and succeeded using cowpox against smallpox, it was Dr. Jenner who wrote about it and vigorously defended it. He championed vaccination without compensation, until it gradually replaced the practice of variolation throughout Europe and, eventually, the world.

Enter the Orphans

Back in Spain, King Charles IV’s Royal Philanthropic Vaccine Expedition was stuck on the supply chain problem. You need a person with a fresh case of cowpox in order to get the vesicular fluid needed to inoculate another person. A case of cowpox only lasted about 10 days; it would take at best one month to get to the Americas. History does not say who came up with the solution but it was a clever and radical thinker. Twenty-two previously unexposed children, ages 5 to 9 would go with the crew on the voyage. Two children would be vaccinated each week with the fluid from the cowpox vesicles induced by the previous weeks’ vaccinations. That way, they would still have fresh material when they arrived.

The King sent out a request to parents to volunteer their children for the expedition in exchange for free food, clothing, and education. No one responded. In the end, the expedition rounded up 22 boys from two orphanages along with one orphanage’s director, Isabel Cendales, to care for the children. She was the only woman on the expedition and she included her 9-year-old son among the human supply chain.

Dr. Francisco de Balmis directed the 1803 expedition that sailed to the Canary Islands, Puerto Rico, Venezuela, Cuba, and Mexico. In Mexico, the expedition’s vice-director, Dr. Jose Salvany separated from the main ship to continue the vaccination effort in other countries. He had the much harder over-land route that took the vaccine as far north as Texas, throughout Central America, Colombia, Ecuador, Peru, Bolivia, and Chilean Patagonia, in what one historian described as an “authentic epic journey of heroism.” Dr. Salvany, who suffered from diabetes and malaria prior to the trip, acquired diphtheria and TB during his campaign, losing sight in one eye and a hand to amputation along the way. He died, exhausted, in Ecuador at the young age of 36.

In the Port of Acapulco, 26 Mexican boys were recruited to continue the vaccination campaign across the ocean into the Philippines. That leg of the journey was also successful. From the Philippines, Dr. de Balmis went on to vaccinate citizens in Macau and the Port of Canton in China. He returned to Spain with full honors from King Charles IV and died there at the age of 66.

The original orphans, having completed their task, were left behind in Mexico City at the Real Hospicio de Pobres in the care of the local bishop. All of their names are known and none of them died on the trip. It is reported that many were adopted by teachers and merchants in Mexico. Imagine the stories they had to tell their grandchildren!

The Spanish government financially and logistically supported this ten-year effort to bring the smallpox vaccine via a chain of arm-to-arm vaccinations from Spain to the Americas and into Asia. And rightfully so, as 300 years earlier his countrymen had brought the disease. It is estimated that over a 1.5 million people were vaccinated during these expeditions— the first major worldwide public health campaign to carry out a preventive health measure. The last case of smallpox in Mexico was recorded in 1951.

The risks good people will take to prevent and relieve suffering when we want to is awe-inspiring. Scientists and gardeners, kings and orphans, risked their arms, their eyes, their hands and their lives to help others when they wanted to. When did so many of us stop wanting to?


Carlos Franco-Paredes, Lorena Lammoglia, 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, Volume 41, Issue 9, 1 November 2005, Pages 1285–1289,

The World’s First Immunization Campaign: The Spanish Smallpox Vaccine Expedition 1803-1813 Catherine Mark and Jose G. Rigau-Perez. Bulletin of the History of Medicine Vol 83, #1, Special Issue: Reassessing Smallpox vaccination 1789-1900 (Pring 2009), pp. 63-94.

Botet FA. Fighting against smallpox around the world: the vaccination expeditions of Xavier de Balmis (1803-1806) and Josep Salvany (1803-1810).


    • Joyce Ely

    • 2 years ago

    Fascinating article, Kristine. Thank you for sharing this bit of medical history with us.

      • Kehinde Kanmodi

      • 2 years ago

      This is a very nice article!!!! Thank you very much Dr Shields for the enlightenment.

      • sigrun hulshouser

      • 2 years ago

      Thanks Kris for sharing this very interesting piece of history showing such courage, resilience and sacrifice for the good of humanity. These people true heroes and their stories should be known to more of us.

    • Miss kitty

    • 2 years ago

    This is a real eye opener! Thank you for the enlightening article…so well written. Real hero’s, willing to sacrifice for the good of humanity to bring a vaccination to us so many centuries ago. You pose a really good question at the end..what has changed ?
    I believe it’s a combination of fear , downright selfishness and believing misinformation that does not support scientific reality.
    💫Thank goodness for the brave souls of the past,
    We all need to take a lesson from them!

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