In the rich tapestry of medical science, vaccines stand out as monumental achievements lauded for their role in controlling, and sometimes eradicating, some of humanity’s deadliest diseases. Yet, the story of vaccines is not just a straightforward account of scientific triumph. It is a complex narrative, woven with evolving methodologies, diverse perspectives, and debates over efficacy and safety.
The story of vaccines—particularly the smallpox vaccine—is more than a chapter in medical history; it’s a reflection of the human journey, marked by groundbreaking discoveries, societal impacts, and ongoing learning. Smallpox, once a formidable scourge, was the first disease to be eradicated through vaccination. However, the path to this success was not linear. It was punctuated with challenges and controversies.
In this series, “Vaccines Revisited” we will explore the multifaceted history of vaccines, examine historical data, and seek a nuanced understanding of vaccine efficacy and safety.
This journey begins with the smallpox vaccine—a starting point that opened doors to modern immunization but also raised questions that resonate to this day.

The Most Fearful Disease in History
The story of vaccines begins with a narrative of groundbreaking triumphs in public health. One of the earliest successes was the development of the smallpox vaccine by Dr. Edward Jenner (1749 to 1823) in the late 18th century, a pivotal moment that demonstrated the potential of the vaccine.Smallpox, caused by the variola virus, was once one of the world’s most feared diseases. Characterized by fever, malaise, telltale pustules on the skin, disfiguring scars, and blindness in many survivors, it has a storied history that intersects with the evolution of human civilization.


Edward Jenner’s 1796 Invention
The smallpox vaccine was introduced by Dr. Jenner in 1796. The story of this first vaccine started with a belief among milkmaids that cowpox infection could prevent smallpox.Inspired by this belief, Dr. Jenner experimented on an 8-year-old boy, James Phipps. Dr. Jenner used material from a dairymaid’s cowpox lesions and scratched it onto James. When James didn’t develop smallpox after exposure, Dr. Jenner concluded that the cowpox vaccination was effective.

This process was later termed “vaccination,” derived from the Latin word “vacca,” for cow; and “vaccinia,” for cowpox. Dr. Jenner’s 1798 paper claimed lifelong immunity from smallpox through this method.
This single-person study evolved into the modern narrative being told in our textbooks for hundreds of years that “inspired by milkmaids, Dr. Jenner invented the smallpox vaccine consisting of the so-called cowpox virus, conferring cross-protection against smallpox.”
Different Viruses, Different Diseases
Smallpox results from the variola virus, a DNA virus belonging to the Orthopoxvirus genus. This virus only infects humans. Unique to humans, who are its only known reservoir, it spreads primarily through inhaling respiratory droplets or through direct contact with infected material on mucous membranes. Importantly, it is not transmitted from cows.Moreover, the horsepox virus further complicated the story, as Dr. Jenner had also used lymph from horsepox lesions to prepare the smallpox vaccine in 1813 and 1817. Horsepox causes pustular lesions in horses and horse handlers.
The cowpox virus, horsepox virus, and smallpox virus are all different viruses. Even so, Dr. Jenner used various sources, including cows and horses, to create vaccine substances. This practice led to the development of multiple vaccine concoctions, often used without a full understanding of their composition.


The vaccines were commonly applied by scratching the arms or thighs, then using the material to vaccinate others, a method known as arm-to-arm vaccination. Dr. Jenner’s vaccine lacked standardization and safety testing.
Despite the uncertainties, lack of quality standards, and inadequate investigation of ingredients, nobody knew exactly what was inside the cocktail derived from different sources—like a broth of hundreds of thousands of microbes. Nevertheless, Jenner’s vaccination concept was widely adopted based on a superstition.
Medical Skepticism
Dr. Jenner’s vaccines met early challenges.Dr. Robert Hall Bakewell, a physician who treated leprosy, and others have pointed out the risks associated with vaccination. They cited examples where vaccination was spreading diseases such as leprosy rather than preventing infection, challenging the notion of vaccination.

In 1799, shortly after Jenner published his paper on using cowpox to get lifelong protection from smallpox, Dr. Drake, a surgeon from England, conducted a vaccination experiment on three children with a vaccine obtained directly from Edward Jenner.
Unfortunately, when challenged with smallpox inoculation all three vaccinated children developed smallpox. The vaccine had failed.
Failures Since 1804
Over time, numerous instances of vaccination not working were reported. Despite initial promises of protection, people were still contracting smallpox after being vaccinated.In 1809, Lord Henry Petty said in the House of Commons, “Unless Dr. Jenner was completely blinded by conceit, he must have recognized that the general faith in vaccination, exhibited in 1801, had been much shaken by the experience of the succeeding seven years.”
In the Committee of Supply on July 29, 1807, Mr. Shaw-Lefevre, speaking upon the motion for a public grant to Dr. Edward Jenner, referred to the report of a Commission of Inquiry, which stated that “the practice of vaccine inoculation was the infallible preventive of smallpox.” He emphatically denied the truth of this document and showed that in 56 cases of vaccine inoculation, smallpox had followed. “Here we have fifty-six cases of real failure,” said Mr. Shaw-Lefevre.

1818: Scottish Surgeon’s 1,200 Cases
In 1818, after vaccinating 1,200 healthy people, Dr. Thomas Brown, a Scottish surgeon with 30 years of clinical experience, found that many vaccinated people still contracted the virus and even died from smallpox.Dr. Brown discussed the complications and failures associated with smallpox vaccination. He described situations where individuals, despite being vaccinated (as indicated by a properly formed areola around the vaccine puncture), still contracted smallpox. In some of these cases, the smallpox was severe (confluent) and even led to death. Notably, he mentions instances where smallpox pustules developed within the area of the vaccine puncture itself.
In the context of smallpox disease, “confluent” refers to a severe form of illness where the characteristic skin lesions known as pustules, merge and cover a significant portion of the body. Instead of discrete, separate pustules, the lesions become densely clustered, creating a continuous rash or eruption. This severe form of smallpox is often associated with a higher risk of complications and a more severe course of the disease.
Dr. Brown further emphasized that reports from around the world, wherever vaccination has been practiced, indicated a significant increase in vaccination failures.
He also mentioned that when those who have been vaccinated for more than six years come in contact with a strong and active smallpox infection, nearly all of them end up getting smallpox. This raises major concerns about whether the smallpox vaccine works well over a long period and if it actually protects against the disease.

1845: The Lancet Reports Surge After Vaccination
In 1845, Mr. Stanley, president of the Royal Medical and Chirurgical Society, published an article in The Lancet on a paper by Dr. George Gregory, a physician from the London Smallpox Hospital.The hospital played a significant role in treating patients with smallpox and was crucial to the development of smallpox treatments and vaccination efforts in the 18th and 19th centuries.
Dr. Gregory wrote about how his hospital, after enjoying freedom from smallpox in the years 1842 and 1843, was hit with an epidemic in 1844 and a significant rise in weekly deaths from the disease. Here are the key points:
In 1844, there were 647 smallpox patients admitted to the Smallpox Hospital, marking one of the highest admission rates since the hospital’s founding in 1746.
During the 1844 smallpox epidemic, 312 smallpox patients were vaccinated with the smallpox vaccine, accounting for 48 percent of admitted patients.
Among the 312 vaccinated patients, 100 experienced a milder form of the disease, and nearly two-thirds had moderate to severe disease. Of the 312 vaccinated patients, 24 died—a mortality rate of nearly 8 percent.
In summary, the 1845 Lancet article indicated that smallpox vaccination in the 19th century was not as effective as expected in preventing the spread or reducing the severity of smallpox, as evidenced by the significant number of cases and deaths during the 1844 epidemic.