A 300 year old lesson from history: Smallpox

The following is the story of the eradication of smallpox from the world. The story has many twists and turns over the centuries that still have direct bearing on vaccines and vaccine hesitancy even today.

Vaccine hesitancy is not a new social phenomenon. It’s beginning dates back to the 18th century and smallpox outbreaks in New England. Tracing the eradication of smallpox from the world is instructive for us to understand vaccinations as a whole and why we do them. It is also instructive on issues in vaccination that we face today. In taking a very small risk in vaccination, a much larger risk of death and disability from a dangerous infectious disease is avoided. This is the time-honored lesson of smallpox eradication.

The history of the eradication of Smallpox from the world

On April 22, 1721, in Boston, Massachusetts, a dreaded disease arrived from Barbados aboard the passenger ship HMS Seahorse, commanded by Captain Wentworth Paxon. Several sailors on board had recently survived smallpox. The severe form of this disease, variola major, routinely killed 30% to 35% of those who contracted it.

Variola minor, another form of smallpox, was 20% fatal. After an incubation period of about 10-14 days, people with smallpox suddenly developed a flu-like illness with fever, fatigue, severe back pain, vomiting, and headache. 

A few days later, a terrible rash appeared. Flat spots spread all over the body, turning into pus-filled blisters. This process often left severe scars. Many who survived were severely scarred, with many losing appendages like earlobes and noses, resulting in lifelong disfigurement and disability.

One sailor (AI imagined image to the right) aboard the HMS Seahorse became ill just one day after arrival in Boston. Having been exposed on the ship, he in turn exposed others on land.

Upon arrival, the ship bypassed the harbor hospital and docked. When Boston customs officials finally inspected the ship, two or three additional cases of smallpox were discovered. The ship was ordered to leave the harbor.

The ill sailor was quarantined in the home where he was staying. Nine other seamen were quarantined on Spectacle Island near Boston, housed in a lodging to prevent the disease's spread. Despite these efforts, smallpox entered the Boston community.

Cotton Mather, a Boston Puritan minister, wrote in his journal on May 26, 1721: "The grievous calamity of the smallpox has now entered the town."

Before modern times, smallpox and other communicable diseases cyclically devastated communities worldwide. This pattern had persisted for thousands of years, affecting various civilizations, including the Egyptian pharaohs, the Chinese, and peoples across Africa, Europe, and later the American colonies.

Native peoples of the Americas, never before exposed to smallpox, lacked immunity to the disease and thus did not experience outbreaks until European exploration of the New World. Consequently, waves of smallpox epidemics brought from Europe severely impacted these populations, leading to staggering losses. By the time the Pilgrims landed at Plymouth Rock in 1620, they settled on land that had once belonged to the thriving Wampanoag culture, which had already been largely decimated by smallpox introduced earlier by European explorers.

Globally, smallpox epidemics were cyclical, often affecting entire communities upon arrival, with survivors developing permanent immunity. The spread of such infectious diseases was frequently facilitated by travelers. In Boston, the last smallpox epidemic had occurred in 1703, creating an 18-year period for the population to grow through births and immigration. This growth resulted in a large, vulnerable population susceptible to smallpox, thus creating favorable conditions for an epidemic in Boston in 1721.

Cotton Mather played a significant role in combating smallpox outbreaks in the American colonies. His involvement began in 1707 when his congregation gifted him an enslaved West African man, whom Mather named "Onesimus," after the biblical figure.

Onesimus revealed he had undergone a procedure, known in 1721 as inoculation (and now as variolization), which involved deliberately exposing oneself to smallpox in a controlled manner. The aim was to induce lifelong immunity by causing a milder form of the disease, thereby protecting against deadly natural smallpox infection while significantly limiting the risk of death. This technique involved introducing dried smallpox scabs or fluid from the pustules of an infected individual into scratches made on a non-immune person's skin. Contracting the virus in this way reduced the disease's severity and avoided the natural route of infection through the nose, mouth, and lungs, which resulted in a much more severe disease.

While the mortality rate for natural smallpox was around 30% to 35%, those who underwent variolization during this period faced a significantly lower mortality rate of approximately 2%. With further improvements, this rate would eventually decrease to about 1 in 500 inoculations.

Mather, who possessed a keen interest in public welfare, was particularly influenced by a letter from Dr. Emanuel Timoni, a physician and the British ambassador to Constantinople, Turkey. This letter, describing the practice of variolization, was presented to the Royal Society in London in 1714 and subsequently published in the Philosophical Transactions of the Royal Society.

Mather also gained firsthand knowledge of variolization from Onesimus, who had undergone the procedure himself. To further explore and understand variolization, Mather corresponded with the Royal Society.

In 1721, when the smallpox outbreak struck Boston, Cotton Mather urged local physicians to combat the disease through variolization. Only Zabdiel Boylston, whose medical training came from apprenticeships (including one with prominent Boston physician Hiram Cutter), agreed to Mather's request. Boylston successfully inoculated his six-year-old son, his 36-year-old slave, and the slave's two-year-old son; all survived.

Encouraged by these early successes, Boylston proceeded to inoculate 247 more people, with only 6 fatalities, achieving a mortality rate of 2%. He also inoculated 15 individuals at Harvard University; all survived, captivating the student body and faculty.

However, politics soon intervened. The Boston Selectmen, the city council, moved to restrict Boylston from further inoculations, effectively ending his smallpox prevention experiment despite its proven success in reducing morbidity and mortality. Undeterred, Harvard tutor Thomas Robie, inspired by the new research, continued to inoculate non-immune individuals on Spectacle Island near Boston.

Among these volunteers was Nicholas Sevier, another Harvard tutor, who returned to Harvard 16 days later, alive and well. These events further galvanized the Harvard faculty in favor of inoculation.

Not everyone in Boston was so easily convinced, however. A divisive societal debate, often escalating into violence, erupted over inoculations. Mather championed inoculation as a divine gift to spare the population from smallpox. Boylston, as a physician, viewed it as his God-given duty to protect the populace, advocating variolization as the preferred method.

Many in Boston, however, viewed the procedure as flawed, dangerous, and even immoral. James Franklin, Benjamin Franklin's brother, established The New England Courant newspaper during the smallpox epidemic. Its very first issue featured an article criticizing inoculators, questioning, "Can any man infect a family in the morning, and pray to God in the evening that the disease will not spread?"

Other Boston physicians also opposed Boylston's work. Dr. William Douglas, one of the city's few formally trained physicians, made derogatory comments, regularly published in local newspapers like The New England Courant, referring to Boylston as a "quack."

Even some of Mather's fellow clergymen distanced themselves, citing scripture about "not murdering thy brother." However, a few clergy members, including Mather's father, Increase Mather (then president of Harvard University), eventually supported inoculations, allowing Boylston to resume his work.

The resumption of inoculations, however, led to physical attacks and death threats against Dr. Boylston by riotous mobs. Boylston went into hiding for two weeks to avoid further assault. The mob violence then turned to Mather.

After inoculating his nephew, Reverend Walter, Cotton Mather offered him a place to recover from the mild, inoculated smallpox at his home. This offer provoked a mob to hurl a crude bomb with a lighted fuse through the window of Walter's room. Though the bomb did not explode, a note attached to it read: "Cotton Mather, I was once of your meeting, but the cursed lye you told of - you know who, made me leave you, you dog, and damn you, I will inoculate you with this, with a pox on you."

By February 1722, the smallpox epidemic in Boston was on the decline, with no new cases reported. Of Boston's 1721 population of 10,700, records indicate that 5,889 people had contracted smallpox by this time.

Crucially, many Bostonians were already immune to smallpox due to previous outbreaks. Consequently, by February 1722, the vast majority of those susceptible to the disease in the city had contracted it. Of those 5,889 who contracted smallpox, 855 died, representing a mortality rate of about 15% (or one in six people). It is possible that more deaths occurred but went unrecorded. In stark contrast, only six of Boylston's 247 inoculated patients died, a 2% death rate compared to the 15% from naturally acquired smallpox. These compelling statistics were widely noted and published throughout the colonies.

In 1723, Dr. Boylston was honored in London by King George for his pioneering work with inoculation. While there, he published An Historical Account for the Smallpox Inoculated in New England.

Lady Mary Wortley Montagu conducted similar experiments during a simultaneous outbreak in London, further corroborating Boylston's results and confirming the effectiveness of inoculations in preventing smallpox deaths.

In the months and years following the outbreak, Benjamin Franklin, the young 16-year-old publisher of The New England Courant, mocked Cotton Mather and Dr. Boylston for their stance on preventing smallpox deaths. While these words boosted newspaper sales, they would later haunt Franklin. He remained at The New England Courant for only 18 more months, fleeing his brother's physical abuse, before moving to Philadelphia.

Many years later, Benjamin Franklin reflected on this period in his autobiography:

"In 1736 I lost one of my sons, a fine boy of four years old, by the smallpox taken in the common way. I long regretted bitterly and still regret that I had not given it to him by inoculation. This I mention for the sake of the parents who omit that operation, on the supposition that they should never forgive themselves if a child died under it; my example showing that the regret may be the same either way, and that, therefore, the safer should be chosen." (Source: Franklin's Autobiography)

Franklin eventually came to regret his decision to forgo smallpox inoculation for his son, Francis "Franky" Folger Franklin, in 1736, a regret he carried for the rest of his life.

Over time, a combination of research findings (including Franklin's experience), the persistent smallpox death toll, and the academic influence of Harvard University in the colonies firmly established inoculation. It became the primary method to prevent smallpox death and disability in both England and the colonies.

Smallpox inoculation also played a significant role in the American Revolution. On February 5, 1777, George Washington wrote to John Hancock, then President of the Continental Congress, to inform him of his intent to inoculate the entire Continental Army against smallpox. A relevant excerpt from that letter is provided below:

"The small pox has made such Head in every Quarter that I find it impossible to keep it from spreading thro' the whole Army in the natural way. I have therefore determined, not only to inoculate all the Troops now here, that have not had it, but shall order Docr Shippen to inoculate the Recruits as fast as they come in to Philadelphia. They will lose no time, because they will go thro' the disorder while their cloathing arms and accouterments are getting ready." George Washington

While the final draft of the letter to Hancock is presented above, George Washington's aide-de-camp, Tench Tilghman, first penned an earlier draft. This initial version was eventually crossed out and reworded as Washington's decision to inoculate became firmer:

"The small Pox is making such Head in every quarter that I am fearful it will infect all the Troops that have not had it. I am divided in my opinion as to the expediency of inoculation, the Surgeons are for it, but if I could by any means put a stop to it, I would rather do it. However I hope I shall stand acquitted if I submit the Matter to the Judgment and determination of the medical Gentlemen."

Washington clearly harbored tremendous ambivalence regarding the smallpox threat. Should he inoculate his troops or not? His indecision is evident in the revisions and striking out of words in his drafts. This raises the question: why would he use the word "acquitted" in his deliberations and writings about the procedure?

At this time, many states had enacted laws prohibiting inoculation, fearing it would spread smallpox. Washington's hopes of acquittal were therefore justified; these laws placed him in legal danger if he ordered his troops inoculated. With no national consensus on controlling this dread disease and conflicting laws among state and nascent federal authorities, Washington's concern about acquittal and his legal jeopardy becomes entirely understandable.

At the time, 75% of the Continental Army lacked immunity to smallpox. In contrast, most of the British army was immune, having either been inoculated or previously contracted the disease in childhood.

During the height of the American Revolutionary War, George Washington took the decisive action of inoculating his entire army against smallpox through variolization. This clandestine operation was carried out in 11 hospitals across the country in 1777 and at Valley Forge during the harsh winter of 1778. This is considered the first mass immunization campaign in American history. Despite smallpox raging through the American colonies at the time, not a single regiment under Washington's command was incapacitated by the disease throughout the entire war. The resulting immunity of his troops proved crucial to winning the American Revolutionary War.

The smallpox eradication story moves to the year 1796 and introduces Edward Jenner, born in Berkeley, Gloucestershire, England. Orphaned at age five and raised by his brother, Jenner developed an interest in science and nature. Having survived smallpox inoculation as a young boy, he became deeply interested in preventing the disease. At 13, he was apprenticed to a country surgeon and apothecary in Sodbury, near Bristol. It was during this apprenticeship that he overheard a milkmaid declare, "I shall never have smallpox for I have had cowpox. I shall never have an ugly pockmarked face."

Cowpox is a disease in cows that causes blisters and illness, and is genetically very similar to smallpox. Other similar pox viruses, such as horsepox, monkeypox, and dolphinpox, also exist in nature.

[Note: In recent years, Monkeypox has spread outside of Africa where the disease has been more commonly found in the past. This development has raised global health concerns as more and more cases have been identified in humans. Monkeypox symptoms resemble those of smallpox, including fever, headache, and a characteristic rash, although it is generally less severe than smallpox. Effective vaccines and treatments, such as the smallpox vaccine, which offers cross-protection, can help control outbreaks. Public health measures, including surveillance, isolation of cases, contact tracing, and vaccination, are essential to prevent its spread and protect human populations from this emerging disease.]

Milkmaids who handled cows with active cowpox infections often contracted a mild human form of the disease, developing blisters on their hands and arms, along with mild general symptoms like fatigue and anorexia. This illness was almost always mild in humans, in stark contrast to smallpox. Crucially, milkmaids who recovered from cowpox were subsequently protected from smallpox infection.

Jenner concluded that developing a mild cowpox infection in humans—a process known as zoonosis—provided protection against the more deadly smallpox. Zoonosis refers to any disease or infection naturally transmissible between animals and humans. He then sought to explore and utilize this phenomenon as a preventive measure against smallpox.

In May 1796, Edward Jenner encountered Sarah Nelms, a young milkmaid with fresh cowpox lesions on her hands. On May 14, 1796, he inoculated an 8-year-old boy named James Phipps with material from Nelms' cowpox lesions. The boy developed cowpox and experienced mild symptoms, such as anorexia, for a few days before recovering fully.

Two months later, in July 1796, Jenner inoculated the boy again, this time with material from a fresh smallpox lesion. Remarkably, despite the exposure, no smallpox illness developed. Jenner concluded that James Phipps was immune and protected from smallpox. A preventative cure had been found.

Jenner named this new procedure "vaccination." The Latin word for cow is vacca, and for cowpox virus is vaccinia. Thus, at that time, "vaccination" specifically referred to intentionally giving a human the zoonotic disease cowpox to prevent smallpox. Over time, the meaning of "vaccination" broadened to encompass all interventions preventing infectious diseases.

Jenner dedicated the rest of his life to promoting smallpox vaccination. He tirelessly worked to gain recognition for his discovery from the UK's medical society. Notably, Jenner did not seek to profit from his discovery; his sole goal was to protect as many people as possible from smallpox.

In 1800, Jenner sent vaccine material to Benjamin Waterhouse, a professor of physics at Harvard University. Waterhouse introduced vaccination in New England and persuaded Thomas Jefferson to implement it in Virginia. Jefferson proved influential in promoting vaccination across America. He appointed Waterhouse as a vaccine agent in the National Vaccine Institute, an organization established to implement a national vaccination program in the U.S. However, due to the problem of scale, it would take years for this practice to reach the majority of the U.S. population.

For approximately 80 years following Jenner's 1796 discovery, the primary method for disseminating and maintaining the smallpox vaccine supply was human arm-to-arm vaccination using vaccinia strains (cowpox virus). This method was known as Jennerian vaccination. However, this strategy presented two major disadvantages. First, arm-to-arm transmission risked the co-transmission of other infectious diseases, such as syphilis and strep infections. At that time, both diseases were untreatable and potentially deadly.

Another challenge was that the effectiveness of human-to-human transmission of the vaccinia virus (cowpox) in preventing smallpox appeared to diminish with each successive arm-to-arm transfer. The virus seemed to change, becoming less effective when passed between humans. Consequently, a direct source of the vaccinia virus from cows became necessary.

After a lengthy and thorough process, inoculation with material directly from cowpox lesions in young calves gradually replaced older methods for smallpox prevention, including variolization.

The demand for large quantities of potent, uncontaminated cowpox virus from cows for smallpox vaccination spurred the establishment of vaccine farms. These farms repeatedly grew the same strain of cowpox in newborn calves. Giuseppe Negri initiated the process of "animal vaccination" in Naples, Italy, in 1840, sharing it with French medical student Ernest Chambon in 1860.

Chambon convinced his friend Gustave Lanoix to visit Naples and learn the technique. Lanoix returned to Paris with a heifer that had been inoculated with Negri's cowpox virus strain. In 1864, Chambon and Lanoix established the Institute of Animal Vaccines in Paris. The institute initially used Negri's Italian vaccinia virus strain, but later replaced it with a French cowpox strain known as the "Beaugency lymph." This French strain was derived from spontaneous cases of cowpox found in cows in Beaugency, France, in 1866.

To maintain a continuous supply of the cowpox virus, young calves were successively inoculated with the Beaugency lymph. Once the cowpox lesions on the calves matured, the pulp was harvested and ground with a mortar and pestle. This was then suspended in a solution called "vaccine lymph."

This method ensured the consistent production of high-quality smallpox vaccine. Animal vaccination was rapidly adopted around the world. In 1870, physician Henry Austin Martin of Boston introduced the "animal vaccine" concept to the United States. Dr. Martin acquired the vaccinia virus strain from Dr. Jean-Anne-Henri Depaul, Director of the Vaccination Services of the Paris Academy of Medicine. Depaul provided Martin with vaccine from the 258th, 259th, and 260th passages of his continuous series of cowpox lesions, originating from the Beaugency heifer. This "animal vaccine" reached New York in September 1870 and was immediately used to inoculate additional calves. The resulting vaccine was then used exclusively in the United States for the next six years.

Following the Civil War, numerous "vaccine farms" were established across the U.S., mass-producing "animal vaccine." By 1897, at least 14 primary vaccine farms supplied the U.S. market. These efforts led to the widespread use of many variants or different strains of the vaccinia virus vaccine. Modern sequencing technologies are now being used to understand the origins of the various vaccinia virus variants that emerged from these farms during this period. Interestingly, some variants produced on these farms were genetically closer to horsepox than cowpox. Nevertheless, the vaccine proved effective in preventing smallpox.

In response to contamination issues at vaccine farms, Congress passed the Biologics Control Act of 1902. This act mandated that the U.S. Secretary of the Treasury require licenses for the production and sale of vaccines and other biologicals within the U.S. These initial biological licensees eventually evolved into many of the major American industrial vaccine manufacturing companies that exist today.

Three generations of smallpox vaccines were eventually developed to control the disease. The first-generation vaccines utilized the method known as cowpox vaccination.

Second-generation smallpox vaccines were developed using a modified form of the original cowpox-based vaccination. Instead of using the live vaccinia virus, scientists utilized a strain called Modified Vaccinia Ankara (MVA), which had been further attenuated (weakened) to ensure safety while still offering protection against smallpox. This vaccine was less likely to cause complications, though it still carried a small risk of severe disease and even death from the vaccine itself.

Third-generation smallpox vaccines, known as modern or recombinant vaccines, were developed using advanced biotechnology. These vaccines introduce non-replicating vaccinia virus genes into a harmless virus or DNA to trigger an immune response. Examples include MVA-BN and ACAM2000. These vaccines are extremely safe and carry a very low risk compared to their live virus predecessors.

Routine smallpox vaccination is no longer recommended since the disease was eradicated in 1978. However, vaccine stockpiles are maintained for potential outbreaks due to bio-terrorism, monkeypox, or research. The smallpox virus is stored in two authorized laboratories: the CDC in the U.S. and the VECTOR Institute in Novosibirsk, Russia.

During the battle against smallpox, politics played a major role in efforts to control the disease. Anti-vaccination movements emerged during this period and remained active for many years.

Here are the highlights of the battle for the eradication of smallpox:

• 1721: Cotton Mather and Dr. Boylston inoculated 247 people; of these, 6 fatalities occurred.
• 1796: Edward Jenner discovered that vaccination with the mild cowpox virus prevents smallpox.
• 1853: Smallpox vaccination was made compulsory in the UK.
• 1866: The Anti-compulsory Vaccination League was formed in the UK.
• 1879: The Anti-Vaccination League of America was formed.
• 1885: The compulsory smallpox vaccination law was repealed in the UK.
• 1905: Jacobson v. Massachusetts, a U.S. Supreme Court case, upheld states' authority to enforce compulsory vaccination against smallpox. The Court's decision articulated the view that individual freedom must sometimes be subordinated to the common welfare and is subject to the state's police power.
• 1922: Zucht v. King, a U.S. Supreme Court case, upheld the authority of states and the school district of San Antonio, Texas, to exclude unvaccinated students from attending schools in the district.
• 1971: Routine smallpox vaccinations stopped in the U.S.
• 1975: The last wild human case of smallpox due to variola major occurred in Bangladesh. This followed a large outbreak that killed thousands of people in India in the early 1970s. Rhima Banu, then two years old, contracted variola major (severe smallpox) and made a full recovery, though she was scarred for life.
• 1977: Ali Maow Maalin was the last person to naturally acquire smallpox caused by variola minor, a milder form of the disease. On October 12, 1977, Ali, a hospital cook, contracted the disease after riding in a vehicle with two smallpox patients. Massive containment efforts were immediately deployed by WHO workers around him. He recovered, and the disease spread no further.
• 1978: Janet Parker was the last known person to die of smallpox. In 1978, Parker worked as a medical photographer at England's Birmingham University Medical School. Her office was located one floor above the Medical Microbiology Department, where smallpox research was underway. She became infected while working in the building and subsequently passed away from smallpox.

In summary, smallpox was the first infectious disease in human history to be successfully eradicated by a vaccine, preventing millions of deaths and sparing millions more from disfigurement and disability. This accomplishment was achieved despite significant societal objections.

Some observations:

• Smallpox posed a significant threat with mortality rates of 14-35%. Initially, variolization reduced the risk of death, though it still carried inherent dangers. The subsequent development of vaccination with the vaccinia virus further minimized these risks. People accepted the smaller risk of vaccination to protect against the much greater risk of death from natural infection. This concept—accepting a minor risk to prevent a larger one—remains central to modern vaccination strategies.
• Spirited public debate, both individual and in the media, surrounded inoculation and later vaccination. Medical pioneers faced ridicule, mockery, and even physical attacks during smallpox eradication efforts.
• At the outset of the battle to eradicate smallpox, there was no proof of vaccine efficacy and little reliable information on the safety of inoculations.
• The most medically educated were quick to adopt the procedure. Many at Harvard, for instance, took the vaccine themselves and administered it to their families and colleagues. Harvard University has a long and distinguished track record in smallpox eradication. This is still true today, physicians have very high rates of vaccinations for their children.
• The media spread false and misleading information, and unprecedented profit-driven coverage surrounded the smallpox inoculation and vaccination story, often vacillating on vaccination's merits over the years.
• Many people refused the vaccine, leading to regret for some, like Benjamin Franklin, when their loved ones died without the protection of inoculation.
• Inoculation and vaccination mandates were repeatedly enacted and repealed in our country, creating a legal quagmire. Despite laws against inoculation, George Washington took considerable legal risks to inoculate his troops during the Revolutionary War. Forced quarantine was also used to control the disease.
• Court battles erupted over the state's authority to enforce vaccinations, levy fines, impose quarantines, and mandate vaccinations for school attendance and employment. Vaccination became a significant political issue.
• Despite resistance, the dedicated efforts of researchers, vaccine producers, contact tracers, and public health workers, combined with global cooperation, ultimately led to the eradication of smallpox in 1977.
• A virology lab accident released material that led to the death of the last person to die from smallpox. The surrounding immune population and effective quarantine contained the disease, preventing its spread.

Does any of this sound familiar?

Summary:

Over the 300 years since the 1721 Boston smallpox outbreak, humanity achieved the monumental eradication of this dreaded disease. Smallpox remains the only illness completely eliminated through vaccination, a feat that significantly improved global safety. Historically, smallpox was devastating, claiming half of all children and 25% of the population; this monumental achievement, however, is now largely forgotten.

Today, every disease we vaccinate against could resurge if herd immunity is lost due to vaccine hesitancy. Vaccines remain essential for protecting our population against deadly diseases. By valuing vaccines, we safeguard ourselves and future generations from past threats, thereby avoiding a reopening of Pandora's Box.

 Why vaccinate your child? To prevent your child from death and severe disability caused by infectious diseases that have been largely conquered by vaccines.

Many parents who refuse vaccines are themselves protected from those diseases by the vaccines they received as children. The irony is that despite benefiting from safe vaccines and advancements offering improved efficacy and reduced side effects, they choose to leave their children unprotected. 

While the eradication of smallpox is a monumental achievement, the story of every vaccine in use today shares a similar narrative: a once-dreaded disease that posed significant risks of death and disability has been brought under control through an effective vaccination program. This process involves the development of a vaccine, widespread adoption, government mandates for school attendance, and ongoing utilization, all contributing to the successful management of these diseases.