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The debate about COVID-19 vaccinations rages with fury -- to an extent that has gone beyond the realm of medicine or rational thought. Some readers might believe that those who are strongly grounded in science are inevitably vaccine advocates, whereas those who are vaccine resistant are willfully ignorant of the facts or live life as religious fanatics.

Such assumptions are horribly unhelpful in the current era. But a short history lesson demonstrates that these preconceptions are historically inaccurate, especially if we explore the origins of vaccination in the U.S. Americans have a strong tradition of both vaccine advocacy and resistance, and the inceptions of these movements are astonishing. We can gain important insights by going back 300 years -- to the Boston Smallpox Epidemic of 1721.

Prior to its eradication, smallpox was an exceptionally serious infectious disease caused by one of two variants of the , variola major and variola minor. Afflicted patients developed fever, vomiting, buccal ulcers, and fluid-filled blisters on the skin which formed highly infectious scabs. The mortality rate was 30%, and it was particularly deadly in children; survivors were left with severe scarring of the skin and often blindness. The disease was spread between people or through contaminated objects.

Smallpox plagued human beings since the dawn of history, typically occurring in outbreaks. For thousands of years, the disease was rampant in Europe, Asia, and Africa, and populations in these continents developed some resistance over the centuries. But in disease-naïve peoples without immunity, the introduction of smallpox . The European conquest of the Americas was almost entirely attributable to the importation of smallpox (and other infectious diseases) to the Aztec and Incan empires. In the the landing of Cortes in Mexico, 25% to 50% of the indigenous population died from the disease. Even in more recent history, smallpox ravaged mankind: in the 100 years prior to its eradication, smallpox was responsible for the deaths of 500 million people.

People almost never contracted smallpox twice, and those with a mild infection (typically caused by variola minor) were immune for life. Accordingly, many societies developed efforts to intentionally expose people to tiny amounts of virus, hoping to induce a short-lived illness that would have very low morbidity and mortality but would induce permanent immunity to serious disease. The procedure of exposing people to an attenuated load of smallpox virus with the intent of inducing immunity was referred to as variolation.

Different regions of the world developed different . In the earliest record (from the 15^th century), Chinese practitioners collected dried-out scabs from mildly infected patients and delivered a powdered form by nasal insufflation. For centuries, Brahmin practitioners in India punctured the skin of the upper arm using a sharp iron needle that had been dipped into a smallpox pustule. Arabic women in the Sudan transmitted small amounts of virus through a cloth band that was placed onto a small cut in the skin.

Word of variolation eventually spread to Europe, albeit slowly. The Danish physician Thomas Bartholin wrote about variolation in 1675. The first scientific paper describing variolation was by the Italian physician Emmanuel Timoni in Philosophical Transactions. But the paper went unnoticed in England for years. Yet, surprisingly, it generated considerable interest in Boston, one of the central hubs of the British colonies in North America.

was a New England clergyman who served as the ultraconservative theocratic leader of the Puritan community in Boston in the late 17^th and early 18^th century. Known for his religious fanaticism, Mather played the central role in igniting the furor leading to the Salem witch trials in 1692, which accused more than 200 people of consorting with the Devil and led to the execution of 19 people -- one of the most notable examples of mass hysteria in colonial America. To many, Mather's name lives in infamy. But his legacy is far more complex.

In 1706, Mather purchased a West African , who described how people in Africa had been using variolation for centuries to protect themselves from smallpox. Onesimus had been inoculated as a child, and he was one of many. The practice was so effective in conferring immunity that African slaves sold in Massachusetts at the time were deemed to be if they bore the scar of variolation. Subsequently, Mather read Timoni's 1714 paper and became committed to introducing variolation in New England before the next smallpox outbreak might occur. These outbreaks typically occurred every 10 years, but miraculously, there had been no outbreak since 1702. By 1721, Bostonians were getting overconfident.

Citing Onesimus as a main source, Mather wrote letters to physicians throughout Boston, advocating variolation, but his proposal met with stiff resistance from both the medical community and the general public, who were suspicious of "African" medicine. Many ridiculed Mather for relying on the testimony of a slave and raised suspicions that variolation was a ploy to poison white citizens. As historian :

"As word spread of the new medicine, the people of Boston were terrified and angry. According to Mather, they 'raised an horrid Clamour.' Their rage came from many sources; fear that inoculation might spread smallpox further...and a righteous fury that it was immoral to tamper with God's judgment in this way. There was a racial tone to their response as well, as they rebelled against an idea that was not only foreign, but African (one critic, an eminent doctor, attacked Mather for his 'Negroish' thinking). Some of Mather's opponents compared inoculation to what we would now call terrorism -- as if 'a man should willfully throw a Bomb into a Town.' Indeed, one local terrorist did exactly that, throwing a bomb through Mather's window, with a note that read, 'COTTON MATHER, You Dog, Dam You; I'l inoculate you with this, with a Pox to you.'"

In 1721, a horrific smallpox epidemic struck Boston, afflicting more than half of the city's 11,000 residents. Of the 6,000 people who contracted the disease, 14% died. But Zabdiel Boylston, a Bostonian physician who believed in Mather's advocacy of variolation, inoculated his own son, his slaves, and as many people who would agree to his proposal. The mortality rate in the 248 people variolated by Boylston was 2.5% (no P values here -- Karl Pearson did not invent them for another 179 years!). Nevertheless, Mather, a religious fanatic (by anyone's definition), had been right.

You might think that the experience with variolation in Boston might be convincing to those who believed in science in the British American colonies. But this proved not to be the case.

Benjamin Franklin was North America's first great scientist. A leading intellectual of his time, Franklin was a major figure in the American Enlightenment, famed for his discoveries regarding electricity, his many inventions, and his work to establish the University of Pennsylvania and Pennsylvania Hospital, the first hospital in the U.S. By anyone's definition, Franklin was the embodiment of science.

Born in Boston, Franklin's first career was as a writer of opinion pieces for a newspaper established by his elder brother, James Franklin. His brother despised Mather, and thus, when Mather emerged as an advocate for variolation, James Franklin was determined to take the opposite viewpoint, purely out of spite. He characterized Mather as the "arch-hypocrite of New-England" who had abandoned his religious principles by his support for the smallpox inoculation. In 1721, James Franklin established The New-England Courant (the first independent newspaper in the U.S.) to give voice to the opinions of , a highly qualified but controversy-stoking physician, who was vehemently opposed to variolation and wrote polemical articles condemning the practice. Benjamin Franklin and helped to write articles that for his brother's newspaper.

Over the next 15 years, Benjamin Franklin eventually became a supporter of variolation, but he failed to inoculate his 4-year-old son, who died of smallpox. Opponents of variolation circulated rumors that the child had actually been inoculated and that the vaccination was responsible for his death. When Franklin became aware of the gossip, he published a declaration in his own newspaper (The Pennsylvania Gazette), stating: "I do hereby sincerely declare, that he was not inoculated, but receiv'd the Distemper in the common Way of Infection." Years later, Franklin , "In 1736 I lost one of my sons, a fine boy of four years old, by the small-pox, 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 parents who omit that operation."

To be sure, variolation is no longer practiced. In 1798, British physician and scientist Edward Jenner proposed that inoculation be carried out using the less virulent cowpox (variolae vaccinae), a safer approach to the prevention of smallpox ("vaccinae," the species name for cowpox, is the basis of our word "vaccination"). As a result of Jenner's work, the last case of naturally occurring smallpox in the U.S. occurred in 1948, and smallpox was eradicated worldwide by 1977-1980.

Those who read this essay will recognize striking similarities between the events of 1721 and the events of today. In both epidemics, fear and misinformation were rampant; there were sharp divisions regarding the role of inoculation in the prevention of a serious viral disease; and the discourse yielded highly polarized and politicized viewpoints (replete with accusations of racism) that often degenerated into personal attacks. But above all, it is notable that 300 years ago, the strongest vaccine advocate was a religious fanatic, and America's first great scientist began his career as a vaccine skeptic.

My advice: making assumptions and value judgments about the roots of vaccine advocacy and resistance is a horribly insensitive way of solving our current societal trauma. And doing so belies history.

Milton Packer, MD, is currently distinguished scholar in cardiovascular science at Baylor University Medical Center at Dallas and visiting professor at Imperial College in London. Packer is an internationally recognized clinical investigator who has made many seminal contributions to the field of heart failure, both in understanding its mechanisms and defining its rational management. His work has spanned more than 40 years and has established the cornerstone of the current modern treatments for heart failure, including ACE inhibitors, beta-blockers, angiotensin neprilysin inhibitors, and SGLT2 inhibitors. He has authored nearly 600 peer-reviewed publications and has been the overall principal investigator for 20 large-scale international trials of novel interventions in heart failure.

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