From Cotton Mather to Dr Fauci: Historical Markers of Vaccine Hesitancy

Vaccine hesitancy might be perceived as a new phenomenon, but its history is as long as the history of immunization.

After completing this article, readers should be able to:

1. Describe determinants of vaccine hesitancy.

2. Appreciate the long history of vaccine hesitancy.

3. Apply determinants of vaccine hesitancy to devise strategies to mitigate it.

Immunization, one of humanity’s most important medical advances, has a firmly established role in current health-care systems and is one of the most cost-efficient public health tools. (1) Vaccine discovery and vaccination programs implementation led to the eradication of smallpox; elimination of poliomyelitis in the Americas; and control of measles, rubella, tetanus, diphtheria, Hemophilus influenzae type B, and other infectious diseases in the United States and other parts of the world. (2) According to the World Health Organization (WHO), “vaccination currently prevents 2–3 million deaths a year, and a further 1.5 million deaths could be avoided if the global coverage of vaccinations improved.” (2) Vaccination has vastly improved our current society because of a decrease in disease cases, hospitalizations, deaths, and health-care costs. (3)

As long and tumultuous as the story of immunization is, so is that of its constant companion, the anti-immunization movement. Most vaccine discoveries have been met with a range of opinions, from enthusiastic acceptance and unbridled optimism to vehement opposition. Somewhere around the middle of the spectrum, between unconditional adoption and steadfast denial, lies vaccine hesitancy. Although antivaccination opinions have been around for as long as vaccines have, the term “vaccine hesitancy” was coined recently, becoming prominent in the public sphere and as a research topic during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) pandemic.

In this review, we describe several historical immunization moments and analyze them using the “5Cs” vaccine hesitancy framework.

Vaccine hesitancy has been defined by the WHO Strategic Advisory Group of Experts as “delay in acceptance or refusal of vaccines despite availability of vaccine services.” (4) In 2019, WHO listed vaccine hesitancy as a top ten threat to global health. (2) The so-called “3Cs” model describes the determinants of vaccine hesitancy as: confidence, complacency, and convenience. (5) Further work in establishing a framework for understanding vaccine hesitancy expanded the model to include the 5Cs:

1. Confidence: Trust in public health science and the safety and effectiveness of vaccine.

2. Complacency: Perception of the disease as a threat.

3. Constraints: Structural and psychological barriers related to vaccination intention and uptake.

4. Risk calculation: Comparison of personal health risks of infection versus vaccination.

5. Collective responsibility: The desire and willingness to become vaccinated to protect others or to generate population or herd immunity.” (6)

The 5Cs model provides a context for research about vaccine hesitancy and a structure to monitor changes in vaccine hesitancy over time.

By 1720, when smallpox reached Boston Harbor aboard a commercial ship, 18 years had passed since the previous outbreak; therefore, a fair proportion of Boston’s population was susceptible to the “speckled monster.” After the customary public health measures such as sanitation, isolation of sick people in “pest houses,” and ship quarantines were implemented and failed, the city found itself in the middle of a violent outbreak.

Cotton Mather, a prominent Puritan clergyman who was known for his role in the Salem witch trials, was a man with a range of eclectic interests, including medicine and science. He was familiar with inoculation against smallpox through 2 quite dissimilar sources. First, there were the reports in the Philosophical Transactions of the Royal Society of London for Improving Natural Knowledge, published by physicians familiar with the technique from their work in the Middle East. At the time, inoculation was gaining popularity in England thanks to Lady Wortley Montague, a former Ottoman Empire ambassador's wife. Herself a victim of smallpox, with scars on her beautiful face to prove it, she learned about ancient methods of preventing aggressive forms of smallpox by inserting tiny amounts of infectious material, such as scabs or pustule fluid in the skin of healthy subjects.

The second source of Mather’s familiarity with inoculation was through 1 of his slaves, Onesimus, a gift to him from his congregation. When Onesimus was asked if he was previously infected with smallpox, he gave a peculiar answer: “Yes and no.” He had been inoculated with smallpox in the Western African Coast and when infected with smallpox, had a more benign form of the disease.

By 1716, Mather had already written a communication to the Royal Society proposing the inoculation of the vulnerable Bostonian population to prevent the devastating effects of smallpox. (7) His letter remained without an answer but, when confronted with the 1721 outbreak, Mather submitted the same proposal to Boston’s 14 physicians. He only managed to persuade one of them, Zabdiel Boylston.

With a reputation already established as a skilled and daring surgeon (credited with the first mastectomy procedure), Boylston undertook the new practice of inoculation based solely on 2 reports from the Royal Society and knowledge gathered from the African slave Onesimus. As a testament to his faith in inoculation, 1 of the first 3 people on whom he tried the procedure was his own son. (8) By the end of the outbreak, in 1722, Boylston inoculated 248 people, 246 of whom survived. (8) Of the 5,759 townspeople who contracted smallpox during the epidemic, 844 of them died. (9)

Demonstrably safer than the natural disease, inoculation (or variolation) had its own risks, including the transmission of bloodborne diseases such as syphilis and tuberculosis, and the transmission of smallpox itself. It was not until 1766, when George Washington mandated the procedure for the whole Continental Army, that inoculation gained widespread acceptance. Afterwards, it remained the main preventive measure against smallpox until the introduction of Edward Jenner’s vaccination.

While witnessing the first immunologic experiment, another revolutionary event took place in Boston at the same time, the birth of independent colonial journalism. The vibrancy of this new media contributed to the heated public debate sparked between 2 warring factions: the proinoculation camp, led by clergy and Cotton Mather, and the anti-inoculation camp, led by Boston’s only physician with formal medical education, William Douglass. Eerily familiar to the contemporary reader, the pamphlet wars led to bitter animosity and even physical violence. “COTTON MATHER, You Dog, Dam You; I’ll inoculate you with this, with a Pox to you” was written on a note tied to an unexploded bomb thrown into Mather’s house. (10)

In this historical account of the 5Cs model, one can recognize hints of modern determinants of vaccine hesitancy: confidence, constraints, and risk calculation. Confidence was tested when 2 important recipients of public trust, the clergy and the medical professionals, found themselves on opposing sides of the debate and attacked each other viciously. Constraints were felt by an individual in a small community (Boston at the time had a population of 11,000) with a highly active media. Certainly, risk calculation played a significant role, given the risks associated with a new and unproven procedure.

It is quite sobering, looking back 3 centuries to find arguments and behaviors so similar to the ones observed during the recent response to the introduction of COVID-19 vaccines: a sharply divided society, whipped into a frenzy by media and opinion leaders, aggressive public discourse, and skepticism in the face of a new therapy perceived as insufficiently studied.

Small outbreaks of poliomyelitis were recorded in the United States starting in the last part of the 19th century. Its incidence grew steadily throughout the first half of the 20th century, reaching a peak in the summer of 1952, with 60,000 cases and 3,000 deaths. (11) Widespread images of children with leg braces and crutches and large wards filled with iron lungs filled an entire nation with fear. The threat was ubiquitous in the national conscience. In fact, a national poll in 1955 found that “polio was only second to the atomic bomb as the thing Americans feared the most.” (12)

Stricken with polio himself at the age of 39 years, President Roosevelt was instrumental in raising funds for polio-related research and treatment support through the National Foundation for Infantile Paralysis (NFIP). A fundraising juggernaut, the foundation was enormously successful in turning poliomyelitis into the most acute health-care problem the country was facing. Though the number of deaths caused by polio was much lower than those caused by more common diseases such as pneumonia, the emotional impact of its victims, mostly young, was overwhelming. The March of Dimes campaigns, organized by NFIP, engaged everybody, from school children to Hollywood celebrities in the fight against a common enemy. (13)

Multiple laboratories, with grants from NFIP, were engaged in poliomyelitis research. Dr Jonas Salk, medical researcher at the University of Pittsburgh, building on his previous work on the influenza vaccine, was able to inactivate the polio virus while preserving its immunogenicity and use it to develop an antipolio vaccine. With positive results from an initial pilot trial, the Salk vaccine was tested in 1 of the largest and most publicized trials ever performed. This massive financial and logistical undertaking sponsored by the NFIP involved 1.5 million subjects and 300,000 volunteers. (14) The results of the trial, proclaiming the vaccine was “safe, effective and potent” were announced on April 12, 1955, 10 days after FDR’s death. The news triggered a national celebration. Dr Salk himself quickly became the subject of public adulation and the center of a veritable media frenzy, making him the first physician celebrity. (15)(16) It took almost 70 years for another physician celebrity, Dr Anthony Fauci, to reach the level of fame Dr Salk attained.

Only hours after the results of the trial were announced, 5 pharmaceutical companies were granted licenses to produce the long-anticipated vaccine. Mass vaccination campaigns were undertaken shortly afterwards. NFIP again played a key role in the vaccine distribution, not only through its organizational efforts, but also through funding of the vaccine for all first- and second-grade school students, the population considered to be at the highest risk for contracting the disease.

Two weeks after the campaign distribution started, the Public Health Service started to receive reports of children getting sick with poliomyelitis after receiving their vaccine. The Communicable Disease Center (currently the Centers for Disease Control and Prevention) launched an investigation through its rapidly established Epidemic Intelligence Service and found that 120,000 vaccine doses, manufactured by the Cutter Laboratories in Berkeley, California, contained live poliovirus. (17) Among the children who had received the faulty vaccine, “40,000 developed abortive polio (characterized by headache, stiff neck, fever, and muscle weakness), 51 were permanently paralyzed, and five died…113 people in contact with the children who received the Cutter Laboratory vaccine were paralyzed and five died.” (17)

Numerous reports were written about the difficult transition from Dr Salk’s formaldehyde inactivation technique to mass production. In fact, Cutter Laboratories was not the only pharmaceutical company that encountered difficulties. Wyeth, 1 of the 5 companies licensed to produce the vaccine, also had live vaccine in some of its product but with a much lower incidence. (18) There has been less documentation and commentary on the government’s role in the testing and distribution process that made such a public health disaster possible. As is still the case, the role of government in health care at the time was a matter of heated debate. Conservative-leaning politicians argued that any governmental involvement more than the licensing of private companies for production and distribution was equivalent to the introduction of “socialized medicine through the back door,” while their liberal counterparts supported aggressive government involvement in massive, timely, and fair vaccine distribution. (19)

Despite President Eisenhower’s support for unrestricted vaccination access for children, his cabinet performance in bolstering vaccine testing and building distribution channels was less than exemplary. In fact, the lack of strict testing procedures at the time of the antipolio vaccine launch was, at least partially, to blame for the unfortunate consequences of its speedy approval. In response to reports of vaccinated children getting sick, the Surgeon General’s actions ran the gamut from denial, to defense of Cutter Laboratories, to partial shut-down, and later to complete shutdown of the antipolio vaccination program. (17) In addition, the chaotic involvement of the Health, Education, and Welfare Department in vaccine distribution exacerbated the public’s well-justified fear and anger. With stricter quality control measures in place, the antipolio vaccination program was restarted in May 1965, but by that time, public confidence was irreparably damaged. The incidence of poliomyelitis in the United States decreased sharply only after the eventual introduction of Sabin’s oral vaccine. (20)

Besides the obvious result of increased vaccine hesitancy, the Cutter incident led to an increased governmental involvement in the oversight of vaccine production and distribution. In the lawsuit filed against Cutter Laboratories on behalf of Anne Gottsdanker, 1 of the children paralyzed from a faulty vaccine, the company was found liable but not negligent. (21) The ruling opened the pharmaceutical industry to an onslaught of lawsuits and thus, at the beginning of the COVID-19 pandemic, only 4 companies were involved in vaccine development and production.

The introduction of the Salk antipolio vaccine could have not come at a more favorable moment, from a vaccine hesitancy perspective. It came at a time of relative political calm and prosperity, of high confidence in science, minimal complacency (polio being perceived as a major public health threat), with favorable risk calculation and collective responsibility. Unfortunately, the Cutter incident completely shattered the public trust in science, pharmaceutical companies, and governmental agencies. In its aftermath, theories such as the link between the diphtheria-tetanus-pertussis vaccine and neurologic damage or the link between the measles-mumps-rubella vaccine and autism found a fertile ground. As a result, vaccine hesitancy grew to a such extent that we see today outbreaks of vaccine-preventable diseases such as measles, mumps, and pertussis. (22)

COVID-19 vaccine development, building on 2 decades of work in coronavirus vaccine research, was an enormously impressive scientific success. Only 1 year passed between the virus emergence and the administration of the first m-RNA vaccine. (23) Since November 2022, it is estimated that the US COVID-19 vaccination program has prevented 3.2 million deaths, 18.5 million hospitalizations, and 120 million COVID-19 infections, and has saved $1.15 trillion in medical costs. (24) Despite these staggering numbers, one-third of the US population is unsure about or refuses COVID-19 vaccination. (25)

Judging from the perspective of vaccine hesitancy determinants, apart from some new nuances like the widespread disinformation made possible by social media, the same factors are present in COVID-19 vaccine hesitancy: lack of confidence, complacency, constraints in vaccine administration, unfavorable risk calculation, and lack of collective responsibility. A lack of confidence in scientists could be seen in the example of Dr Fauci, the head of the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health, who was rumored to have funded a Wuhan laboratory to transform an innocuous virus into a lethal weapon. (26) An atmosphere of complacency was suggested by the widespread belief that COVID-19 infection was not worse than a common cold. A vaccination program with a less than successful start created constraints to vaccine uptake. Many also displayed an unfavorable level of risk calculation, rationalizing that getting infected was less dangerous than getting injected with a microchip, for example. Further, there was a lack of collective responsibility, especially in the parts of the country where vaccination was politicized, and vaccine refusal was viewed as a badge of honor.

Vaccine hesitancy has roots deep within the social fabric, dating back to times before vaccines, if one considers the anti-inoculation sentiments from the beginning of the 18th century. Over time, myriad factors have influenced vaccine decision making, with their significance ebbing and flowing. Given its enduring nature, vaccine hesitancy cannot be dismissed or taken lightly. The variables influencing immunization decisions often shift with the social context, but 1 constant remains central: confidence. Trust in science, authorities, public discourse, and health-care providers is the bedrock upon which successful vaccination programs are built. While it is a tall order to expect vaccine hesitancy to fade away entirely, by fostering trust and open communication, its impact can be diminished. To effectively cultivate confidence, we propose 3 primary approaches:

It is essential to be open about the vaccine development and approval processes, potential side effects, and the benefits of vaccination. When people understand the rigorous scrutiny vaccines undergo, they are more likely to trust their safety and efficacy. Moreover, addressing concerns head-on, rather than dismissing them, promotes open dialogue. Using plain language, clear visuals, and relatable examples can demystify complex topics.

Local community leaders, religious figures, or even celebrities can wield considerable influence over public perceptions and actions. Engaging with these individuals to share accurate vaccine information can be very impactful, as was demonstrated with the COVID-19 vaccination program.

Campaigns tailored to specific cultural and demographic groups are more impactful. Understanding the beliefs, values, and concerns unique to each group allows for the creation of messages that speak directly to them. By employing familiar faces, voices, and languages in campaign materials, a sense of community and belonging is cultivated, further encouraging immunization.

While vaccine hesitancy is unlikely to disappear, these strategies can pave the way for more confident and informed immunization decisions. The aim is not to persuade through pressure but to inform, understand, and build trust. A respectful and inclusive approach stands the best chance of mitigating the effects of vaccine hesitancy.