From Farms to Pharma: A “Natural” History of Vaccine Production and Vaccine Skepticism

Abstract

In the era of synthetic biology, vaccine skeptics have made claims that vaccines are “unnatural,” that the technology used to develop them is risky and untested, and that “naturally acquired” immunity is superior to vaccination. Public health practitioners and physicians alike have attempted to respond to these concerns by reminding patients and the public that vaccines generate a “natural” immune response. These negotiations over the language to describe vaccines are nothing new.

This article puts the relationship between vaccines and concepts like “nature” and “natural” in historical perspective. In the mid- to late 19th century, the smallpox vaccine, then the only vaccine available, was propagated on farms. Vaccine farmers—usually enterprising physicians—kept herds of cattle infected with cowpox, cultivating the virus “stock” from which the vaccine was derived.

By exploring how vaccine farmers established and maintained public confidence in their products, we can see that debates over vaccine safety have always involved concerted efforts to persuade the public to place their trust in technologies that might at first seem novel, strange, or even dangerous. More broadly, this article encourages readers to think about the shifting valences of the category “natural,” particularly in a public health context. (Am J Public Health. 2024;114(2):193–201. https://doi.org/10.2105/AJPH.2023.307508)

Opponents of vaccination argue that “natural” immunity acquired through infection with disease is superior to the “artificial” immunity produced by vaccines. Organizations that spread vaccine misinformation have also stoked public fears that the COVID-19 vaccine is particularly dangerous because it is “unnatural” or “synthetic.”¹ These ideas seem to be making an impact. Data suggest that some parents are hesitant to vaccinate young children against COVID-19 because of the perceived novelty of the vaccine and the technologies used to create it.² Many parents who reject vaccines also have a preoccupation with the “natural body,” “natural living,” and “natural childbirth.” As sociologist Jennifer A. Reich points out, public health messaging that emphasizes that vaccines produce a “natural immune response” is a tactful response to these concerns. But such efforts can do little to address parents’ broader concern that they live in a world full of dangerous, invisible, or unnatural toxins and chemicals.³ Concerns about whether the substances that enter our bodies are “unnatural” are not limited to vaccines, but they are uniquely important when applied to a technology that requires widespread adoption to be maximally effective.

Anxieties surrounding corruption and pollution, of both bodies and vaccines, have animated debates over vaccination since its inception. For many in the 19th century, when vaccination first became widespread, the practice seemed to compromise bodily integrity by introducing dangerous foreign matter into the bloodstream.⁴ Those who opposed vaccination argued that it was fundamentally “unnatural” or even “impious to engraft upon a Christian the diseases of a brute.”⁵ But, those who promoted vaccination emphasized its connections with both the laws of nature and the natural world. They framed vaccination as a “singular Gift of Providence” that represented God’s will, rather than defying it.⁶ They insisted that it was far safer than contracting “inoculated smallpox” or “natural cowpox.”⁷ And they also sought to associate the practice with pastoral or rural spaces, which symbolized health and vitality in the 19th-century imagination.

Vaccines, then, have not always been seen as particularly scientific or technological products. In the 19th century, terms like “nature,” “natural,” and “unnatural” were moving targets, and they remain so today. Their definitions are plural and fluctuate over time. This history is a source of both caution and hope. On one hand, specific and historically contingent definitions of “natural” and “unnatural” have been a feature of debates over the safety of vaccines are unlikely to ever fully disappear. On the other hand, vaccine producers and promoters have been successful in adapting their language to persuade people to undergo vaccination. This, too, seems unlikely to change.

FROM ARMS TO FARMS

In 1798, English physician Edward Jenner published An Inquiry Into the Causes and Effects of the Variolæ Vaccinæ, which demonstrated that exposure to cowpox could generate immunity to smallpox in humans. He had learned about the protective power of cowpox from dairy maids and tested it on a series of human subjects.⁸ News of Jenner’s discovery quickly spread around the world, as did the vaccine. Initially, the arm-to-arm method was the most popular. Physicians would administer cowpox scabs or dried pus into a lancet incision, wait until the patient had an inflamed lesion, and then transfer pus from one patient to another.⁹ While many physicians on both sides of the Atlantic embraced vaccination and became involved in governmental efforts to centralize vaccine supplies, others began to express doubts. Physicians disagreed about whether the smallpox vaccine conferred lifelong immunity and debated whether a person needed medical training to safely perform vaccinations. In the United States, these arguments contributed to the wholesale abandonment in the 1820s of efforts to maintain a vaccine supply at the federal level.¹⁰

By the mid-19th century, more serious concerns about vaccination had emerged. For instance, in England, efforts to enforce compulsory vaccination were met with immediate resistance. Parents were concerned that arm-to-arm vaccination could spread “cancer, syphilis, scrofula, or mental illness,” and that it constituted a form of “blood pollution” that was “unChristian.”¹¹ In the United States, the problem was initially one of supply, rather than resistance. During the Civil War, when the Confederate and Union armies began to experience severe smallpox outbreaks, both tried to stop the spread of the disease with mass vaccination campaigns.¹² However, the vaccine was in short supply, and there were many reports of “spurious” or inactive vaccine matter and syphilis transmission. Most gruesomely, men who were already sick or malnourished sometimes developed gangrene and other secondary infections at vaccination sites.¹³ By the 1870s, American medical journals acknowledged that arm-to-arm vaccination could spread illness.¹⁴ The war, then, had a mixed legacy. It left Americans both more aware of the need for vaccination and more cognizant of its potential risks.¹⁵

Those who supported vaccination struggled to secure a vaccine supply and restore public trust in the practice. But they also looked for creative ways to mitigate the risks of vaccination. In 1840, an Italian physician named Giuseppe Negri began maintaining his vaccine supply within a herd of infected cattle, instead of relying on human hosts. It was not until the 1860s, after a medical conference in Lyon, France, that physicians outside of Italy learned of Negri’s method. While they were impressed, there was some suspicion about the quality of the “Neapolitan ‘stock’ of virus.” Some feared that it was the result of “retro-vaccine,” a technique that involved vaccinating cows with vaccine matter harvested from infected humans. Many physicians believed that this technique was unsafe or ineffective.¹⁶ To avoid potential contamination, doctors professed the need for a source of vaccine that was “purely and exclusively animal.”¹⁷ Negri’s “stock” might not have spread far, but his ideas did, and they would soon revolutionize vaccine production.¹⁸

In 1866, a French doctor named Jean DePaul, who was the director of vaccination services for the Paris Academy of Medicine, reported a “spontaneous case” of cowpox in Beaugency, a region along the Loire River.¹⁹ After the authenticity of the Beaugency case was widely reported, American physician Henry A. Martin sent an agent on his behalf to purchase samples.²⁰ Martin became fiercely insistent about the authenticity of his stock—he claimed he had received samples from “the 258th, 259th, and 260th animal of Dr. DePaul’s series, beginning with the heifer of Beaugency.”²¹ By the 1880s, Martin’s farm outside of Boston, Massachusetts, had vaccinated “at least five thousand animals,” and provided many of the most reputable vaccine farms in the United States with their supply of the virus.²² But the virus alone was not enough. Vaccine farm proprietors developed specific production and marketing techniques to cultivate favorable reputations.

CULTIVATION AND SANITATION

The enterprising physicians who owned and operated vaccine farms debated the finer points of vaccine cultivation, but their methods were broadly similar. To begin the process, physicians would move cows to an operating room with stanchions or strap the animals to tables. Cows were then vaccinated by lancet incisions along their bellies and buttocks.²³ This was done anywhere from 10 to 30 times on each animal (Figure 1).²⁴ Some vaccine producers left incisions to heal in the open air, while others protected the developing lesions with cotton and bandages. Once the cow had contracted the disease, scabbing was removed with delicate washing or scraping, and the lymph that leaked from cows’ lesions was collected and poured over lancet tips, which were then left to dry. Some farms stored the liquid in pipettes, selling these tubes of lymph for a higher cost to physicians who preferred to dress their own lancet tips.²⁵ Regardless of their technique, vaccine farm proprietors and their customers agreed that sanitation was paramount.

FIGURE 1—

An Artist’s Rendering of the Process of Harvesting the Vaccine From an Infected Cow

Source. “Points for Inoculation. Where Vaccine Virus Is Grown for Use Against Small-Pox,” St Louis Post-Dispatch, July 22, 1894: 22.

The Civil War had thrown the importance of sanitation into sharp relief. In the aftermath, many American cities established boards of health. These boards were responsible for a range of interventions, including building sewers, relocating slaughterhouses, ensuring a clean water supply, and improving ventilation. At the time, public health policy was based on the idea that disease was caused by miasma, or “bad air,” produced by human waste or decaying plant or animal matter.²⁶ Perhaps unsurprisingly, as cities grew over the course of the 19th century, illness became associated with dirty urban environments, while the countryside was seen as a healthful place where one might go to heal.²⁷ In fact, life in the country was thought to be so restorative that farming, while notoriously laborious, was still seen as a profession “favorable to the enjoyment of sound health.”²⁸ Vaccination raised concerns about bodily purity, but vaccine farms provided an opportunity to associate the practice with the healing power of rural life.

Physicians keenly observed their environmental surroundings in an effort to preserve the health of their patients.²⁹ Those who established vaccine farms, then, thought carefully about where they should be located and communicated this decision-making process to their potential customers. For instance, physician Hamill M. Alexander opened a vaccine farm in Marietta, Pennsylvania, which he called Lancaster County Vaccine Farms. Alexander chose Marietta because he was convinced that vaccine farms thrived in “open country, where pure air, perfect cleanliness and the best sanitary conditions,” could be achieved.³⁰ Alexander implored his fellow vaccine farmers to keep their operations “well ventilated … free from filth … and entirely free from foul or impure air.”³¹ Advertisements for the Lancaster County Vaccine Farms showed a pastoral scene with green fields and rolling hills. Such images emphasized that these natural spaces were located far from the dirt and pollution of urban environments (Figure 2). Vaccine farm proprietors ascribed to the 19th century belief succinctly expressed by English social reformer Edwin Chadwick: “All smell is disease.”³²

FIGURE 2—

Images of the Lancaster County Vaccine Farms Emphasized the Pastoral Setting

Source. Library Company of Philadelphia, Chromolithograph promoting the Lancaster Country Vaccine Farms (Philadelphia: Craig, Finley & Co, 1885), https://commons.wikimedia.org/wiki/File:Lancaster_County_Vaccine_Farms_(17029767503).jpg

VIRAL LINEAGES

Vaccine producers emphasized sanitation to convince customers that their product was of the highest quality. But they also borrowed a strategy from stockbreeders and aimed to establish the pedigree of their viral stock. Pedigree was a record of an animal’s ancestry, which conveyed information about the traits it was likely to inherit. According to 19th century stockbreeders, “the value of any pedigree will depend upon its authenticity, completeness, and the quality … of the animals comprised in the ancestry.”³³ Stockbreeding was not seen as an effort to artificially engineer life. On the contrary, it was often perceived as a noble pursuit associated with the “dignity, social position, and breeding” of the wealthy aristocratic classes who engaged in it. According to historian Harriet Ritvo, individuals who bred cattle had to “exercise constant vigilance” to ensure “the purity of bloodlines.”³⁴ When Martin explained precisely how far removed his viral “stock” was from the “heifer of Beaugency,” he was appealing to this sensibility. For vaccine farmers, safety and efficacy depended upon carefully maintained viral lineages.

Producing Beaugency became both a point of pride and a form of marketing. The Eastern Dispensary in New York advertised lancet quills and tubes of fluid that were “the result of a continued reproduction from the famed Beaugency stock, propagated under our own immediate supervision” (Figure 3).³⁵ The Jenner Vaccine Farm, in Chambersburg, Pennsylvania, relied upon a famous name both for its farm and for the virus it produced. It sold Beaugency virus at a rate of $1.00 for five quills, or $2.00 for tubes of lymph.³⁶ The New York City health department had established its own vaccine farm, which provided for the vaccination of 50 000 to 100 000 people per year by the 1880s. The farm purportedly “propagated” virus that was “a lineal descendent of the Beaugency stock introduced into America by Dr. Martin.”³⁷ By the 1880s, the American medical establishment was increasingly convinced that maintaining a “stock” of authenticated cowpox virus with pure lineages was crucial for maintaining the public’s trust in vaccination.

FIGURE 3—

The Eastern Dispensary Advertised That Its Vaccine Was “the result of a continued reproduction from the famed Beaugency stock.”

Source. “Advertisement 17—No Title,” Medical Record 15, no. 12 (March 22, 1879): 27.

This concern featured prominently in the medical literature of the time. In 1882, the journal Medical News launched a commission to inspect vaccine farms. Demand for vaccination was growing, the commission explained, “due to a wider appreciation of the value and safety of vaccination” and because “boards of health throughout the country” were “dispensing the virus at little or no cost.” As a result, “all matters connected with its production” had become “exceedingly interesting, not only to the profession, but also to the general community.”³⁸ The stakes of vaccine production were high. The commission insisted that anyone who discovered “an original stock of virus of the highest excellence, like the Beaugency,” should ensure that it was “perpetuated by animal vaccination with almost religious care.”³⁹ According to the commission’s reports, the public had begun to refuse “humanized virus,” even during smallpox epidemics. On the other hand, the public reacted to vaccination campaigns with the “freest acceptance” when municipal authorities purchased bovine virus.⁴⁰ Supply had to respond to demand.

The same strategies that vaccine producers used to maintain public trust also protected their economic interests. Martin’s name became nearly synonymous with Beaugency, due in no small part to his penchant for self-promotion. According to Martin, DePaul’s original stock of Beaugency virus had been destroyed during the 1870–1871 Siege of Paris, and Martin’s samples were the last to be distributed.⁴¹ He thus positioned himself as uniquely qualified to determine which vaccine farms propagated authentic Beaugency. As in the world of stockbreeding, pedigree falsification was a serious concern for vaccine farms.⁴² Martin was cutting in his critiques of vaccine farms that made fraudulent claims. “One ingenious propagator advertises that his virus was imported direct from the ‘vast herds of the Duke of Beaugency,’” he complained, “doubtless a bucolic French noble, who … appears in history for the first time.”⁴³ The lineage of Martin’s virus, his professional reputation, and his economic success were one and the same.

By the 1880s, many physicians felt that they should consolidate exclusive control over vaccine farms. In 1883, an article in Medical Record warned that the Board of Health in St Louis, Missouri, had awarded a contract to a vaccine farm run by a “dry goods merchant,” resulting in 10 000 vaccinations without a single “perfect success.” The author argued that this was the risk of allowing vaccination to be a “purely commercial venture.”⁴⁴ That same year, the Medical Society of New Jersey launched a committee to explore “Where and of Whom Reliable Vaccine Virus May be Obtained,” which found that much of the vaccine lymph on the market was “impure and unreliable.” One member of the committee found a specimen containing “epithelial cells, hairs … [and] vegetable substances of various kinds.” The committee concluded that since “the propagation of animal virus” required “very exact management,” the members of the society should purchase their vaccine from Martin’s farm or one run by a physician with a similarly high standing.⁴⁵ These remarks foreshadowed a growing debate about regulation and inspection in a context when what it meant to be a reputable vaccine producer was changing.

VACCINE FARMS UNDER THE MICROSCOPE

The late 19th century saw the rise of bacteriology, which would transform many aspects of public health and public life.⁴⁶ Vaccine production was no exception. In 1885, G. W. McCaskey, a professor at the Fort Wayne College of Medicine, wrote to the editor of Medical Record asserting that it was the responsibility of vaccine farm proprietors to secure a “medical expert” who could enforce the principles of “modern science, and especially practical biology.”⁴⁷ An 1896 newspaper article explained that because of “the progress of bacteriology,” there was now almost no “danger of infecting a vaccinated person with the germs of any other diseases.” The article went on to describe vaccine farms that used tuberculin tests for cows (killing any that tested positive), applied bichloride to disinfect vesicles, carefully ventilated operating rooms, used screens to keep out flies, disinfected knives, and had operators wear “a clean suit of white duck.”⁴⁸ Vaccine producers also added glycerin to lymph to reduce its bacterial count.⁴⁹ The boundary between the farm and the laboratory was beginning to blur.

By the 1890s, boards of health increasingly relied upon bacteriological laboratories to inspect vaccine farms and the products they sold.⁵⁰ Some producers willingly submitted to inspections. For instance, in 1894, H. M Alexander suggested the formation of a “National Board of Health” with agents who would inspect “every Vaccine establishment of the country, and … allow no Vaccine to be sold without a registry number, guaranteeing to the druggist, the physician, and the layman that the article he buys … has received the sanction of the proper authorities.” This, according to Alexander, was an essential step before instituting mandatory vaccination laws, and was preferable to establishing a government-controlled vaccine supply, which would undercut the “superior” lymph cultivated by private producers.⁵¹ Alexander was protecting his own interests in a competitive marketplace. Larger and more established vaccine farms, like Alexander’s, had the resources to access new bacteriological techniques and technologies.

In 1897, the Pennsylvania State Board of Health employed a bacteriologist and veterinarian to inspect vaccine farms. They noted that it was “somewhat humiliating” that three of the four farms in the state were paying little attention to “hygienic precautions or even to ordinary cleanliness.” However, they found it “gratifying to our State pride” to point out that the Lancaster County Vaccine Farms operated with “the strictest observance modern surgical asepsis.”⁵² Alexander, it seems, supported inspections at least in part because he suspected that they would expose his competitors as subpar. Some farms incorporated inspections by or patronage from boards of health into their marketing. The Missouri Vaccine Farm, for instance, informed potential customers that its vaccine was used by boards of health in “St. Louis, Cincinnati, Nashville, Memphis, New Orleans, Kansas City, etc., etc.”⁵³ Smaller vaccine farms generally opposed state inspections, correctly predicting that more robust regulation would make them less competitive and eventually put them out of business.⁵⁴

FARMS BECOME PHARMA

Vaccine production, and the anxieties of those who opposed vaccination, continued to shift. By the turn of the 20th century, bacteriology had eclipsed “Beaugency” when it came to conversations about vaccine safety and authenticity. Vaccine farms gradually transformed into biologics laboratories and pharmaceutical companies, but even this was insufficient to entirely placate vaccine skeptics (Figure 4).⁵⁵ Throughout the 19th century, antivaccination leaders had argued that vaccination went against God’s will.⁵⁶ In 1872, Reverend William Hume-Rothery wrote an antivaccination treatise that characterized the practice as existing “in violent opposition … to the Divinely-established order of nature.” He went on to decry those who “would be a party to the perpetration of this unnatural deed.”⁵⁷ These views persisted in the 20th century, but included added concerns about the fallibility of laboratory safety measures. Such fears were not entirely baseless. In 1901, 13 children died from tetanus in St Louis, Missouri, after being administered a contaminated supply of diphtheria antitoxin.⁵⁸ Soon after, nine more children died from tetanus in Camden, New Jersey. After a thorough investigation, state authorities could find no direct evidence that any diphtheria antitoxin from nearby producers was contaminated. But the damage had been done, and the American public viewed vaccines with renewed suspicion, even as smallpox epidemics were sweeping the country.⁵⁹

FIGURE 4—

By the Turn of the Century, Advertisements Emphasized That While Vaccine Production Was “Situated” on a Farm, It Took Place in a Laboratory With Sanitary Precautions in Place

Source. Boston Public Library, Chromolithograph promoting H. K. Mulford Company (ca. 1870‒1900), https://www.digitalcommonwealth.org/search/commonwealth:tm70nb293

After observing these incidents, Milton Joseph Rosenau, a scientist at the Marine-Hospital Service’s Hygienic Laboratory in Washington, DC, bought samples from eight different major vaccine producers across the United States. In February 1902, he presented his findings to the New York Academy of Medicine, reporting wild variations in the level of bacterial colonies found in vaccines and what one medical journal referred to as a “ridiculous amount of impurity.” Rosenau concluded that, “Our results so far have plainly indicated that the manufacture of vaccines is too important a subject to leave to commercial enterprise without restrictions.”⁶⁰ On July 1, 1902, the Biologics Control Act was signed into law. Manufacturers of vaccines, serums, and antitoxins would need to apply for federal licensing to continue their trade and submit to inspections by a federal board.⁶¹ This system of legal regulation markedly improved the quality of the American vaccine supply, but it also forced at least one third of biologics producers out of business. Some manufacturers could afford to achieve “a scientific image,” and others could not.⁶² That vaccines were a laboratory product, something that could be controlled, purified, and replicated, was considered a mark of safety that distanced them from their agricultural origins.

However, much has changed in the century since. The belief that we will eventually conquer infectious disease—prevalent in the middle of the 20th century—has faded, as has confidence that the solutions to society’s most pressing problems will be crafted in a laboratory. As historian Elena Conis has shown, the most recent iteration of vaccine skepticism is buoyed by a mistrust of big corporations—particularly pharmaceutical companies—and the government. Like the earlier antivaccination movement, this one is grounded to some degree in historical reality. By the 1970s, environmental disasters, unethical medical experimentation, and medical disregard for women’s health issues had all contributed to a broad loss of faith in the potential of technological innovation and in medical authority.⁶³ The journey of “synthetic” technologies has been similar. In the mid-20th century, many Americans thought that synthetic products were superior to “natural” ones. But when scientific innovation resulted in indiscriminate chemical use and ecological disasters, this optimism began to fade.⁶⁴

According to anthropologist Sophia Roosth, terms like natural, organic, and traditional are now prized adjectives for foods and fibers among those who can afford them. There is a gap, then, between the way the public relates to the categories “natural” and “nature” and the ways some scientists discuss them. Synthetic biologists insist that the work they do is “undoubtedly an improvement upon nature … [that] life manufactured following human logic and design principles … surpasses and refines any naturally occurring organism.”⁶⁵ This belief became even more evident as efforts to develop the COVID-19 vaccine began. In March 2020, for instance, one headline read: “Synthetic Biologists Think That They Can Develop a Better Coronavirus Vaccine Than Nature Could.”⁶⁶ They may well have succeeded. But it is not clear that the American public sees it that way. While the data are still provisional, it appears that the COVID-19 pandemic did not bolster public confidence in the health care or pharmaceutical industries and may even have damaged it.⁶⁷ And, while Americans’ overall confidence in childhood vaccines remains high, their skepticism about the safety of the COVID-19 vaccine appears to be much higher.⁶⁸ Overcoming vaccine hesitancy in the era of synthetic biology will require deft marketing and concerted efforts to educate the public. Scientists and those who communicate their findings to the public will have to tread carefully to ensure that when they suggest that vaccines are “better” than nature, they do not also imply that they are contrary to it.