In parallel with the attempts to visualize this new virus (which was called Marburg, based on the location of the first reports of the disease), work was afoot to determine how the virus had found its way into Germany and Yugoslavia. It was understood a single Marburg-infected monkey must have triggered the crisis. After some extraordinary epidemiological detective work, it was determined the victims had all been involved in vaccine research and each had come into contact with monkeys days or hours before their symptoms began.28 Strangely, the monkeys responsible for initiating the outbreaks in Belgrade, Frankfurt, and Marburg were each from a different source, so a single point of contamination seemed highly unlikely. As is often the case in detective work, the cause of the outbreak in retrospect resulted from a series of unlikely and highly unfortunate events with plot twists that would be unbelievable if ever inserted into even the worst Hollywood B-movie.
On June 5, 1967, the tiny nation of Israel was facing imminent invasion from much larger neighbors to the north, south, and east.29 Though vastly outnumbered, the Israeli Defense Forces (IDF) launched an audacious series of preemptive airstrikes that utterly devastated the Egyptian, Jordanian, and Syrian air forces in quick succession. The fighting was particularly hot over the skies of Egypt, which bore the heaviest brunt of the blow from the Israeli jets.
The air combat over the Sinai and into the heart of Egypt caused most airlines to divert or cancel flights from Africa to Europe. Among the affected were multiple planes containing cargo of East African Grivet monkeys (Cercopithecus aethiops), a favorite of researchers and vaccine developers. Rather than being transported directly to Germany or Yugoslavia, as would have been routine, the planes were forced into a flight path far to the west and were then diverted to London.30 A complicating factor was that London was amidst an airport strike that effectively shut down freight and passenger transfers. Consequently, many cages of monkeys sat for two days in an airport hangar. Complicating things further, at least two monkeys escaped from their cages, gaining free access to the warehouse before finally being recaptured. During this unanticipated and eventful stay in Britain, the monkeys were apparently in sufficiently close quarters that one infected monkey was able to transmit Marburg to others. At the time of infection, it was presumed that Marburg spread solely by direct contact. Consequently, the two temporarily liberated monkeys were implicated as the culprits responsible for transmitting the virus from cage to cage and thereby seeding the infections that would blossom simultaneously in three cities and two countries. As revealed by accidental events many years later in Reston, Virginia, and intentional events conducted by the Soviet, Russian, American, and British biowarfare experts, we now know that Marburg and its closest cousin, Ebola virus, retain the ability to spread infection via an airborne route as well.31, 32, 33 Thus, the exact means by which the disease had spread remains a bit of a mystery.
Returning to the story of diphtheria, the improvements in antisera production, largely made possible through the intervention of Paul Ehrlich (though again, his contributions were largely ignored by Behring), facilitated widespread availability. The public health outcomes were dramatic. The Hôpital des Enfants Malades in Paris witnessed a 50 percent decline in the death rates of children with diphtheria.34 Similar findings were reported throughout Europe. By the turn of the century, most major American cities had adopted the practice. However, the popularity of antiserum was destined to serve up other victims as triumph soon gave way to tragedy.
The St. Louis Incident
The early 20th century was a tough time to be a horse. This was a period of great transition, when a millennia-old reliance upon our four-footed equestrian helpers was supplanted by gasoline-powered mechanical contraptions. What to do with the excess animals? The discoveries out of Berlin and Paris provided one solution. Within two years after word spread about the outcomes attributed to Behring, major cities throughout the world mobilized to produce diphtheria antisera. The example of New York City is typical. Public health officials launched a series of studies to immunize virtually anything with four legs with the goal of developing life-saving antisera. Experiments were conducted with dogs, goats, horses, and sheep, but just as Behring had observed, the horse was found to be the most efficient factory for producing the much-needed diphtheria remedy.35, 36 The city maintained a stable of a baker’s dozen of these animals, primarily retired service animals, and periodically drew blood from the immunized animals to keep a steady reserve of the medication. These animals were extolled by the media and revered by the public as lifesavers, and the fodder and housing for these animals were underwritten by ample donations from a grateful public.
It may come as a surprise to many on either coast of the United States, but the city of St. Louis has a long tradition as a progressive innovator. A site just a few miles east of the modern city had served as the capital of the Native Mississippian culture, a civilization that spread from as far north as the Canadian border to Florida and from the Atlantic to the Red River valleys. Although the modern city of St. Louis was founded by French immigrants as a fur trading post in the mid-1600s, its population surged dramatically in the wake of the failed European socialist uprisings of 1848. Specifically, many German socialists relocated to St. Louis, and the city’s population swelled eightfold from 1840 to 1860, reaching 160,000 (passing New Orleans) and eventually surpassing all other American cities except New York, Chicago, and Philadelphia by 1900. The socialist-led waves of immigration drove other innovations, such as the creation of urban parkland museums, all of which were launched and remain free to the public. For example, Forest Park in west central St. Louis is twice the size of Central Park in New York. This land served as the site of the 1904 World’s Fair and the third ever Olympic Games, the first and only time the same city has served both roles at the same time.
Amidst the excitement associated with planning for the upcoming events, St. Louis’s city fathers were eager to embrace the new antisera technology. At the same time New York was initiating their horse-based program, the St. Louis Health Commission established a factory and farm in Forest Park in 1894. True to its socialist roots, the city precluded private-sector companies from manufacturing or distributing the antitoxin, as the city intended to offer it for free to the poorest of the population.37 The city also recruited a physician by the name of Armand Ravold, whose training was conducted in Paris and overseen by none other than Louis Pasteur, to lead the diphtheria antisera program. For more than five years, Dr. Ravold’s program was the talk of the town and allayed parents’ fears that the Spanish Strangler would come for their child.
On January 8, 1899, an article in the local newspaper, the Post-Dispatch, reported the stabling of a herd of horses in Forest Park. Some of the animals were dedicated solely to the production of diphtheria antitoxin.38 The Post-Dispatch was a struggling local newssheet that had been put up for auction in 1878. It had been purchased by a Hungarian immigrant by the name of Joseph Pulitzer (and was led by a member of the Pulitzer family until 1995). Joseph was an entrepreneurial publisher, who later bought the New York World (also at an auction), founded an eponymous prize for reporting, and introduced the concept of sensational headlines, better known today as yellow journalism.39 One of these headlines would highlight the story of a horse named Jim.
Photographs of the time reveal Jim was good-natured, powerful, and large. As a young colt, Jim pulled ambulances throughout town, but as the years went by, Jim slowed down and was retired to pull milk wagons (which don’t require quite as much speed or stamina).40, 41 Eventually, these wagons too became overly burdensome, and in 1898, Jim was sold to the St. Louis Health Commission to serve his remaining days as a living and breathing factory for the production of diphtheria antitoxin.42
Ever the vigilant worker, Jim reliably produced high quality product, contributing more than 30 quarts of serum over a few years.43 Dr. Ravold bled Jim on September 30, 1901 and obtained what would become his last contributions to public health. Two day later, Jim’s
handlers noticed an anxious expression on his face. His tail was rigid and held out straight, the telltale signs of tetanus. Ironically, the local veterinarians did not have access to tetanus antisera, and the reliable old workhorse had to be euthanized. As word of this became known, Dr. Ravold instructed the elderly janitor, Henry Taylor, who happened to be nearby at the time, to discard the sera obtained two days earlier. It is not entirely clear what happened next, as Henry’s later court testimony appears to have been coerced. However, it seems that rather than disposing of the serum, someone at the Health Commission elected to process the sample, most likely because sera collected the previous week had already been depleted and perhaps because a local diphtheria outbreak was starting to pick up steam.44 The culprit is unlikely to have been Henry, whose position as a janitor is hardly consistent with making such a decision, but nonetheless, the elderly, African-American janitor became a classic fall guy. Likewise, it seems unlikely that the decision was made by Ravold, who staunchly defended Henry to the end but would also shoulder some of the blame.
The decision to proceed with the processing of Jim’s antitoxin had a disastrous result. According to a news story in the St. Louis Republic (Pulitzer’s cross-town rival) dated two weeks before Ravold bled Jim for the last time, Dr. R.C. Harris of Number 130S North Garrison Avenue returned to St. Louis after a much-needed vacation in the “northern resorts.”45 The soothing effect of this vacation must have been short-lived, as Harris was called on the evening of October 19 to the home of Bessie Baker, who was suffering from advanced diphtheria (recall that house calls were commonplace in that long-forgotten time).46 Consistent with his recent training as a young physician, Dr. Harris administered the antitoxin. To be safe, he also injected her two siblings.
Four days later, Bessie’s frantic parents called Dr. Harris back to their home. While the girl had been convalescing nicely from diphtheria, she displayed the classic symptoms of tetanus and was far beyond medical treatment.47 She died the next day, on October 24, 1901. Adding to the parents’ grief, both of Bessie’s siblings were also ill with the same symptoms, and they too would be dead within days.
The same thing was happening all throughout St. Louis. In total, thirteen children died, each displaying the excruciatingly painful symptoms of a rigid spine and neck, broken only by waves of terrible spasms and an inability to swallow. As the damage from the tetanus toxin increased, the patients suffered from extreme hypertension, culminating in a slow and agonizing death. Although this story would grab headlines under any condition, it was a piece of raw meat for the voracious Joseph Pulitzer. His Post-Dispatch blared with headlines proclaiming the tragedy and further amplified the story nationwide via his ownership of the New York World.
Almost concurrent with Dr. Harris’s treatment of Bessie and her siblings with diphtheria antitoxin, Camden, New Jersey, was experiencing a smallpox outbreak. An eight-year old girl succumbed to smallpox in early October 1901, triggering the local school board to enforce a law requiring vaccination for all students. The city hastily floated a contract for smallpox vaccine, and the bid was awarded to a relatively new and ambitious Philadelphia-based vaccine maker, H. K. Mulford. One factor working in favor of Mulford’s bid for the work was that the company operated a relatively new antitoxin manufacturing plant in nearby Glenolden, Pennsylvania, fifteen miles away from Camden.48 However, the production of an antisera made in horses was quite different from a smallpox vaccine produced in cows. Because of growing concerns about a burgeoning smallpox outbreak, time was of the essence, and Mulford was told to switch from the production of horse antitoxins to cow-based smallpox vaccine.49 Widespread vaccination of students with the Mulford smallpox vaccine began within a week.
Shortly after the first student was diagnosed with smallpox in nearby New Jersey, the smallpox outbreak spread to Philadelphia’s Pennsylvania Hospital. Panic ensued. As the Mulford vaccine was already being manufactured for Camden, some of this vaccine was diverted to assist with the Philadelphia outbreak as well.
On November 1, a sixteen-year old Camden student, William Brower, died of tetanus. Just three weeks earlier, William had been vaccinated for smallpox. Within days, ten Camden schoolmates or patients at the Pennsylvania Hospital likewise were sickened and died with the same symptoms.50 A subsequent investigation implicated Mulford in general and cross-contamination between their horse-based antitoxin and cow-based vaccine manufacturing activities in the same Glenolden plant. In a manner remarkably reminiscent of present-day accusations of “fake news,” Mulford’s defense opted for an aggressive offense and accused its various business rivals of fraud and slander. Allegations and counter-allegations flew in all directions among Mulford and rival manufacturers Parke-Davis and H. M. Alexander. Once again, Joseph Pulitzer found his story, and the finger pointing made it even more salacious. The public became outraged. Likewise, powerful editorials in the Journal of the American Medical Association and the mainstream New York Times, among others, advocated strongly for government oversight of vaccine manufacturing.51
As the stories emerging from St. Louis and New Jersey became sensationalized throughout the United States, change came from a rather unexpected source. The Medical Society of the District of Columbia, founded in 1817, was and remains an advocacy organization focused on public health. Given its proximity to the Capitol, its members cited the twin tragedies in Missouri and New Jersey as reasons why federal intervention was necessary. The Medical Society challenged local District of Columbia health commissioners to draft legislation to regulate the production of vaccines (both active and passive vaccines). Propelled by popular outrage, the bill was expanded to include the entire nation and sailed through Congress. The Biologics Control Act was signed by President Theodore Roosevelt on July 1, 1902.52
This legislation was particularly impactful given the rapid rise of the vaccine and antisera industry. In a few short years between their discovery and the passage of the Biologics Control Act, the diphtheria and tetanus antitoxins developed by Kitasato and Behring had given way to an enormous number of different antisera products. As might be expected of an unregulated industry, the claims made by some manufacturers often went far beyond what could be delivered. Many were outright snake oils. The products sold included antisera to combat a range of indications, such as tuberculosis, and were based on speculation or worse (recall that Behring himself had abandoned work on the tuberculosis antisera).53 The new law required that processes for manufacturing of all serum-based products (known as biologicals) must be approved and licensed by the federal government, which would also oversee quality control. Given the double impact of events in St. Louis and New Jersey, the intervention imposed by the 1902 act was embraced by the medical community as well as ethical manufacturers. Many municipal- or home-based manufacturing operations folded due to an inability to conform to the new guidelines.
Oversight for the licensing of serum-derived therapeutics was tasked to a relatively small team known as the Hygienic Laboratory. As described in greater detail in A Prescription for Change, this federal service had its roots in a one-man operation in an obscure corner of the Marine Hospital Service on Staten Island, New York.54 Given its new regulatory responsibilities, the Hygienic Laboratory gained more and more responsibility, later moving to Washington, where it was rebranded as the National Institute of Health. As its impact increased, the name became a plural and the organization evolved into the modern National Institutes of Health, or NIH, in 1930, following passage of the Ransdell Act.55 The NIH, rather than the Food and Drugs Administration (FDA), continued overseeing vaccines and antisera for most of their history. In 1948, vaccine oversight within NIH was transferred from the Division of Biologics Control to the newly created National Microbiological Institute (which came to be known as the National Institute of Allergy and Infectious Diseases, or NIAID).56
A more dramatic change occurred when biologics oversight was transferred in 1972 from the NIH to the FDA, which formed the Center for Drugs and Biologics. Th
e center was again reorganized in 1987 to form the Centers for Biologics Evaluation and Research (CBER) and its counterpart, the Center for Drug Evaluation and Research (CDER). A final change arose in 2002 when oversight of recombinant monoclonal antibodies and some other biologicals was transferred from CBER to CDER, adding these technologies to the portfolio of more conventional medicines that it had historically overseen.
Serum & Sickness
The need for oversight was not limited to risks arising from poor manufacturing processes. Oversight was also necessary because of the inherent nature of the new drugs themselves. Antisera derived from nonhuman species (horses and cows) are inevitably seen as foreign by a chauvinistic human immune system. Shortly after the Berlin team’s antitoxins began to be adopted by pediatricians around the world, this fact was recognized by two investigators working in the world’s leading pediatric center in Austria.
Clemens von Pirquet (unlike Behring, von proclaimed that Clemens entered the world as part of the landed aristocracy) was born in 1874 near Vienna. Consistent with his noble parentage, he attended the finest schools that the Austro-Hungarian Empire could provide.57 Originally entering college as a step towards a career in the priesthood, Pirquet changed his mind, deciding to undergo medical training at the University of Graz.58 The aspiring doctor had fallen in love with the sciences of bacteriology and immunology (fields that had barely begun by this time) while training at the Universitäts Kinderklinic (University Children’s Clinic), a Viennese clinic led by the legendary figure Theodor Escherich.59 Escherich’s name may sound vaguely familiar to contemporary ears today based on his earlier discovery of an eponymous bacterium now known as Escherichia coli (E. coli). This bug is a major component of the gut microbiome and helps us digest our food. Occasionally, the organism makes the headlines for darker reasons. It was the cause of a particularly nasty form of food poisoning that plagued the Jack in the Box restaurant chain in 1993. A variant (O157:H7) sickened at least seven hundred diners, many permanently, and killed four.60
Between Hope and Fear Page 22
