Geography has not been terribly kind to the small nation of Belgium. Wedged between France and Germany, “the Battlefield of Europe” has all too frequently been the focus of its larger neighbors. It was host to major carnage in both the Hundred Years’ War in the 14th century and the Thirty Years’ War that began in the 17th. A century and a half later, the resurgence of Napoleon following his escape from Elba was brought to a halt by the combination of Wellington and Blucher’s stand in the small Belgian town of Waterloo. A century after that, the invasion of Belgium by the Kaiser’s army served as a means to bypass French defenses further to the south and led to the British entry into the Great War. Yet another quarter century later, a Nazi invasion of Belgium occurred not once but twice, first during the lightning campaign to take Western Europe in 1940 and again during the Battle of the Bulge in late 1944.
Despite these challenges, geography has imparted some distinct advantages upon tiny Belgium. One example is its role as the birthplace of Jules Jean Baptiste Vincent Bordet.1 The budding scientist was born in 1870 in the Walloon village of Soignies, a site near the French border that would gain later notoriety as the location where the British Expeditionary Force would first collide with the Germans during the Battle of Mons in 1914. His father was an itinerant schoolteacher from a town near the German border, but the family later settled in Brussels, where the young Bordet completed his primary and secondary education, graduating as a doctor of medicine in 1892. Having gained early distinction for his early work with viruses, Bordet was recognized by the Belgian government in the form of a paid fellowship in 1894 to work at the Pasteur Institute under the auspices of Elie Metchnikoff, who would soon receive the Nobel Prize for his work in discovering the basic tenets of immunology.
During a remarkably productive seven-year stint in Paris, Bordet first discovered the underpinnings of the complement system whereby antibodies can kill bacterial invaders (recall a brief overview of this subject in chapter 6), an accomplishment that would earn Bordet the 1919 Nobel Prize. Towards the end of his time in Paris, Bordet also partnered with another Belgian, Octave Gengou, on a particularly challenging project to identify the cause of whooping cough.2
Four centuries earlier and also in Paris, the physician Guillaume de Baillou was the first to document an epidemic of a disease known as pertussis.3 The symptoms, which overwhelmed the primitive medical establishment of Paris in 1578, were initially indistinguishable from a common cold but quickly progressed to loud fits of violent spams of coughing, accompanied by a characteristic “whooping” sound, which often triggered uncontrollable vomiting. These symptoms could persist for months, earning the disease the moniker “100-day cough.”4, 5, 6 Although this Parisian outbreak is often cited as the first historical description of the disease, new data suggests the disease might have first been detected in Korea as early as 1433 and in Persia in 1484.7
Though the disease had been experienced by children for centuries, its cause remained largely unknown until the early years of the 20th century. Repeated attempts had failed to isolate the organism. Indeed, Bordet and Gengou were repeatedly frustrated by the fact that while the symptoms of the disease could persist for months, the organism responsible for the disease could only be isolated during a very narrow window of time (indeed, the duration of the symptoms reflected the injury done early in the infection and the time needed to fully repair the damage). Compounding the problem of isolating the germ responsible for whooping cough, the bacterium pathogen was restricted to the lung and could not be detected in the blood of an infected child. Worse still, even when small amounts of the bacterium could be isolated from the lung or mucous of infected children, the organism that caused such powerful outcomes was itself surprisingly fragile. The bacterium grew agonizingly slowly and quickly died outside the body.8 The team was finally able to see the pertussis bacterium under a microscope as early as 1900, but the organism died before they could propagate it in the laboratory. Success finally came in 1906 when Bordet and Gengou developed novel ways to isolate and keep the bacterium alive. The breakthrough involved a customized broth that allowed the bacterium to proliferate outside the body.9 The bacterium was named in honor of the more senior of the pair and is now known as Bordetella pertussis.
Having at last isolated the organism, the team then focused on developing a vaccine. Although the fragility of the organism provided a consistent and aggravating impediment, the breakthrough broth they had developed allowed researchers to routinely culture Bordetella pertussis in the laboratory. This ignited a version of the Oklahoma Land Rush to stake the ground for a successful vaccine. On October 9, 1909, the first reports of a vaccine developed by Bordet and Gengou emerged from a study conducted in London by the prominent British physician John Freeman.10 Much excitement accompanied the rumors of success in London, but the effectiveness of this vaccine in preventing whooping cough in children was marginal at best.
By this time, Bordet and Gengou had returned to their native Belgium to lead a branch campus of the Pasteur Institute in Brussels. This seemingly insignificant relocation is rather symbolic in that it coincided with a dispersion of vaccine research beyond the confines of Paris or Berlin. Indeed, just eight days before the publication of the Bordet-Gengou vaccine, John Zahorsky of Washington University in St. Louis was technically the first to report clinical findings of a whooping cough vaccine he had developed. The report appeared in an obscure Midwestern journal.11
Though the promise conveyed by studies of the Zahorsky vaccine was also minimal, this report marks a sort of milestone in that it established the Americans as an alternative to the European domination of vaccine research. Lacking a focused center of gravity such as the Pasteur Institute in Paris or the Koch Institute in Berlin, a more dispersed group of laboratories in the United States quickly rose to become the dominant players in vaccine research and development. We will witness this transition to North America as a dominant theme of this chapter.
Staying on the topic of a pertussis vaccine, little progress, but much hope and frustration, was generated throughout most of the first third of the 20th century. A series of scientific and medical studies were conducted with small populations of patients that in many cases were not necessarily representative of the wider population. The first large-scale studies to optimize a pertussis vaccine were conducted by Louis Sauer in 1933, but this vaccine likewise did not convey the necessary efficacy required to fully protect children from the dreaded whooping cough.12 Consequently and despite the testing and occasional marketing of various pertussis vaccines from 1909 onwards, the incidence of whooping cough from 1909 through the 1940s remained high, with most years witnessing more than 100,000 new cases (and some with many more). Tragically, five thousand to eight thousand children continued to die annually from this dreaded disease throughout this time period.13
Three Women and a Baby
The war against pertussis changed dramatically as the result of contributions from three remarkable American scientists, all of whom happened to be women, one of whom has been relegated to an almost forgotten historical footnote.
Pearl Kendrick was a three-year-old living an otherwise unremarkable life as a preacher’s daughter in Wheaton, Illinois, when she contracted whooping cough in 1896 but survived the ordeal.14 Ever a precocious child, she began questioning some of the tenets of her religious upbringing during debates with her father about the volatile subject of evolution (a prescient topic, since the University of Michigan has since named a professorship for her in evolutionary biology). Evolution, along with women’s right to vote, were the hot-button issues of the day, and the Kendrick family debates occurred two decades before the far more visible Scopes Monkey Trial of 1925. Kendrick’s love of science led her to enroll at nearby Greenville College and later to transfer to far-off Syracuse University, where she obtained a bachelor’s degree in zoology in 1914. At a time when a woman’s choice of career remained highly restricted, she took the conventional approach of teaching school for three yea
rs in upstate New York. Less conformist was her decision to commute down to New York City on the weekends to volunteer as a research assistant. Kendrick had seized upon an opportunity to work with Hans Zinsser, a pioneering typhus researcher, who not only helped discover the bacterium responsible for the disease but later developed a vaccine for its prevention.
Compelled by this experience, Pearl Kendrick committed herself to starting a full-time career as a scientist, first with a job at the New York State Department of Health and two years later with the 1919 offer of a job with the Michigan Department of Health in Grand Rapids. These two job offers were extended to Kendrick not based solely on her past accomplishments and potential but because governmental financial constraints were favorable to hiring less expensive (i.e., underpaid) women like Pearl rather than investing larger sums to attract her male peers.15
Pearl soon became established in Lansing as an assistant to the director of the Bureau of Laboratories, Cy Young (not to be confused with the baseball legend of the same name). In part, Kendrick was attracted to the position based on Young’s policy of supporting the professional development of the women he hired. Seizing this opportunity, Kendrick rose quickly through the ranks and was assigned by Young to lead a satellite laboratory in Grand Rapids, Michigan. In another example of her multitasking capabilities, Kendrick managed to not only fulfill the service requirements expected of this laboratory but also to make it stand out as one of the nation’s most innovative and efficient bacteriological laboratories. All the while, Pearl was earning her doctorate from Johns Hopkins, which was awarded in 1932. In that same fateful year, Pearl Kendrick hired and began nurturing another rising upstart by the name of Grace Eldering.
At roughly the same time Pearl Kendrick began questioning her father about evolution, Grace Eldering was born in 1900 to an immigrant Scottish mother and Dutch father, who left their homelands to settle in the central Montana town of Rancher, which is a ghost town today.16 At the tender age of five, Grace was diagnosed with a particularly virulent case of whooping cough, which left lifelong and vivid memories of painful coughing and vomiting. This experience motivated Eldering to seek a degree in science at the University of Montana. She remained in the state as a school teacher to earn tuition money for college. Grace continued to teach English and science at Hysham High School but was desirous of launching a career in the medical sciences. She found her chance in an advertisement from the Michigan State Department of Health and received an offer soon thereafter. Grace Eldering relocated to Michigan, first to Lansing and then to Grand Rapids, where the team of Kendrick and Eldering would soon begin to make headlines.
In the early years of the Great Depression, Kendrick and Eldering had developed a diagnostic test to detect Bordetella pertussis, and had used this to determine the period in which an infected child was contagious.18 This advance was extraordinary in that it allowed doctors to know when and how long children should be quarantined to curb the spread of the disease.
The pair had also begun to identify opportunities to progress from autogenous therapies to vaccines that could be manufactured en masse. Given the limited time that Bordetella could be isolated and remain alive to be cultured into a vaccine, only small amounts of the bacterium could be obtained. Often, the bacterium from a patient was cultured and then killed to create a personalized vaccine (used only for the donor). This autogenous process was necessary given the inability to produce large amounts of pertussis bacteria, but it was wildly inefficient.19 Kendrick and Eldering were successful in developing a single vaccine that could be given to many, but their ability to deploy this vaccine was limited by a scarcity of funds arising from the financial impact of the Great Depression. This problem was unexpectedly resolved by a 1936 visit from the First Lady of the United States. Eleanor Roosevelt was passionate about public health and had learned of Kendrick and Eldering’s work on improving pertussis vaccine. A later interview with Kendrick detailed the visit of the First Lady to Grand Rapids, revealing that Eleanor “was the only lay person to really understand what we were doing.”20 With help from such a high-profile source, funds were suddenly made available from the federal government. By the end of 1939, the first mass production of what is now known as the “whole cell” pertussis vaccine began to be manufactured in earnest but the production was still insufficient to meet the needs of the entire state of Michigan. The term whole cell refers to the use of the entire (or whole) bacterial cell that has been inactivated prior to use (this distinction will be important later in our story).
The duo that was destined for such great fame was in fact a trio. The third member of the team was the oft-forgotten researcher Loney Clinton Gordon.17 Gordon, fifteen years Grace Eldering’s junior, was an African-American woman born on October 8, 1915 in rural Arkansas. Like many poor Southern blacks, her family participated in the Southern Diaspora (also known as the Great Migration), which witnessed the uprooting of a largely rural population to large cities in the Midwest and North. Whereas nine out of ten African-Americans lived south of the Mason-Dixon line in 1910, that fraction declined to just over one half by 1970. Loney’s parents settled in Grand Rapids, Michigan. At the age of twenty-four, she earned a degree in home economics and chemistry from Michigan State College (now University). Straight out of college, she landed a job as a dietician at a mental sanitarium in Virginia but soon quit, given the poor accommodations of the broken-down institution and equally dismal treatment from its administrators.
Returning to her native Grand Rapids, Loney applied for dietician positions but was declined, being informed that the white male cooks would not take orders from a black female dietician. A mutual friend informed Loney of an open position under Kendrick at the Michigan Department of Health. Gordon was enthusiastic, persistent, and ambitious, and she was offered the job on the spot to conduct a project to improve the way that Bordetella pertussis could be grown in culture. She soon discovered a concoction involving sheep’s blood that served the purpose.
With the arrival of Gordon in the early 1940s, Kendrick and Eldering sought to improve the efficiency of manufacturing large amounts of the vaccine. This problem was one of the first where Gordon’s contributions proved essential. Soon the Michigan Health Department was able to not only make enough material for their home state but also to export to other states throughout the nation and eventually the entire population of the United States.
The team further improved the vaccine by including an adjuvant. To explain the concept of adjuvants, we go back to 1926. In that year, the same Alexander Glenny who, in parallel with Gaston Ramon, had discovered diphtheria toxoid (and named it as such) also demonstrated the value that adjuvants provided for vaccination.21 An adjuvant is a chemical that can amplify the effectiveness of a vaccine. The first adjuvant discovered by Glenny was the one used by the Michigan team—aluminum hydroxide. This chemical is the active ingredient in antacids such as Gaviscon or Mylanta, but Glenny demonstrated that alum (a shorthand used by immunologists for aluminum hydroxide) tweaks the macrophages of the immune system. Specifically, the chemical helps the macrophages gather the perceived foreign antigens of the vaccine, to interact productively with the lymphocytes of the immune system (B and T cells) and become concentrated within lymph nodes and other immunological structures. Each of these properties increases the intensity, breadth, and speed of an immune reaction and thereby amplifies the effectiveness of the vaccine.22 As one example familiar to all who have been immunized, adjuvant-based activation of macrophages (and other immune cells) is responsible for the rapid (sometimes within minutes) redness, swelling, heat, and occasional discomfort associated with the vaccination site.
The inclusion of alum increased the potency of the whooping cough vaccine. The whole cell vaccine began to show promise in the clinic starting in 1943.23 At the same time, the Michigan team initiated the practice of combining the whole cell pertussis vaccine with the toxoids for diphtheria and tetanus. This triple combination, later known as DTP, thereby provided a me
ans to protect children from three notorious pediatric infections at the same time. The vaccine was widely adopted in the years following the end of the Second World War and largely continued in the same form developed by the three women scientists until the mid-1990s. As we will now see, the pertussis component of the vaccine has been a subject of considerable controversy, which has persisted in one form or another to the present day.
A Shot Heard Round the World
The prevalence and deadliness of pertussis meant that any vaccine was warmly embraced by the medical community. This all changed following a presentation by the English pediatrician John Wilson to the Royal Society of Medicine in 1973. In this talk, Wilson suggested a subset of children immunized with the pertussis vaccine demonstrated a spike in fever that preceded seizures and could later progress to coma, permanent brain damage, and death.24 Prior to this, any adverse effects of the vaccine were found to be rare and not particularly damaging.25 Wilson’s work, though preliminary, claimed to definitively link the pertussis vaccine with neurological damage.26
Wilson’s study was focused upon the posh Bloomsbury neighborhood of London. The high-profile, affluent neighborhood of Bloomsbury inspired the likes of E. M. Forster, Virginia Woolf, and John Maynard Keynes and also happens to house much of the British medical and legal elite. The report of children suffering in this high-profile neighborhood unleashed a firestorm of alarmist reports from British tabloids. Wilson fanned the flames through multiple appearances on television, where he adamantly warned parents and physicians not to use the pertussis vaccine.
A year after the publication of the British study, a review by the Japanese government created further consternation. Japan had mandated vaccination with the whole cell pertussis vaccine by the age of three in the months following matriculation in school. Thereafter the rates of pertussis dropped dramatically. Whereas almost twenty thousand children died annually from pertussis in 1947, the number dropped to zero by 1972.27 During the winter of 1974–75, two high-profile deaths were recorded in infants within twenty-four hours following DTP immunization. The tragedy of these deaths was amplified by a hungry media, and the resultant uproar caused the government to suspend vaccination and form a study group to analyze the problem. After intensive investigation, the committee recommended a resumption of the immunization mandate. However, parents began ignoring the mandate, and the rates of infection and death from pertussis again climbed, exceeding forty deaths per year by the end of the decade. In response, the Japanese government instructed the creation of a new pertussis vaccine that would be required to convey “one-tenth” of the side effects associated with the whole cell vaccine.
Between Hope and Fear Page 27
