By the end of the war, Roux and Ramon’s relationship had expanded beyond merely the professional when Gaston married Marthe Momont, Roux’s niece.67 In the following years, Ramon improved the ability to purify antibodies away from other animal proteins in sera to minimize the untoward effects of serum sickness. The early years of the Jazz Age also witnessed his epiphany that the same procedures he had used to preserve antitoxins might be used to inactivate the toxins themselves and thereby create a vaccine. By 1923, Gaston had subjected diphtheria toxin (the same material he routinely used to immunize horses) to a combination of formalin and elevated temperature and found that the modified toxin, which Gaston called “l’anatoxine,” retained the ability to elicit an immune response but did not cause disease.68
As often is the case in science, Gaston did not work in isolation. Credit for discovery of the diphtheria vaccine arose simultaneously from Gaston’s work and that of an English researcher by the name of Alexander Thomas Glenny. In 1899, at the age of seventeen, Glenny began working in the laboratories of the Wellcome Physiological Research Laboratories and simultaneously working towards a college degree at the University of London.69 The company was producing large amounts of diphtheria antitoxin, which required large amounts of toxin that would be injected into horses to produce the antisera. The bacteria were cultured in large clay barrels and were decontaminated between batches using a formaldehyde solution, as was the standard practice of the day. One day in 1904, Glenny noted that a batch of bacteria was unable to infect the horses. Upon investigating the cause, he realized this batch had been improperly rinsed.70, 71, 72 Glenny thereby surmised that the residual formaldehyde must have compromised the bacteria, much as Gaston would realize two decades later. However, Glenny did not follow up on this finding until 1923 (by coincidence, the same year as Gaston). Working with another researcher, Barbara Hopkins, Glenny returned to this finding and demonstrated that the formalin-inactivated diphtheria toxin could elicit an immune response. He referred to this neutralized toxin as a “toxoid.”73
The ensuing row raised concerns that did not quite rise to the level of the Pasteur-Koch feud, but it did create some uncomfortable moments. The key question centered upon who should get credit for the discovery. Glenny only conveyed the 1904 finding in private conversations (one of which appeared in the book A History of Immunization, first published in 1965).74 Likewise, it is not clear whether Glenny was suddenly motivated to investigate the question of formalin treatment of diphtheria toxin only after he heard rumors of Gaston’s success.75 Regardless, time has ruled a sort of split decision in that Gaston Ramon is generally acknowledged to be the discoverer of the vaccine, while Glenny’s nomenclature of “toxoid” (rather than Gaston’s “anatoxine”) has prevailed. Nonetheless, the Nobel committees are notoriously shy about courting such controversies, which begs the question of whether the issue of Glenny’s contributions might explain why, despite 155 nominations, Ramon never received the prize.
The discovery of a diphtheria “toxoid” provided a much-needed vaccine to replace the passive horse-derived antitoxins, particularly given the propensity of the latter to cause serum sickness. Stated another way, the vaccine allowed by a toxoid could prevent the disease from arising in the first place, while the antitoxin was administered after the disease had already gained a foothold.
The introduction of the vaccine also eliminated the need to rush antitoxin to sites of infection. The most notable example of this need occurred in 1925, when an outbreak in Alaska triggered a desperate race from the port town of Seward to Nome in time to prevent diphtheria from wiping out Nome’s population.76 This “Great Race of Mercy” is memorialized annually by the Iditarod Trail Sled Dog Race. Indeed, the antitoxin market, at least for diphtheria and tetanus, has largely disappeared.
Soon after the introduction of the diphtheria vaccines, the Spanish Strangler, which had routinely infected 200,000 children and killed 15,000 per year in the United States alone, was effectively eliminated.77 For example, in the twelve years between 2004 and 2015, only two cases were diagnosed in the United States.78
Despite a success that on its own would have memorialized Gaston for all time, he was not yet done. Using similar approaches to inactivate tetanus toxin, he helped optimize a tetanus toxoid as a vaccine in 1925. The original discovery of a tetanus anatoxin (toxoid) was inspired by Gaston’s work with diphtheria and was first published by Pierre Descombey, Ramon’s colleague from the Pasteur Institute. Additional studies with Gaston and Christian Zoeller demonstrated the clinical efficacy of tetanus toxoids in 1926.79 Appreciating the benefits of tetanus prophylaxis, the United States military was an early adopter, requiring recruits to be vaccinated against tetanus from 1940 onwards, just in time to help increase American preparedness for entry into the Second World War.
Diseases of the Body and the Mind
In an unusual twist, the success of the tetanus toxoid vaccine brings us back to the remarkable figure of Waldemar Haffkine. When we last left the Russian-born, French-trained, and English-supported researcher in India, he had demonstrated the safety and efficacy of his cholera vaccine during a December 1895 talk in London.80 Wildly feted by the English intelligentsia, he could have settled into a comfortable academic position, but he opted to return to India weeks later.
The timing was propitious, as the Black Death had returned to Asia. By the time of his return, a wave of plague had overtaken Asia. As we have seen, bubonic plague is an awful disease made all the worse by a periodic tendency to break out en masse. Fortunately for the continuance of our species, there have only been three such plague pandemics.
The first pandemic was the so-called Plague of Justinian, so named for the sitting emperor of the Eastern Roman or Byzantine Empire. Likely entering the empire on the backs of rats succored by the grain of ships plying the trade route between Alexandria and Constantinople, the plague took hold of the empire by the year 541. This clash with the plague, which infected an estimated one in seven humans on the planet within a year, killed between twenty-five and fifty million people. A detailed history of the plague and its aftermath is captured by the outstanding book Justinian’s Flea by the late William Rosen.81 The disease cut down an attempted resurrection of the Roman Empire after Justinian’s legendary general, Belisarius, reclaimed and reunited much of the former greatness of the earlier days of the empire. However, the massive societal and infrastructural havoc wreaked upon the empire during the vicious outbreak of the Plague of Justinian left it even more susceptible to enemies on every front, including Goths in the north and west, Lombards in the central regions (eventually taking Rome), and Arabs (later Muslims) to the east and south.
Not to be outdone by its prior achievements, the plague returned in force eight hundred years later, to be memorialized in Western literature as the Black Death. This is the pandemic experienced by Guy de Chauliac, which engulfed virtually all of Europe (and much of Asia), dispatching an estimated 100 million victims, almost one quarter of all humans alive at the time. The societal impact of this second plague was even greater than the first and included the elimination of most feudal societies (since a ruling class denuded of many workers could not count on the remaining few to carry on as before).82
Based on these two earlier experiences, fears of the rapidly accelerating third pandemic were manifest. Starting as a natural infection in the Yunnan Province of southwest China in 1850, the pandemic was accelerated, as is so often the case, by strife and warfare.83 Specifically, the Panthay Rebellion, which began in earnest in 1856, represented a revolt by the Muslim Hui people, who had experienced state-sanctioned ethnic and religious persecution from the ruling Qing Dynasty.84 Following a massacre of Muslims in Kunming, the restive Hui rose up against the Qing, triggering a seventeen-year revolt that witnessed the death of up to a million people and the temporary rise of a sultanate.
Though quashed by the Qing rulers, the disorder caused by the revolt helped facilitate the spread of bubonic plague. Canton experie
nced its first cases in 1894 and nearby Hong Kong suffered from 100,000 deaths within a few short weeks. The crisis in Hong Kong led the Pasteur Institute to dispatch the head of its local affiliate in French Indochina, a Swiss-born Frenchman by the name of Alexandre Yersin, to Hong Kong. In a shameful display of nationalism, Yersin was barred from using the facilities of nearby English hospitals but nonetheless commandeered a small ramshackle workshop, where he succeeded in isolating the bacterium responsible for the plague, now known as Yersinia pestis.85 Kitasato Shibasaburo, who had returned to Tokyo after completing work with Robert Koch, might have received the distinction of discovering the bacterium, which he did independent of Yersin, a mere few days later.86 The two appropriately did share the limelight for a time before Kitasato’s contributions were unfortunately forgotten by future generations.
By the early autumn of 1896, the plague had arrived in India, not via its extensive land border with China but the same way it had entered Constantinople, London, Rome, and other cities during previous outbreaks: by sea.87 The primary trading ports of the Raj began reporting cases in quick succession: Bombay, Pune, Karachi, and Calcutta. The terrified British rulers reacted with quarantines, embargoes, and travel bans. Waldemar Haffkine was recruited into the Indian Civil Service and tasked with developing a vaccine using the same principles he had used to develop the cholera vaccine. Continuing the risky practice of testing his vaccine on himself, Haffkine experienced a fever and general malaise but otherwise deemed his new vaccine safe enough to test on others.
His first “volunteers” included prisoners held at the royal prison in Bombay, where the natural form of Yersinia pestis had begun eating through the prison population.88 Positive results from this trial, combined with increasing anxiety about the spreading plague, boosted demand for this new vaccine. Unlike the early days of his cholera vaccine studies, Haffkine’s biggest problem was not in finding volunteers to test his plague vaccine but in meeting the urgent demands of a frightened public.
Haffkine’s diligent efforts saved countless lives, stopping the third pandemic in its tracks before it could cause the civilization-altering devastation rivaling that of the Plague of Justinian or the Black Death. His works were recognized with many awards, including British citizenship and being named a Companion of the Order of the Indian Empire by the empress of India herself, Queen Victoria. All such honors would soon be conveniently forgotten and pushed to the side in the wake of what became known as the “Little Dreyfus Affair.”
After scoring his second major coup with the discovery and implementation of the plague vaccine, Haffkine was soon back in the laboratory developing or refining new medicines. To meet the growing demand during the panic caused by the plague, Haffkine had gained considerable efficiencies by omitting a step in which the vaccine was treated with carbolic acid.89 He did so after learning that this improved procedure had proven successful, as performed by former colleagues at the Pasteur Institute in Paris. Indeed, the experience in India largely revealed that the modified vaccine was as safe and efficacious as the original breakthrough.
On October 30, 1902, 107 patients in the Punjab village of Mulkowal were immunized with a batch of plague vaccine (as were many others across the country).90, 91 However, something had gone terribly wrong and nineteen died, all showing distinctive signs of tetanus (lockjaw) infection. After some quick detective work, all the deaths were linked back to one bottle of vaccine, labeled 53N. As the patients immunized with vaccines from all other bottles remained unharmed, container 53N was identified as the source of the tetanus. Further examination revealed 53N had been manufactured in Bombay almost a month before, and its history was closely tracked.
An inquest very quickly concluded that Haffkine’s failure to include carbolic acid in the manufacture of the vaccine was responsible for the deaths.92, 93 Haffkine was put on what effectively was administrative leave. He retired to London to regroup and was later summarily fired. For two years, he pleaded his innocence and provided rationale that the contamination must have occurred in the village at the time of injection and not during manufacturing. While his evidence was strong, including the fact that all other bottles manufactured before or since had been safe and effective, these protests fell on deaf ears. The inquest panel needed to placate the outrage of those demanding to know who was responsible for nineteen excruciating deaths from tetanus.
Haffkine endured exile and unemployment for four years, continually pleading for the release of the commission’s findings. These were finally released to the Gazette of India in Calcutta on December 1, 1906. Buried in the documents was exculpatory evidence in Haffkine’s defense, including the fact that the bottle was, by standard procedure, sniffed by the vaccinators to ensure that no major contamination had occurred (a pungent odor would betray the presence of a contaminating bacterium, such as that which causes tetanus).94 Most damning was the revelation that the technician administering the vaccines had dropped his forceps in the dirt just prior to using them to remove the stopper from bottle 53N. Clearly, simply wiping the tool with a cloth was insufficient to prevent massive contamination of the bottle with tetanus bacteria, which thrives in the soil.
Reaction from the Indian and British medical societies was loud and damning, led largely by the respected scientist Ronald Ross.95 Comparisons with the French Dreyfus Affair were adopted by the press and propelled both by the fact that evidence was ignored or buried (especially the dirty forceps) and because Haffkine was a high-profile Zionist.96 His arrest by the tsar’s police for defending his community against the anti-Jewish pogroms had led to his exile from his mother country. Moreover, Haffkine had remained a vocal advocate for resettling Russian Jewish refugees in the British-administered territory of Palestine. As support for Haffkine grew, his tribulations gained the moniker “Little Dreyfus Affair.”97
A campaign to exonerate Haffkine was supported by a high-profile group of British scientists, who published an open letter in the Times (London) on July 29, 1907. Their prominence, combined with a full revelation of the findings of the commission, prompted a belated and halfhearted act of contrition from the British India Office, which reinstated Haffkine (though the Raj officials utterly refused to offer an apology). However, the damage had been done, and the consequences of the dirty forceps used to open bottle 53N continued to cloud Haffkine’s reputation for the rest of his short career. At the age of fifty-five, Waldemar retired and gave up on the British altogether, moving to Paris to live with his sister.
The fact that Waldemar Haffkine had effectively cured not just one but two notoriously lethal diseases led Joseph Lister to acclaim Haffkine as “a great savior of mankind.”98, 99 The Russo-Franco-English scientist working in India was remarkable not just for these two achievements but also for inspiring an international blend that applied the French technique to develop vaccines (from his Pasteur days) with the pathogenic organisms identified by the German team led by Robert Koch. Nonetheless, memories are notoriously short, and after Haffkine’s death in 1930, his contributions faded into relative obscurity.
Returning to the theme of international cooperation, we will now turn to the years surrounding the Second World War. This era proved instrumental in defining new approaches pioneered by multinational scientific findings. It also witnessed the transition of vaccine breakthroughs from the Old World to the international melting pot of the United States.
8
Breathing Easier
With the minor exception of Cotton Mather’s pioneering efforts to deploy variolation in the colonies, or the adoption of antitoxins in places such as St. Louis, the United States has not yet figured prominently in our story. While virtually all the research and development of innovative vaccines had occurred primarily in France, Germany, or Britain throughout the 18th and 19th centuries, this would abruptly change immediately after the conclusion of the Great War. This chapter will detail the transition of pioneering vaccine research from the Old World to the New. The list of vaccines and the pioneers
responsible for their discovery are well beyond what could be addressed in a single chapter, so we will focus on one example: the role that American-led vaccine research played in preventing death and diseases of the lung. This chapter will focus not merely on the development of the scientific establishment in the United States but upon another American contribution to the subject, the rise of an organized anti-vaccinator movement. As an example of both trends, we will focus upon the development and deployment of a vaccine targeting the age-old disease known as whooping cough. As our story transitions away from France and Germany and towards America, our flight plan momentarily takes us to a country torn between the two main European powers that have featured so prominently in the history of vaccines.
Between Hope and Fear Page 26
