TALES OF THE FIRST CHOLERA
VACCINE
“The bacteriologist called upon me to take off my coat and bare my arms to above the elbow. With a lancet he cut an incision just above the elbow [in both arms], and into this he injected several drops of the germ-containing bouillon.” Thus wrote the adventurous New York Herald reporter Aubrey Stanholpe after receiving the world’s first anti-cholera vaccine at the hands of Spanish investigator Jaime Ferrán y Clua.
Ferrán, a practicing physician in Tortosa, Spain (in Cataluña), inspired by the discoveries of Pasteur, had created a bacteriology laboratory in his home. In 1884, the year that Robert Koch found the causative vibrio in Egypt, cholera invaded Marseilles. Ferrán
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| Jaime Ferrán y Clua (Wikipedia) |
obtained a sample of vibrios in Marseilles and, using guinea pigs, produced a two-dose live vaccine that, injected subcutaneously, prevented orally induced cholera in the animals. The following year, he tried the vaccine on humans during a cholera outbreak in Valencia province. Government commissions sent to investigate the results were critical of the results, however. After about 30,000 vaccinations Ferrán returned to Tortosa to develop other vaccines, the cholera vaccine’s effectiveness unproven.
A few years later, in 1890, a young Russian scientist at the Pasteur Institute, Waldemar Mordecai Wolfe Haffkine, began work
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| Waldemar Haffkine (Wikipedia) |
on a cholera vaccine. Waldemar, born in Odessa, had earned a degree in zoology studying under Eli Metchnikoff and obtained a position at the Museum of Zoology in Odessa. He had also been active in student protests, a member of the Narodnaya Volya, or “Will of the People” party, members of which had assassinated Tsar Alexander II, and was Jewish. After undergoing multiple arrests, one prison term, and a severe pogrom, he left Russia in 1888 and, with Metchnikoff’s help, secured a minor position at the Pasteur Institute, from where he moved into a post as assistant to Emil Roux, Director of Services.
Using techniques developed by Pasteur, Haffkine reduced the virulence of one strain of the vibrio by culturing it in the presence of moving air and enhanced the virulence of another by serial culture in animal tissue. He injected himself with the less virulent strain in the left flank and six days later injected the virulent strain in the right flank, with only modest side effects. Interestingly, the American, Theobald Smith, had reported on the successful use of killed bacteria to immunize pigeons in 1887 and later Emil Roux encouraged
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| Emil Roux (Wikipedia) |
British authorities, however, invited Haffkine to India. He set up a laboratory to produce vaccine and inoculated thousands throughout the country. By 1896, due to shortages, he was using only the more virulent strain as a one-dose subcutaneous regimen. He strove to prove the efficacy of the vaccine, a matter that Ferrán had neglected. Various factors hampered statistical evaluation: the disease was so prevalent that many people had partial immunity, vaccination was voluntary (by British order), and the dosage of vaccine often varied due to problems of supply and transportation.
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| Haffkine (in tie) vaccinating a child in the flank (from Haffkine's Protective Inoculation against Cholera, 1913, courtesy Wellcome Library) |
Haffkine realized that to measure the preventive effect of the vaccine he needed a control group of similar individuals. He used controls in trials in two jails, vaccinating every other prisoner. At the second jail, though, he broke the protocol because of the high mortality rate among unvaccinated prisoners, highlighting the ethical problems that arise in controlled trials. The most exacting trials were in a large tea plantation, where control groups were possible with a compliant labor force. Some analyses have supported a modest preventive effect of the vaccine lasting about six months, though skepticism persisted.
Publications by Haffkine provoked a sharp response from Ferrán, who claimed priority. Ferrán criticized Haffkine’s culture techniques and stressed that he was the first to create and use a cholera vaccine. A bitter exchange of letters and reports ensued. The issues were never fully resolved. The two antagonists were possibly placated to some degree as each received the esteemed Bréant Prize for work on cholera.
The Bréant Prize (Le Prix Bréant) originated from an 1849 bequest of 100,000 francs by a French industrial chemist, Jean-Robert Bréant. He intended the award to go to whomever discovered a cure for cholera or discovered its cause. Meanwhile, the interest on the sum was to be awarded by the French Academy of Sciences to a person who advanced knowledge of cholera or other epidemic disease. Many have received the interest-generated awards, though Filippo Pacini, who first saw the vibrios microscopically in 1854, and John Snow, famous for halting cholera’s transmission by removing the handle of a London water pump in the same year, never received the prize (both were nominated). Robert Koch received it for
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| Robert Koch (Wikipedia) |
discovery of the TBC bacillus, not the cholera bacillus. Ferrán received the prize in 1907 and Haffkine in 1909, both for their laboratory and field work. In neither case was their vaccine’s efficacy commented on. A recent review of the Bréant Prize files supports the conclusion of the inability to assess vaccine efficacy for each contender.
A new disease, plague, struck India in 1896. The Indian Medical Service took over cholera control and appointed Haffkine to create a vaccine against plague. His laboratory produced millions of doses, used worldwide, and eventually grew into the Haffkine Institute in India.
Today, Haffkine is recognized as a pioneer vaccine producer, a tireless worker in a difficult environment, and, most importantly, the first to appreciate the need for controls in evaluating vaccine efficacy and to attempt such trials. Modern cholera vaccines are given orally, their efficacy established by controlled trial.
SOURCES:
Löwy, I, “From Guinea Pigs to Man: The Development of Haffkine’s Anticholera Vaccine.” J Hist Med Allied Sci 1992; 47(3): 270-309.
Bornside, G H, “Waldemar Haffkine’s Cholera Vaccines and the Ferran-Haffkine Priority Dispute.” J Hist Med Allied Sci 1982; 37 (4): 399-402.
Bulloch, W, “Waldemar Mordecai Wolff Haffkine.” J Path Bact 1932; 34 (2): 125-29.
Hawgood, B, “Waldemar Mordecai Haffkine, CIE (1860-1930): Prophylactic Vaccination against Cholera and Bubonic Plague in British India.” J Med Biog 2007; 15: 9-19.
E Lutzker, C Jochnowitz, “The Curious History of Waldemar Haffkine.” Commentary 1980; 69 (6): 61-64.
Stanhope, A, On the Track of the Great: Recollections of a Special Correspondent.
Eveleigh Nash, London, 1914.
Alpuente Ferrer, et al, “Jaime Ferrán i Clúa (1851-1929), un Vacunólogo Práctico y Controvertido.” Vacunas 2009; 10 (3): 103-9.
Shama, S, Foreign Bodies: Pandemics, Vaccines, and the Health of Nations. Harper Collins 2023.
Uzcanga, C and Teira, D, “What Evidence for a Cholera Vaccine? Jaime Ferrán’s Submissions to the Prix Bréant.” J Hist Med All Sci 2025; 80 (1): 23-41.
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