In 1885, a vaccine composed of live attenuated bacteria was first inoculated in humans. This event took place in Valencia during an epidemic of cholera, and was carried out by Jaume Ferran i Clua. Born in Corbera de l’Ebre (Tarragona) on February 1, 1851, he studied Medicine in Barcelona and after spending some months in Pla del Penedès, he moved to Tortosa, where he held the position of doctor in charge between 1874 and 1887, date of his definitive establishment in Barcelona. In his quest he combined General Medicine with Ophthalmology, Hydrotherapy and Electrotherapy, as well as holding various administrative positions in some of the population institutions, being the director of the Civil Hospital, doctor-director of the Provincial House of Charity, Director of Maritime Health of the port and subdelegate of the judicial party.
With his partner, chemical engineer Inocencio Pauli, he developed an intense and varied scientific and technical activity, especially in the field of photography and telephony. The result of this joint work was the establishment of the telephone communication between Tortosa and Tarragona, whose distance of 84 kilometers was the largest cover until then by this means.
In Tortosa he established a relationship with the Valencian Josep Joaquim Landerer, who had already published brilliant works on Geology and Astronomy. Ferran was interested in the microscope Landerer used in his petrographic studies and commissioned him to ask for one for him in order to carry out histological works. In the nourished Landerer scientific library, he was able to read the Notes that microbiologist Louis Pasteur published in the journal Comptes Rendus of the Paris Academy of Sciences and soon became passionate about an already incipient discipline, Microbiology. In his own home he assembled in 1880 a small bacteriological laboratory and personally manufactured many of the utensils. There, he prepared, for the first time in Spain, the vaccines against charcoal and swine erysipelas that Pasteur had just developed and whose technique he followed step by step. The French bacteriologist himself sometimes provided him with microorganism cultures along with instructions for the preparation of vaccines.
When in 1884 Robert Koch discovered the microorganism responsible for cholera, Ferran began his studies on this disease and its prevention. In his opinion, immunity occurred without the microbial being multiplied and was due to the remote action of substances produced by the germ, called diastases. To obtain cholera prophylaxis, he proposed the same method used by Pasteur to prevent fowl cholera, that is, the leakage of choleric blood so that the microbes were retained and the diastases were preserved. He claimed that the inoculation of this filtering, with attenuated virulence and voluntarily adjustable, would continue from a refractory state to cholera. This theoretical reasoning served Ferran to prepare his cholera vaccine that was reflected in his Memoria sobre el parasitismo bacteriano (‘Memory on bacterial parasitism’), awarded by the Royal Medical Academy of Madrid in 1884. That same year, the cholera epidemic had reached Europe from India, and in August, Barcelona City Council designated Ferran as the bacteriologist from a commission sent to Marseilles to study the disease, accompanied by Pauli. In the hospitals for choleric patients of Marseilles and also of Tolon, where the action of the Vibrio cholerae was recently discovered by Robert Koch, Ferran was able to isolate and cultivate this microorganism. Back in Tortosa, he carried live germs, which managed to pass through customs hiding them in match boxes. With them, he continued his bacteriological studies and discovered that subcutaneous injections of living germs immunised against deadly doses of the same germ. After checking the effect of this new vaccine in himself, or in Pauli, and in several relatives and friends, he communicated his discovery to the City Council of Barcelona and to the Academy of Sciences of Paris.
In spite of the adopted preventive measures, cholera entered to Spain in August 1884 in the Alicante town of Novelda, although soon it was under control. However, it reappeared with special virulence in November in Beniopa, outside Gandia. Amalio Gimeno and Manuel Candela, professors of the Faculty of Medicine of Valencia and members of the Provincial Health Board, were commissioned to go to the aforementioned town, and officially declared that the disease was Asian cholera. On December 31, Amalio Gimeno went to the Ferran laboratory in Tortosa to get information directly from the discoveries of the Catalan microbiologist. In the course of this visit, he inoculated himself with the new cholera vaccine Ferran had just experienced.
In mid-March, cholera reappeared in the province of Valencia, specifically in Xativa. Gimeno, consulted by the governor of Valencia on the measures that should be adopted, demanded the presence of Ferran and defended the use of the vaccine. The Catalan doctor arrived in Valencia on April 4 accompanied by his colleague Pauli and the next day he moved to Xàtiva, where he confirmed the nature of the disease. Eight days later the first case was registered in the city of Valencia. It was a railroad employee infected in Xàtiva. In the Town Hall session held on April 15, the mayor was asked that the sanitary measures were not ostensible, so as not to alarm the population and, even, to declare that there had not been a single case of cholera in the capital. For a month the cases were controlled, but the epidemic steadily progressed. The sanitary measures applied were ineffective when encountering the poor collaboration of the population, which continued to pour sewage into the irrigation channels whose waters were watering the fruits and vegetables consumed by the city.
Ferran was called to Valencia again to start a vaccination campaign. He installed his laboratory in the kitchen of a then vacated house, owned by Manuel Candela, and there he began his work, assisted by Pauli and several Valencian doctors. Among the first inoculated people were most of the professors of the Faculty of Medicine, such as Santiago Ramon and Cajal, and more than two hundred doctors. On April 24 he went to Alzira to vaccinate, along with Pauli and Gimeno, who gave a speech in the City Council explaining the benefits of the vaccine. Two-thirds of the inhabitants were vaccinated, thus starting large-scale vaccinations. In this town, Ferran fell sick of malaria and had to return to Tortosa. Once he recovered, he resumed the vaccination campaign in Xiva, Xest, Benifaió and many other locations, along with the Valencian capital. However, the controversy surrounded the whole campaign. Ferranists argued for the efficacy of the vaccine, while antiparticles argued that Ferran’s statistics were not always reliable and that the inoculated liquid did not produce attenuated cholera, it increased the receptivity to the choleric germ, thus the number of infections was higher.
At the beginning of June the number of daily new cases was four to eight, with a mortality of eighty percent and panic seized the city. The authorities were forced to focus their efforts in the Valencian capital, because control of the irrigation of the crops was unfeasible in the fear of hunger. The cleaning of the streets and the sewers was increased, the homes of choleric patients were isolated, it was advised to boil the water and fumigation was carried out with gaseous disinfectants, useless but of great effect in the population. The evolution of cholera was controlled day by day through the analysis of the drinking water made by the chemical laboratory of the municipal laboratory.
During the month of July, the epidemic increased steadily, reaching about 500 invasions and nearly 300 deaths per day. During these days there was a fact that antiparticles cleverly used to discredit the Catalan doctor. Ferran inoculated the nuns and those in the Asylum of the Little Sisters of the Poor of Valencia, in which cholera had caused 65 deaths. Ferran warned that the vaccine was ineffective in already infected people, who were recorded in the vaccination register. In total, 88 people, 8 from the asylum and 80 nuns were vaccinated, 15 of whom had premonitory diarrhea. In the first five days after inoculation, the necessary time for the vaccine to be effective, 30 nuns became ill and 16 of them died. The controversy revived and the Government appointed a commission that, accompanied by Ferran and Gimeno, visited many towns, most of which were hostile to vaccination and vaccination was only possible in Ondara, Cambrils and Santa Pola. Although the results were fully favourable for cholera vaccine inoculation, the commission (made up of doctors alien to bacteriology: an anatomical dissector, a specialist in venereal diseases and an obstetrician) issued a negative opinion, no doubt pressured by the opposition to the vaccine of the Minister of Internal Affairs Francisco Romero Robledo, whose successor ratified on July 28 the ban that nobody, except Ferran, will carry out the inoculations. Before this situation, the bacteriologist refused to continue vaccinating and returned to Tortosa. The epidemic, which had begun to decline, was extinguished in September after 4 919 victims of a total of 7 084 affected. Ferran carried out more than thirty thousand inoculations, of which five thousand were in the capital, with only 54 dead inoculates.
To scientific reasons contrary to the vaccine were added personal confrontations to Ferran, a complicated man, with personalities of medicine without any preparation in the field of bacteriology and that greatly influenced the Government, contrary to him. This was taken advantage of by the opposition parties, liberals and republicans, who defended cholera vaccination to the point that the population attacked or exalted the Catalan physician according to the attitude of their favourite politicians. To this already poisoned controversy, unpleasant sanitary measures, such as sanitary wraps, isolation in small villages and quarantines were added, which aggravated the delicate economic situation of the Valencian counties of that year, which was very punished by frost and floods. Ferran soon showed the inefficiency of these measures and those responsible for the Valencian means of production adhered to his vaccine, the last hope to end the epidemic as soon as possible.
After the cholera vaccination campaign, Ferran began working with the rabies vaccine, implemented by Louis Pasteur that same year 1885. He asked the City Council of Barcelona to establish a Rabies Vaccine Institute, like the French microbiologist had done in Paris. He proposed that in the future the so-called Institute would also take care of manufacturing other vaccines and performing microbiological analyses of water, air and food. Finally, the City Council opted two years later to open a Municipal Microbiological Laboratory under the direction of Ferran. Replaced the Pasteur rabies vaccine pattern, in which successive vaccine doses were inoculated for 20 days, with the so-called supraintensive method, which only needed 5 days. Similarly to Pasteur, Ferran found that the application of the vaccine sometimes caused cases of paralysis, which cost him strong criticism.
In parallel to his research on rabies, Ferran was interested in the prophylaxis of typhoid fever and diphtheria. In 1887, he first attempted a vaccine with live typhoid bacilli. After testing it on himself, he applied it to members of the brigade of workers at the sewers of Barcelona. The strong secondary reactions that this vaccine caused and the numerous criticisms he received for it forced him to abandon this treatment. Four years later, an epidemic of typhoid fever was declared in Barcelona. Ferran sent a letter to the City Council in which he offered to provide, free of charge, through his particular laboratory the vaccine that was necessary. The City Council did not even acknowledged receiving it, which reflected the lack of confidence in the work of Ferran, so many times surrounded by controversy.
He also caused a great deal of controversy over the use of the vaccine that he prepared for diphtheria. He tested it in himself, in two of his children and in the two children of his friend Pere Aldavert, future president of the League of Catalonia. Three of the children became seriously ill, and Aldavert’s youngest son died. This death and the cases of paralysis after the application of the antiviral vaccine led to the constitution of a Governing Committee before which the members of the Laboratory declared. These accused Ferran of having rushed to try rabies and diphtheria vaccines in humans. The Commission agreed to lower the salary of Ferran, to force him to use the Pasteur method in the administration of the rabies vaccine and to prohibit him to carry out trials of vaccines in humans.
When Pierre Roux carried out the first trials on anti-Heterotherapy serotherapy in 1894, Ferran directed a report to the City Council in which he explained the approximate cost of manufacturing this serum in the Municipal Laboratory and the possible revenues that would be reported from selling it. The following year, the serotherapy service was opened at the premises of the Laboratory. This institution also prepared vaccines against different epizootic diseases, such as charcoal and swine erysipelas. Ferran, who was already preparing them in his laboratory in Tortosa, began to produce them on a large scale in Barcelona. As a result of an epidemic of swine erysipelas in Mallorca in 1892, the Provincial Council agreed to request the services of Ferran, who successfully embarked on a vaccination campaign on the island.
The outbreak of a serious epidemic of plague in Porto in 1899 caused Barcelona City Council to appoint a Commission chaired by Ferran to study the disease in the Portuguese city and adopt the most appropriate measures to prevent its penetration in Spain. The Catalan bacteriologist prepared and applied a plague vaccine, with which, when he returned to Barcelona, he also inoculated several members of the laboratory staff. Two of them suffered a strong post-vaccination reaction, so that Ferran again faced accusations of imprudence, in poor practice to not sufficiently mitigate the plague’s bacillus and to vaccinate under threats to the brigade’s members in charge of capturing dogs for the laboratory.
In need of more space in front of the growing activity of his particular laboratory, Ferran moved to the Barcelona neighborhood of La Sagrera in 1900 where he opened the Institute of Experimental and Hygiene Pathology, known as the Ferran Institute. There he held a doctor’s office, practiced inoculations and prepared vaccines for their commercial distribution. Soon after, several critical articles about Ferran’s responsibility in the vaccine accidents that occurred in the Municipal Microbiological Laboratory, as well as with his administrative management, were beginning to appear in the Barcelona press. He described the possible misuse of the money received in payment for the vaccines provided and a possible lack of ethics since the services he provided in his private laboratory matched with those offered by the Municipal one. It was even reported that the remaining diphtheria serum in the latter was diverted to the Ferran Institute. Given the seriousness of these accusations, the City Council opened an administrative file that closed in front of the explanations of Ferran. Nevertheless, the critics increased when four died by rabies after the inoculation of the vaccine provided by the Municipal Laboratory. Workers from the centre, from the Deputy Director Lluís Claramunt to the labourers, reported several irregularities in the management of Ferran and highlighted the bad environment that reigned at work, their loss of personal and professional prestige and the lack of a clear separation between his public activity and his private work at the Sagrera Institute. One of the most critical voices was that of Ramon Turró, who directed the bacteriological section in charge of food inspection. The City Council opened a new administrative file on Ferran. His lawyer, Juan Sol and Ortega, sent a letter to a group of renowned researchers who exposed Ferran’s situation and asked their opinion about his work. Personalities of the likes of Pierre Roux and Eli Metchnikoff among others emphasised their importance as a microbiologist, focusing almost exclusively on their work on cholera. The commission investigating the responsibility of Ferran ruled that these testimonies did not allow to calibrate the value of his rabies vaccine. This led in 1905 to his dismissal as director of the Municipal Microbiological Laboratory, a position that he replaced him by Ramón Turró.
Separated from his work as a civil servant, Ferran dedicated the rest of his life to private activity at his Sagrera Institute. The study of tuberculosis occupied most of its time. While in Tortosa he had already been interested in the cultivation of the Koch bacillus and its microscopic observation. By using different means of cultivation than those used at this time, he observed morphological characteristics of the bacilli unknown until then, so he proposed an evolutionary cycle of the tuberculosis germ that caused it to be derived from a sudden mutation of a saprophytic bacterium, the one that he called alpha, contracted by all during childhood. From this theory, he developed a vaccine, called anti-alpha, intended to prevent the passage of the alpha, innocuous, to the pathogenic or gamma form and began its manufacture.
Ferran tried his anti-alpha vaccine for the first time in 1919 in Alzira, where he had also begun the cholera vaccination campaign in Valencia in 1885. He did so at the request of the tuberculosis expert Josep Chabás, a determined supporter of the microbiological theories of Ferran on the Koch bacillus. On this occasion he had the support of the general director of Health Manuel Martín Salazar. He conducted fourteen thousand inoculations, without any mishaps, and with the enthusiastic collaboration of the Alzira population who remembered with great success the vaccination against cholera years ago.
Two years later, he carried out a tuberculosis vaccination campaign in Mallorca, although this time some sectors showed their hostility to the new vaccine. While carrying out this campaign, several cases of rabies were declared on the island. From the local press the authorities were pressured to consult Ferran about the treatment of the disease and the possibility of opening in Mallorca an Anti-rabies Institute similar to the one existing in Barcelona. Ferran asked his son Joan, who directed a private centre of these characteristics in the city of Barcelona, to obtain the necessary material to organise an anti-rabies service, whose assembly and training of the vacant staff took over the Casa de Socorro of the city. The controversy caused by this campaign caused that when returning to Barcelona, Ferran resigned to his position as a member of the Royal Medical Academy of this city, withdrawing the entry speech he had already handed over to this corporation.
In 1925, the Barcelona medical journal El Laboratorio organised an expedition formed by Spanish and Spanish-American doctors, chaired by Ferran, in order to visit the main German research centres and laboratories, which carried out various acts of homage to the scientific work of the Catalan microbiologist. Two years later, his delicate state of health and his advanced age did not prevent him from accepting an invitation from the Argentine government to preside over the First Pan American Tuberculosis Congress in Córdoba. Buenos Aires had been the first city outside Spain in which the anti-alpha vaccine was successfully used.
During the dictatorship of Primo de Rivera, the subsidy that the Ferran Institute was receiving in exchange for supplying its tuberculosis vaccine to the Charity centres was suppressed. Ferran showed with numerous statistics the efficacy of his vaccine and Francisco Murillo, General Director of Health, issued a Royal Order recommending its application to children admitted to charities. However, the anti-alpha vaccine was replaced shortly after by the BCG vaccine, which began to be introduced in Spain by the hand of the Catalan tuberculosis expert Lluís Sayé i Sempere.
During his visit to Barcelona in May 1929, King Alfonso XIII wanted to meet Ferran, to whom he informed of his intention to grant him a decoration or a noble title, but Ferran refused any kind of distinction. Jaume Ferran i Clua died on November 22 of that year.
María José Báguena Cervellera
“López Piñero” Institute of History of Medicine and Science – Universitat de València
Personatges i espais de ciència (‘Science characters and spaces’) is a project of the Unit of Scientific Culture and Innovation of the University of Valencia, with the collaboration of the “López Piñero” Institute of History of Medicine and Science and with the support of the Spanish Foundation for Science and Technology and of the Ministry of Economy, Industry and Competitiveness.
