- Email: [email protected]
The Military Institute of Hygiene and the creation of the laboratory of rabies vaccine
v a c u n a s . 2 0 1 8;1 9(2):105–109
Vacunas www.elsevier.es/vac
History of Vaccinology
The Military Institute of Hygiene and the creation of the laboratory of rabies vaccine夽 J.M. López González a , J.L. Duro Torrijos b , J. Tuells b,∗ a b
Enfermero militar, Sección de Sanidad ALA 35, Ejército del Aire, Spain Cátedra Balmis de Vacunología, Universidad de Alicante, Alicante, Spain
a r t i c l e
i n f o
a b s t r a c t
Article history:
The success of the rabies vaccine discovered by Pasteur was attended with a wide dis-
22 January 2019
semination and impact throughout the world. The finding gave way to a model of science that materialised in the foundation of the Pasteur Institute, centre that was erected as the international reference for training and acquisition of new scientific knowledge. For this reason, and as an example of file transfer and update of scientific developments,
Keywords: Laboratory of the Army Rabies vaccine The rabies virus Military Institute of Hygiene
were commissioned two groups of doctors of the Spanish Military Health Service, one in 1886 and the next in 1901, to obtain a pre-emptive treatment effective against rabies, which would reduce the morbidity and mortality of the disease. A few contacts that threw various reports intended for the assessment of the implementation of the rabies vaccine among the troops, and that, together with an analysis of various primary sources preserved in the Military file of Segovia, identify the main characteristics that wrapped around to the creation of a laboratory for processing and production of rabies vaccine in the Military Institute of Hygiene in Madrid, in force until the last quarter of the twentieth century. ˜ S.L.U. © 2018 Published by Elsevier Espana,
El Instituto de Higiene Militar y la creación del laboratorio de vacuna antirrábica r e s u m e n Palabras clave:
El éxito de la vacuna contra la rabia descubierta por Pasteur contó con una amplia difusión y
Laboratorio del ejército
repercusión por todo el mundo. El hallazgo dio paso a un modelo de ciencia que se material-
Vacuna antirrábica
izó en la fundación del Instituto Pasteur, centro que se erigió como el referente internacional
Virus rábico
para la formación y adquisición del nuevo conocimiento científico.
Instituto de Higiene Militar
Por este motivo y como ejemplo de transferencia y actualización de las novedades científicas, fueron comisionados dos grupos de facultativos del Cuerpo de Sanidad Militar, uno
DOI of original article: https://doi.org/10.1016/j.vacun.2018.11.002. Please cite this article as: López González JM, Duro Torrijos JL, Tuells J. El Instituto de Higiene Militar y la creación del laboratorio de vacuna antirrábica. Vacunas. 2018;19:105–109. ∗ Corresponding author. E-mail address: [email protected] (J. Tuells). https://doi.org/10.1016/j.vacune.2018.12.002 ˜ S.L.U. 2445-1460/© 2018 Published by Elsevier Espana, 夽
106
v a c u n a s . 2 0 1 8;1 9(2):105–109
en 1886 y el siguiente en 1901, para obtener un tratamiento preventivo eficaz contra la rabia que permitiera reducir la morbi-mortalidad de la enfermedad. Unos contactos que arrojaron diversos informes destinados a la evaluación de la implantación de la vacuna antirrábica entre las tropas, y que, junto al análisis de diversas fuentes primarias conservadas en el archivo Militar de Segovia, permiten identificar las principales características que envolvieron a la creación de un laboratorio de elaboración y producción de vacuna de antirrábica en el Instituto de Higiene Militar de Madrid, vigente hasta el último cuarto del siglo XX. ˜ S.L.U. © 2018 Publicado por Elsevier Espana,
Rabies and the Pasteurian revolution “Until recently our knowledge of rabies was tainted by many prejudices. It was believed, for example, that rabies could arise spontaneously and its causes were even described as being the root of evil. In the streets of certain cities, small pewter vessels full of water were often placed along the walls in summer so that dogs could quench their thirst. Many people believed that if these precautions were not taken the animals would be exposed to rabies. However, it is a fact that under no physiological or pathological condition will a dog or any other animal manifest signs of rabies unless it has been bitten or licked by another animal that has rabies when the wound occurs; but they will say, surely it is necessary that there must have been a first animal with rabies? This demand simply raises the question of the origin of all cases, and is absolutely outside the domain of scientific investigations.”1
This was how Louis Pasteur (1822–1895) in his letters on the subject of rabies, argued his contrary stance against the belief of the times regarding the spontaneity of diseases. When Pasteur began his investigations for obtaining a human virus against rabies there was already extensive knowledge available on the disease, its means of transmission through animal bites, the presence of a virus in saliva, several perfectly identifiable clinical symptoms and the existence of the latency or incubation period. Within this context, between 1881 and 1882 Pasteur published dozen articles which contained his findings regarding insulation and the attenuation of the virulence of the virus, the production of paralytic rabies by direct intravenous inoculation, and several trials which enabled him to develop an effective vaccine in dogs.2 A human vaccine was thus created, the proof of which was successfully put to the test in 1885 when treating the young 10 year old Joseph Meister, and 15 year old Jean Baptiste Jupille, a shepherd by profession. In both cases they had been attacked by a rabid dog in their French localities of Alsacia and Arbois respectively, from where they journeyed, terrified, to Pasteur’s laboratory in Ulm street in Paris.3 On 26th October that same year, Pasteur presented his findings at the Science Academy in Paris. From that moment onwards, the success of the vaccine against rabies became widely disseminated with worldwide repercussions, triggering a new scientific revolution: the Pasteurian revolution. A scientific model materialised with the foundation of the Pasteur Institute which was initially dedicated to the research and
treatment of rabies and was later extended to include other diseases and vaccines.4 The Pasteur Institute became a pilgrim’s centre not just for everyone who had been bitten by a rabid dog but also as an international benchmark centre for the training and acquisition of new scientific knowledge. This project raised great expectations for the military health system, which was greatly influenced by the new scientific concepts of diseases. This led to the promotion of the progressive optimisation of a rudimentary laboratory in the first Military Hospital of Madrid, which had been operative since 1843 and was now equipped with a microscope and kitchen with running water, later to be called the histological and histochemical laboratory.5 On the other hand, the low control of animal health in the colonies and the high rate of rabid dog bites in the peninsular created health problems for the troops. The healthcare infrastructures for the development of military research were generally in keeping with the day, but staff training in the latest methods was required so as to stay at the forefront of science. As a result, two groups of military physicians were commissioned at the Ulm Street laboratory in Paris, one in 1886 and the other in 1901, in order to obtain an effective preventative treatment against rabies which would reduce the morbidity and mortality of the disease. Each group drew up a report which became the deciding factor for definitive introduction of the anti-rabies vaccine among the troops.
The beginnings of the anti-rabies vaccine through the Pasteur method reports On 26th May 1886, the Chief Physician José Alabern y Raspall, Assistant Officer of the Histological Hospital, was transferred to Paris on official business with the mission to study the Pasteur method for treating rabies. He was accompanied by the soldier Alonso Bravo Méndez, who had been bitten in Granada by a dog suspected of suffering from hydrophobia.5 The military commissioners found themselves in an environment where “it was difficult to escape from the obsession which completely embraced not just the spirits of unlearned people but also of the political and scientific press, scholarly corporations and the highest powers of the State of this neighbouring nation, who made of Mr. Pasteur and his so-called discovery, an infallible axiom.”6 Despite this, there was no general acceptance of the method and Pasteur had adversaries, among whom were colleagues of his profession who questioned both technical
v a c u n a s . 2 0 1 8;1 9(2):105–109
issues and ethical aspects related to experimentation in humans, without sufficient tests on animals.6 These adversaries used the press as the sounding bell of these considerations, making public those failures which had occurred in France and in other countries of individuals who had been said to be cured by the Laboratory.4 The military commissioners’ four-month stay allowed them to make detailed observation of the anti-rabies method and this information was included two years later by Alabern in a report he made together with the physician Major Gregorio Andrés y Espala in 1888,6 the conclusions of which were to determine the publication of the Royal Order and Circular of 3rd July 1890 which lay down that no anti-rabies inoculations were to be practised in the Army, with the exception of vaccinations requested “by express petition of the interested parties and under the responsibility of the Institutes verifying this, without in any case, any direct or active intervention from the chiefs and officials of the Military Sanitary Corps, when its opinion is in general contrary to the goodness and usefulness of repeated treatment.”7 Ten years later and due to the continuous success stories about the anti-rabies vaccine, Royal Order of 1st May 1901 decreed that a new commission from the Military Institute of Hygiene formed by Physician Major Manuel Martín Salazar, the first assistant medical officer Alfredo Pérez Dalmau and the Chief physician Miguel Slocker de la Pola, become informed about the definitive value of anti-rabies inoculation in the army.8 This second Commission confirmed that the international scientific and medical community, with acquired experience through accumulated casuistry and results obtained, fully supported the goodness of the Pasteur method. “Today, after fifteen years of experience, not one person, in all conscience would refuse to provide prophylactic inoculation to all individuals who have been bitten by an animal infected with rabies.”9 Following this report, and the publication of Royal Order of 11th March 1902, the regulations to be followed relating to the examination of the suspected animal, and the application of treatment to the wounded person were dictated. Animal examination was to be carried out by the site military veterinary surgeon (or by the civil veterinary surgeon if there was no military one) and in the case of hydrophobia confirmation, the medulla oblongata would be sent to the Chief of Health, who would send it to the Military Institute of Hygiene for examination. The wounded individuals would be urgently sent to centres with proven scientific accreditation, preferably national, “if the Military Institute of Hygiene did not provide this service.”10
Interest in anti-rabies production and vaccination for the troops In 1901, the Alfonso XIII Institute of Serum therapy, Vaccination and Bacteriology was commissioned with the manufacture of the anti-rabies vaccine using the Pasteur11 method. This was not the only centre in which this activity was undertaken, several municipal and private centres located in the major cities of Spain served as reference for the urgent treatment of members of the army affected by potentially rabid animal bites. One paradigmatic example was
107
the Municipal Microbiological laboratory of Barcelona, whose director was the outstanding vaccinologist Jaime Ferrán y Clúa (1851–1929),12 discoverer of the cholera vaccine, and who created his own anti-rabies laboratory13 when his term as director ceased. In the case of the military, in 1915, after a report had been requested by the Health Section of the Ministry of War, the creation of an area inside the Military Institute of Hygiene dedicated to the production of the anti-rabies vaccine was turned down due to the low rate of disease incidence and the proximity of civil vaccination centres. “Although the installation of the anti-rabies service would be easy and possible in this Centre, and it would even been flattering that army personnel who had been bitten could find appropriate treatment in this institution, it is not financially viable (. . .), that even not counting installation costs, the costs of maintaining the service would be far higher than those of the patient care in the civil establishments today where, due to the higher number of cases they may offer this care at proportionately lower costs, and due to their distribution in several capitals of the Peninsula, the patients may be attended to more rapidly than through centralising the service in Madrid.”14 Despite this, inoculation of troops was progressively moved from civil vaccination centres to military hospitals and clinics. To do this, the Alfonso XIII Institute was contacted, from where the necessary rabbit medulla oblongata were supplied for the preparation of the anti-rabies vaccine and its immunisation technique by the Högyes15 method. In return, the institute demanded that the military physicians in charge of medulla elaboration and inoculation go through a training period in the institute. “This institute, after taking all types of precautions in such a delicate matter, demands that a prior condition be made for the sale of the before-mentioned medullas, that the Doctor who is to administer the inoculation be admitted to the Centre for 15 days, in order to learn everything there is to know about the anti-rabies treatment technique.”16 From that time forth, they began to authorise military health centres which, due to their geographic location, were of interest for the application of the anti-rabies vaccine. As a result, in 1916 the Military Hospitals of Seville, Ceuta and Melilla were given permission to administer the anti-rabies treatment, with prior services commission by the doctors who were sent for training to the Alfonso XIII17,18 institute. A year later, after meeting these instructive precepts, the establishment of anti-rabies treatment was ordered in the Military Hospitals of Madrid-Carabanchel, Valencia, Barcelona, ˜ Sta. Cruz de Tenerife and Zaragoza, Burgos, Valladolid, Coruna, Mahón.
The creation of the anti-rabies vaccine laboratory, the Military Institute of Hygiene During the ordinary meeting on 27th January 1917 of the Medical Board of the Military Institute of Hygiene, after costeffectiveness justification had been made, it was concluded pertinent to create an anti-rabies vaccine production and
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Högyes method application Laboratory within the Institute, pending the creation of branch laboratories in the different capital cities.19 Two months later, Royal Order of 12th March 1917 formalised and regulated the necessary infrastructure for the production of the anti-rabies vaccine in the Military Institute of Hygiene, from where the Military Hospitals would be supplied. As proposed in the ordinary session, the Högyes method was chosen as the technique to be used for vaccine production and immunisation. This method replaced the dried medullas used by the Pasteur technique with fresh medullas with virus fixed in dilution with saline in decreasing volumes. This procedure was more advantageous because the fresh medullas were more precise with regard to virulence compared with their age in extraction, thus facilitating the calculation of their dose in relation to the amount of fixed and dilution virus, and this was cheaper. The efficacy of immunisation would depend on the urgency of treatment application from the moment the lesion occurred. As a result and because it was impossible to treat all the necessary military staff with the anti-rabies vaccine due to distances and difficulties in communication at that time, it became obvious that there was a need for the creation of Military Institute of Hygiene branches to which the necessary rabbit medulla oblongata could be systematically and periodically sent: “the virulent medulla oglongata are inserted in neutral sterilised glycerine, taking advantage of the sticking power of this liquid, as is performed in other centres of this kind.”20 In this same act the Medical Board of the Institute also considered the list of materials required for the creation of the vaccine and inoculation of the dose to affected patients, in addition to the minimum staff required for optimum functioning of the laboratory which was to have a Second Assistant Medical Office as Head Doctor and a Chief Physician. These would be sufficient for “the constant preparation of medullas, their meticulous treatment with paraffin and packaging for dispatch to the branches as well as the necessary research studies for making diagnoses in suspected cases. All these operations are of an urgent, laborious nature and an essential technical importance; they are beyond the possible for a single person to perform and fulfil with precision and the appropriate scientific rigour.”21 On 12th May 1917, the installation of the anti-rabies laboratory in the Military Institute of Hygiene22 was completed and the Minister of War ordered in writing that activities were authorised to begin. The Doctor Major Celestino Moreno Ochoa, one of its most active advocates, was commissioned with managing the laboratory. Five years after the start of activities, on 2nd August 1922, Moreno Ochoa himself, as CEO of the anti-rabies laboratory and the Colonel doctor Eduardo Semprún y Semprún, as Manager of the Military Institute of Hygiene requested authorisation from the Minister of War to disseminate the results of their investigations. The rabies virus was to be inactivated without any loss of its immunising qualities: “. . .resolving a problem that has concerned all scientific institutions established for this type of study, that until today has not been possible,”22 highlighting the importance of the Military Institute of Hygiene in meeting this challenge “since the priority of discovery totally belongs more than to ourselves to this Institute, since the costly
experiences which have been undertaken, which are in the making and which must necessarily continue are being met by resources supplied by the State for this establishment of this type of work.”22 Two days later, by post, they received praise and compliments from the headquarters of the Health Department of the Ministry of War, encouraging outreach “. . .we are pleased to inform you that S.M.would like this interesting topic to be discussed in the conference which V.S. is to give in Karlsbad (Germany) at the end of September.”23 Paradoxically, the initiative was inactivated from that time onwards. It was not reflected in the media, nor entered into the literature of the time, with greater significance being attached to the fact that Colonel Semprún did not allude to the findings during his conference at the International Congress on Balneology and Balneotherapy celebrated in Karlsbad in September 1922, and focused his presentation on the future surgical therapy of cancer.24 One possible explanation for the non existences of the event in scientific literature could be the lack of financing by the State for the publication and attainment of the patent since, as the Director of the Institute states in his communication regarding the discovery, it spoke of “costly experiences which have been undertaken, which are in the making and which must necessarily continue . . .”22 These considerations were reinforced by writs sent to negotiators with financial decision-making capacities, such as the Head of the Health Department of the Ministry of War, Juan Valdivia, who would request authorisation for them from the Assistant Secretary of the Ministry, with absolute support on 11th August 1922. Despite early reactions, no response was received until two months later, and when it did arrive it would result in, at least, a major delay in resolution time “. . .it is necessary to know the quantity of them [of the patent costs] for their inclusion (sic) in the chapter and article of the Budget to which they correspond (. . .) and, at the same time, to be given the authorised report from the Ministries of War and Navy Civil Intervention and from the Protectorate of Morocco.”25 It is a fact that from the moment when the Director of the Institute requested authorisation for the publication and the patent of discovery until the budget request of the expenses pertaining to them was returned to him, seven months elapsed. Should the request have been made by the Institute, one must assume that authorisation could have been delayed even further. It becomes apparent that the communication to scientific forums of “such an important discovery” in the words of the Director of the Institute, did not occur as there is no reference whatsoever to confirm this. Going back to the manufacture of the anti-rabies vaccine in the army, we should underline several noteworthy events relating to the initial implementation of the Högyes type production method and several measures aimed at the control of animals suspected to be suffering from the disease. These include the Order and Circular of 22nd September 1934, which governed anti-rabies prophylaxis, establishing hospitalisation for individuals who had been bitten; the observation of dogs suspected to have rabies by military veterinary staff and the procedure to be maintained for the carrying out of autopsies on dead dogs. Thirty years later, a Ministerial Order of 1st June 1934, modified the imposition of hospital admittance of the wounded person and authorised outpatient treatment in the unit of the
v a c u n a s . 2 0 1 8;1 9(2):105–109
centre to which the wounded person was attached, under the supervision of the doctor in charge of care. For the practice of outpatient treatment a SEMPLE type formalin-inactivated vaccine was to be used, to be requested from the nearest military pharmacy. The anti-rabies vaccine continued to be manufactured in the Military Institute of Hygiene, and then in the “Capitán médico Ramón y Cajal” Institute of Preventative Medicine until 1976. From then onwards, and with justification regarding economic costs, its production was withdrawn, as it was determined that “the Semple type vaccine may be acquired by the Bodies, Centres and Branches in the corresponding provincial healthcare headquarters; it is envisaged that in Madrid it may be acquired from the National HealthSchool.”26 As a result, the production and application of anti-rabies treatment in the Institute ceased from that time onwards. The prevention of rabies in the army became limited to the control and vaccination of the official staff dogs. Anti-rabies campaigns are conducted annually and supervised by General Headquarters, under the regulations dictated by the Personnel Management (Veterinary Division) which, in general, are in keeping with those issued annually in a joint Circular from the Ministries of Health and Agriculture.
9.
10. 11.
12. 13.
14.
15. 16. 17.
references 18. 1. Schneider MC, Santos Burgoa C. Tratamiento contra la rabia humana: un poco de su historia. Rev Saúde Pública. 1994;28:454–63. 2. Darmon P. Pasteur. París: Ed Fayard; 1995. 3. Geison GL. The private science of Louis Pasteur. Princeton: Princeton University Press; 1995. 4. Tuells J, Duro Torrijos JL. El proceso de creación del Instituto ˜ Pasteur (1886–1888) según la prensa espanola de la época. Vacunas. 2011;12:154–9. 5. Moratinos Palomero P, Moratinos Martínez MM, Martín Sierra F, Guijarro Escribano FJ. Historia del Instituto de Medicina Preventiva del E.T., Capitán Médico Ramón y Cajal. Med Mil (Esp). 2003;59:5–17. 6. Andres Espala G, Alabern y Raspal J. Las inoculaciones antirrábicas según el método Pasteur Informe emitido según comisionados por R.O. de 27 de mayo de 1886. Madrid: Biblioteca de la Rev San Mil; 1888. 7. Montalvo Escobar A, Pascual Narváez A, Méndez Montesino JR, Martín Sierra F, Martín Yagüe A, Espinosa Urbina J, et al. Medicina preventiva de la rabia. Med Mil. 1986;42:173–86. 8. Real Orden de 1 de mayo 1901 por la que se ordena la elaboración de un informe definitivo sobre el valor de las
19.
20.
21.
22.
23.
24. 25.
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inoculaciones antirrábicas en el Ejército. Diario Oficial núm. 99 de 3 de mayo. Martín Salazar M, Pérez Dalmau A, Slocker M. Valor profiláctico de las inoculaciones antirrábicas con aplicación al Ejército Informe oficial emitido por la Comisión designada al efecto por R.O. 1 mayo 1901. Madrid: Biblioteca de la Rev San Mil; 1901. Real Orden de 11 de marzo de 1902. Colección Legislativa del Ejército. Diario Oficial núm. 58. Porras Gallo MI. Antecedentes y creación del Instituto de Sueroterapia Vacunación y Bacteriología de Alfonso XIII. Dynamis. 1998;18:81–105. Tuells J. Jaime Ferrán i Clúa (1851–1929), un vacunólogo práctico y controvertido. Vacunas. 2009;10:103–9. Archivo General Militar de Segovia (AGM). Informe sobre el crédito científico de los establecimientos antirrábicos de Barcelona. Secc 2a , Div 14, Leg 98. Archivo General Militar de Segovia (AGM). Acta de reunión de la Junta Facultativa del Instituto de Higiene Militar sobre la conveniencia de la creación de una Sección de vacuna antirrábica (3 de noviembre de 1915). Secc 2a , Div 14, Leg 95. Del Castillo J. Profilaxis de la rabia en Hungría. Rev San Mil. 1901;332:190–7. Archivo General Militar de Segovia (AGM). Escrito de Capitanía de la 2a Región Militar E.M. Secc 2a , Div 14, Leg 113. Archivo General Militar de Segovia (AGM). Escrito del Coronel Jefe de la Sección de Operaciones de E.M. del Ejército de ˜ en África de 20 de nov 1916. Secc 2a , Div 14, Leg 113. Espana Archivo General Militar de Segovia (AGM). Escrito del General ˜ en África de fecha 7 dic 1916. Secc Jefe del Ejército de Espana 2a , Div 14, Leg 113. Archivo General Militar de Segovia (AGM). Acta de sesión de la Junta Facultativa del Instituto de Higiene Militar celebrada el 27 enero de 1917. Secc 2a , Div 14, Leg 99. Archivo General Militar de Segovia (AGM). Acta de la Junta de Sanidad Militar del Ministerio de la Guerra de 16 feb 1917. Secc 2a , Div 14, Leg 99. Archivo General Militar de Segovia (AGM). Escrito de la Sección de Sanidad a la Subsecretaría del Ministerio de la Guerra de 27 marzo 1917. Secc 2a , Div 14, Leg 99. Archivo General Militar de Segovia (AGM). Escrito del Director del Instituto de Higiene Militar al Ministro de la Guerra; Rf. Instituto de Higiene Militar, número 2268 de 2 de agosto 1922. Secc 2a , Div 14, Leg 99. Archivo del Instituto de Medicina Preventiva de la Defensa “Capitán Médico Ramón y Cajal”. Escrito del Jefe de la Sección de Sanidad, 2◦ Negociado n◦ 1989/2305 de 4 de agosto. ˜ XII Núm. 20. 15 de Variedades. Revista de Sanidad Militar. Ano octubre de 1922. Archivo General Militar de Segovia (AGM). Escrito de Intendencia General Militar 11 de octubre de 1922. Secc 2a , Div 14, Leg 99.
Vacunas www.elsevier.es/vac
History of Vaccinology
The Military Institute of Hygiene and the creation of the laboratory of rabies vaccine夽 J.M. López González a , J.L. Duro Torrijos b , J. Tuells b,∗ a b
Enfermero militar, Sección de Sanidad ALA 35, Ejército del Aire, Spain Cátedra Balmis de Vacunología, Universidad de Alicante, Alicante, Spain
a r t i c l e
i n f o
a b s t r a c t
Article history:
The success of the rabies vaccine discovered by Pasteur was attended with a wide dis-
22 January 2019
semination and impact throughout the world. The finding gave way to a model of science that materialised in the foundation of the Pasteur Institute, centre that was erected as the international reference for training and acquisition of new scientific knowledge. For this reason, and as an example of file transfer and update of scientific developments,
Keywords: Laboratory of the Army Rabies vaccine The rabies virus Military Institute of Hygiene
were commissioned two groups of doctors of the Spanish Military Health Service, one in 1886 and the next in 1901, to obtain a pre-emptive treatment effective against rabies, which would reduce the morbidity and mortality of the disease. A few contacts that threw various reports intended for the assessment of the implementation of the rabies vaccine among the troops, and that, together with an analysis of various primary sources preserved in the Military file of Segovia, identify the main characteristics that wrapped around to the creation of a laboratory for processing and production of rabies vaccine in the Military Institute of Hygiene in Madrid, in force until the last quarter of the twentieth century. ˜ S.L.U. © 2018 Published by Elsevier Espana,
El Instituto de Higiene Militar y la creación del laboratorio de vacuna antirrábica r e s u m e n Palabras clave:
El éxito de la vacuna contra la rabia descubierta por Pasteur contó con una amplia difusión y
Laboratorio del ejército
repercusión por todo el mundo. El hallazgo dio paso a un modelo de ciencia que se material-
Vacuna antirrábica
izó en la fundación del Instituto Pasteur, centro que se erigió como el referente internacional
Virus rábico
para la formación y adquisición del nuevo conocimiento científico.
Instituto de Higiene Militar
Por este motivo y como ejemplo de transferencia y actualización de las novedades científicas, fueron comisionados dos grupos de facultativos del Cuerpo de Sanidad Militar, uno
DOI of original article: https://doi.org/10.1016/j.vacun.2018.11.002. Please cite this article as: López González JM, Duro Torrijos JL, Tuells J. El Instituto de Higiene Militar y la creación del laboratorio de vacuna antirrábica. Vacunas. 2018;19:105–109. ∗ Corresponding author. E-mail address: [email protected] (J. Tuells). https://doi.org/10.1016/j.vacune.2018.12.002 ˜ S.L.U. 2445-1460/© 2018 Published by Elsevier Espana, 夽
106
v a c u n a s . 2 0 1 8;1 9(2):105–109
en 1886 y el siguiente en 1901, para obtener un tratamiento preventivo eficaz contra la rabia que permitiera reducir la morbi-mortalidad de la enfermedad. Unos contactos que arrojaron diversos informes destinados a la evaluación de la implantación de la vacuna antirrábica entre las tropas, y que, junto al análisis de diversas fuentes primarias conservadas en el archivo Militar de Segovia, permiten identificar las principales características que envolvieron a la creación de un laboratorio de elaboración y producción de vacuna de antirrábica en el Instituto de Higiene Militar de Madrid, vigente hasta el último cuarto del siglo XX. ˜ S.L.U. © 2018 Publicado por Elsevier Espana,
Rabies and the Pasteurian revolution “Until recently our knowledge of rabies was tainted by many prejudices. It was believed, for example, that rabies could arise spontaneously and its causes were even described as being the root of evil. In the streets of certain cities, small pewter vessels full of water were often placed along the walls in summer so that dogs could quench their thirst. Many people believed that if these precautions were not taken the animals would be exposed to rabies. However, it is a fact that under no physiological or pathological condition will a dog or any other animal manifest signs of rabies unless it has been bitten or licked by another animal that has rabies when the wound occurs; but they will say, surely it is necessary that there must have been a first animal with rabies? This demand simply raises the question of the origin of all cases, and is absolutely outside the domain of scientific investigations.”1
This was how Louis Pasteur (1822–1895) in his letters on the subject of rabies, argued his contrary stance against the belief of the times regarding the spontaneity of diseases. When Pasteur began his investigations for obtaining a human virus against rabies there was already extensive knowledge available on the disease, its means of transmission through animal bites, the presence of a virus in saliva, several perfectly identifiable clinical symptoms and the existence of the latency or incubation period. Within this context, between 1881 and 1882 Pasteur published dozen articles which contained his findings regarding insulation and the attenuation of the virulence of the virus, the production of paralytic rabies by direct intravenous inoculation, and several trials which enabled him to develop an effective vaccine in dogs.2 A human vaccine was thus created, the proof of which was successfully put to the test in 1885 when treating the young 10 year old Joseph Meister, and 15 year old Jean Baptiste Jupille, a shepherd by profession. In both cases they had been attacked by a rabid dog in their French localities of Alsacia and Arbois respectively, from where they journeyed, terrified, to Pasteur’s laboratory in Ulm street in Paris.3 On 26th October that same year, Pasteur presented his findings at the Science Academy in Paris. From that moment onwards, the success of the vaccine against rabies became widely disseminated with worldwide repercussions, triggering a new scientific revolution: the Pasteurian revolution. A scientific model materialised with the foundation of the Pasteur Institute which was initially dedicated to the research and
treatment of rabies and was later extended to include other diseases and vaccines.4 The Pasteur Institute became a pilgrim’s centre not just for everyone who had been bitten by a rabid dog but also as an international benchmark centre for the training and acquisition of new scientific knowledge. This project raised great expectations for the military health system, which was greatly influenced by the new scientific concepts of diseases. This led to the promotion of the progressive optimisation of a rudimentary laboratory in the first Military Hospital of Madrid, which had been operative since 1843 and was now equipped with a microscope and kitchen with running water, later to be called the histological and histochemical laboratory.5 On the other hand, the low control of animal health in the colonies and the high rate of rabid dog bites in the peninsular created health problems for the troops. The healthcare infrastructures for the development of military research were generally in keeping with the day, but staff training in the latest methods was required so as to stay at the forefront of science. As a result, two groups of military physicians were commissioned at the Ulm Street laboratory in Paris, one in 1886 and the other in 1901, in order to obtain an effective preventative treatment against rabies which would reduce the morbidity and mortality of the disease. Each group drew up a report which became the deciding factor for definitive introduction of the anti-rabies vaccine among the troops.
The beginnings of the anti-rabies vaccine through the Pasteur method reports On 26th May 1886, the Chief Physician José Alabern y Raspall, Assistant Officer of the Histological Hospital, was transferred to Paris on official business with the mission to study the Pasteur method for treating rabies. He was accompanied by the soldier Alonso Bravo Méndez, who had been bitten in Granada by a dog suspected of suffering from hydrophobia.5 The military commissioners found themselves in an environment where “it was difficult to escape from the obsession which completely embraced not just the spirits of unlearned people but also of the political and scientific press, scholarly corporations and the highest powers of the State of this neighbouring nation, who made of Mr. Pasteur and his so-called discovery, an infallible axiom.”6 Despite this, there was no general acceptance of the method and Pasteur had adversaries, among whom were colleagues of his profession who questioned both technical
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issues and ethical aspects related to experimentation in humans, without sufficient tests on animals.6 These adversaries used the press as the sounding bell of these considerations, making public those failures which had occurred in France and in other countries of individuals who had been said to be cured by the Laboratory.4 The military commissioners’ four-month stay allowed them to make detailed observation of the anti-rabies method and this information was included two years later by Alabern in a report he made together with the physician Major Gregorio Andrés y Espala in 1888,6 the conclusions of which were to determine the publication of the Royal Order and Circular of 3rd July 1890 which lay down that no anti-rabies inoculations were to be practised in the Army, with the exception of vaccinations requested “by express petition of the interested parties and under the responsibility of the Institutes verifying this, without in any case, any direct or active intervention from the chiefs and officials of the Military Sanitary Corps, when its opinion is in general contrary to the goodness and usefulness of repeated treatment.”7 Ten years later and due to the continuous success stories about the anti-rabies vaccine, Royal Order of 1st May 1901 decreed that a new commission from the Military Institute of Hygiene formed by Physician Major Manuel Martín Salazar, the first assistant medical officer Alfredo Pérez Dalmau and the Chief physician Miguel Slocker de la Pola, become informed about the definitive value of anti-rabies inoculation in the army.8 This second Commission confirmed that the international scientific and medical community, with acquired experience through accumulated casuistry and results obtained, fully supported the goodness of the Pasteur method. “Today, after fifteen years of experience, not one person, in all conscience would refuse to provide prophylactic inoculation to all individuals who have been bitten by an animal infected with rabies.”9 Following this report, and the publication of Royal Order of 11th March 1902, the regulations to be followed relating to the examination of the suspected animal, and the application of treatment to the wounded person were dictated. Animal examination was to be carried out by the site military veterinary surgeon (or by the civil veterinary surgeon if there was no military one) and in the case of hydrophobia confirmation, the medulla oblongata would be sent to the Chief of Health, who would send it to the Military Institute of Hygiene for examination. The wounded individuals would be urgently sent to centres with proven scientific accreditation, preferably national, “if the Military Institute of Hygiene did not provide this service.”10
Interest in anti-rabies production and vaccination for the troops In 1901, the Alfonso XIII Institute of Serum therapy, Vaccination and Bacteriology was commissioned with the manufacture of the anti-rabies vaccine using the Pasteur11 method. This was not the only centre in which this activity was undertaken, several municipal and private centres located in the major cities of Spain served as reference for the urgent treatment of members of the army affected by potentially rabid animal bites. One paradigmatic example was
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the Municipal Microbiological laboratory of Barcelona, whose director was the outstanding vaccinologist Jaime Ferrán y Clúa (1851–1929),12 discoverer of the cholera vaccine, and who created his own anti-rabies laboratory13 when his term as director ceased. In the case of the military, in 1915, after a report had been requested by the Health Section of the Ministry of War, the creation of an area inside the Military Institute of Hygiene dedicated to the production of the anti-rabies vaccine was turned down due to the low rate of disease incidence and the proximity of civil vaccination centres. “Although the installation of the anti-rabies service would be easy and possible in this Centre, and it would even been flattering that army personnel who had been bitten could find appropriate treatment in this institution, it is not financially viable (. . .), that even not counting installation costs, the costs of maintaining the service would be far higher than those of the patient care in the civil establishments today where, due to the higher number of cases they may offer this care at proportionately lower costs, and due to their distribution in several capitals of the Peninsula, the patients may be attended to more rapidly than through centralising the service in Madrid.”14 Despite this, inoculation of troops was progressively moved from civil vaccination centres to military hospitals and clinics. To do this, the Alfonso XIII Institute was contacted, from where the necessary rabbit medulla oblongata were supplied for the preparation of the anti-rabies vaccine and its immunisation technique by the Högyes15 method. In return, the institute demanded that the military physicians in charge of medulla elaboration and inoculation go through a training period in the institute. “This institute, after taking all types of precautions in such a delicate matter, demands that a prior condition be made for the sale of the before-mentioned medullas, that the Doctor who is to administer the inoculation be admitted to the Centre for 15 days, in order to learn everything there is to know about the anti-rabies treatment technique.”16 From that time forth, they began to authorise military health centres which, due to their geographic location, were of interest for the application of the anti-rabies vaccine. As a result, in 1916 the Military Hospitals of Seville, Ceuta and Melilla were given permission to administer the anti-rabies treatment, with prior services commission by the doctors who were sent for training to the Alfonso XIII17,18 institute. A year later, after meeting these instructive precepts, the establishment of anti-rabies treatment was ordered in the Military Hospitals of Madrid-Carabanchel, Valencia, Barcelona, ˜ Sta. Cruz de Tenerife and Zaragoza, Burgos, Valladolid, Coruna, Mahón.
The creation of the anti-rabies vaccine laboratory, the Military Institute of Hygiene During the ordinary meeting on 27th January 1917 of the Medical Board of the Military Institute of Hygiene, after costeffectiveness justification had been made, it was concluded pertinent to create an anti-rabies vaccine production and
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Högyes method application Laboratory within the Institute, pending the creation of branch laboratories in the different capital cities.19 Two months later, Royal Order of 12th March 1917 formalised and regulated the necessary infrastructure for the production of the anti-rabies vaccine in the Military Institute of Hygiene, from where the Military Hospitals would be supplied. As proposed in the ordinary session, the Högyes method was chosen as the technique to be used for vaccine production and immunisation. This method replaced the dried medullas used by the Pasteur technique with fresh medullas with virus fixed in dilution with saline in decreasing volumes. This procedure was more advantageous because the fresh medullas were more precise with regard to virulence compared with their age in extraction, thus facilitating the calculation of their dose in relation to the amount of fixed and dilution virus, and this was cheaper. The efficacy of immunisation would depend on the urgency of treatment application from the moment the lesion occurred. As a result and because it was impossible to treat all the necessary military staff with the anti-rabies vaccine due to distances and difficulties in communication at that time, it became obvious that there was a need for the creation of Military Institute of Hygiene branches to which the necessary rabbit medulla oblongata could be systematically and periodically sent: “the virulent medulla oglongata are inserted in neutral sterilised glycerine, taking advantage of the sticking power of this liquid, as is performed in other centres of this kind.”20 In this same act the Medical Board of the Institute also considered the list of materials required for the creation of the vaccine and inoculation of the dose to affected patients, in addition to the minimum staff required for optimum functioning of the laboratory which was to have a Second Assistant Medical Office as Head Doctor and a Chief Physician. These would be sufficient for “the constant preparation of medullas, their meticulous treatment with paraffin and packaging for dispatch to the branches as well as the necessary research studies for making diagnoses in suspected cases. All these operations are of an urgent, laborious nature and an essential technical importance; they are beyond the possible for a single person to perform and fulfil with precision and the appropriate scientific rigour.”21 On 12th May 1917, the installation of the anti-rabies laboratory in the Military Institute of Hygiene22 was completed and the Minister of War ordered in writing that activities were authorised to begin. The Doctor Major Celestino Moreno Ochoa, one of its most active advocates, was commissioned with managing the laboratory. Five years after the start of activities, on 2nd August 1922, Moreno Ochoa himself, as CEO of the anti-rabies laboratory and the Colonel doctor Eduardo Semprún y Semprún, as Manager of the Military Institute of Hygiene requested authorisation from the Minister of War to disseminate the results of their investigations. The rabies virus was to be inactivated without any loss of its immunising qualities: “. . .resolving a problem that has concerned all scientific institutions established for this type of study, that until today has not been possible,”22 highlighting the importance of the Military Institute of Hygiene in meeting this challenge “since the priority of discovery totally belongs more than to ourselves to this Institute, since the costly
experiences which have been undertaken, which are in the making and which must necessarily continue are being met by resources supplied by the State for this establishment of this type of work.”22 Two days later, by post, they received praise and compliments from the headquarters of the Health Department of the Ministry of War, encouraging outreach “. . .we are pleased to inform you that S.M.would like this interesting topic to be discussed in the conference which V.S. is to give in Karlsbad (Germany) at the end of September.”23 Paradoxically, the initiative was inactivated from that time onwards. It was not reflected in the media, nor entered into the literature of the time, with greater significance being attached to the fact that Colonel Semprún did not allude to the findings during his conference at the International Congress on Balneology and Balneotherapy celebrated in Karlsbad in September 1922, and focused his presentation on the future surgical therapy of cancer.24 One possible explanation for the non existences of the event in scientific literature could be the lack of financing by the State for the publication and attainment of the patent since, as the Director of the Institute states in his communication regarding the discovery, it spoke of “costly experiences which have been undertaken, which are in the making and which must necessarily continue . . .”22 These considerations were reinforced by writs sent to negotiators with financial decision-making capacities, such as the Head of the Health Department of the Ministry of War, Juan Valdivia, who would request authorisation for them from the Assistant Secretary of the Ministry, with absolute support on 11th August 1922. Despite early reactions, no response was received until two months later, and when it did arrive it would result in, at least, a major delay in resolution time “. . .it is necessary to know the quantity of them [of the patent costs] for their inclusion (sic) in the chapter and article of the Budget to which they correspond (. . .) and, at the same time, to be given the authorised report from the Ministries of War and Navy Civil Intervention and from the Protectorate of Morocco.”25 It is a fact that from the moment when the Director of the Institute requested authorisation for the publication and the patent of discovery until the budget request of the expenses pertaining to them was returned to him, seven months elapsed. Should the request have been made by the Institute, one must assume that authorisation could have been delayed even further. It becomes apparent that the communication to scientific forums of “such an important discovery” in the words of the Director of the Institute, did not occur as there is no reference whatsoever to confirm this. Going back to the manufacture of the anti-rabies vaccine in the army, we should underline several noteworthy events relating to the initial implementation of the Högyes type production method and several measures aimed at the control of animals suspected to be suffering from the disease. These include the Order and Circular of 22nd September 1934, which governed anti-rabies prophylaxis, establishing hospitalisation for individuals who had been bitten; the observation of dogs suspected to have rabies by military veterinary staff and the procedure to be maintained for the carrying out of autopsies on dead dogs. Thirty years later, a Ministerial Order of 1st June 1934, modified the imposition of hospital admittance of the wounded person and authorised outpatient treatment in the unit of the
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centre to which the wounded person was attached, under the supervision of the doctor in charge of care. For the practice of outpatient treatment a SEMPLE type formalin-inactivated vaccine was to be used, to be requested from the nearest military pharmacy. The anti-rabies vaccine continued to be manufactured in the Military Institute of Hygiene, and then in the “Capitán médico Ramón y Cajal” Institute of Preventative Medicine until 1976. From then onwards, and with justification regarding economic costs, its production was withdrawn, as it was determined that “the Semple type vaccine may be acquired by the Bodies, Centres and Branches in the corresponding provincial healthcare headquarters; it is envisaged that in Madrid it may be acquired from the National HealthSchool.”26 As a result, the production and application of anti-rabies treatment in the Institute ceased from that time onwards. The prevention of rabies in the army became limited to the control and vaccination of the official staff dogs. Anti-rabies campaigns are conducted annually and supervised by General Headquarters, under the regulations dictated by the Personnel Management (Veterinary Division) which, in general, are in keeping with those issued annually in a joint Circular from the Ministries of Health and Agriculture.
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references 18. 1. Schneider MC, Santos Burgoa C. Tratamiento contra la rabia humana: un poco de su historia. Rev Saúde Pública. 1994;28:454–63. 2. Darmon P. Pasteur. París: Ed Fayard; 1995. 3. Geison GL. The private science of Louis Pasteur. Princeton: Princeton University Press; 1995. 4. Tuells J, Duro Torrijos JL. El proceso de creación del Instituto ˜ Pasteur (1886–1888) según la prensa espanola de la época. Vacunas. 2011;12:154–9. 5. Moratinos Palomero P, Moratinos Martínez MM, Martín Sierra F, Guijarro Escribano FJ. Historia del Instituto de Medicina Preventiva del E.T., Capitán Médico Ramón y Cajal. Med Mil (Esp). 2003;59:5–17. 6. Andres Espala G, Alabern y Raspal J. Las inoculaciones antirrábicas según el método Pasteur Informe emitido según comisionados por R.O. de 27 de mayo de 1886. Madrid: Biblioteca de la Rev San Mil; 1888. 7. Montalvo Escobar A, Pascual Narváez A, Méndez Montesino JR, Martín Sierra F, Martín Yagüe A, Espinosa Urbina J, et al. Medicina preventiva de la rabia. Med Mil. 1986;42:173–86. 8. Real Orden de 1 de mayo 1901 por la que se ordena la elaboración de un informe definitivo sobre el valor de las
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inoculaciones antirrábicas en el Ejército. Diario Oficial núm. 99 de 3 de mayo. Martín Salazar M, Pérez Dalmau A, Slocker M. Valor profiláctico de las inoculaciones antirrábicas con aplicación al Ejército Informe oficial emitido por la Comisión designada al efecto por R.O. 1 mayo 1901. Madrid: Biblioteca de la Rev San Mil; 1901. Real Orden de 11 de marzo de 1902. Colección Legislativa del Ejército. Diario Oficial núm. 58. Porras Gallo MI. Antecedentes y creación del Instituto de Sueroterapia Vacunación y Bacteriología de Alfonso XIII. Dynamis. 1998;18:81–105. Tuells J. Jaime Ferrán i Clúa (1851–1929), un vacunólogo práctico y controvertido. Vacunas. 2009;10:103–9. Archivo General Militar de Segovia (AGM). Informe sobre el crédito científico de los establecimientos antirrábicos de Barcelona. Secc 2a , Div 14, Leg 98. Archivo General Militar de Segovia (AGM). Acta de reunión de la Junta Facultativa del Instituto de Higiene Militar sobre la conveniencia de la creación de una Sección de vacuna antirrábica (3 de noviembre de 1915). Secc 2a , Div 14, Leg 95. Del Castillo J. Profilaxis de la rabia en Hungría. Rev San Mil. 1901;332:190–7. Archivo General Militar de Segovia (AGM). Escrito de Capitanía de la 2a Región Militar E.M. Secc 2a , Div 14, Leg 113. Archivo General Militar de Segovia (AGM). Escrito del Coronel Jefe de la Sección de Operaciones de E.M. del Ejército de ˜ en África de 20 de nov 1916. Secc 2a , Div 14, Leg 113. Espana Archivo General Militar de Segovia (AGM). Escrito del General ˜ en África de fecha 7 dic 1916. Secc Jefe del Ejército de Espana 2a , Div 14, Leg 113. Archivo General Militar de Segovia (AGM). Acta de sesión de la Junta Facultativa del Instituto de Higiene Militar celebrada el 27 enero de 1917. Secc 2a , Div 14, Leg 99. Archivo General Militar de Segovia (AGM). Acta de la Junta de Sanidad Militar del Ministerio de la Guerra de 16 feb 1917. Secc 2a , Div 14, Leg 99. Archivo General Militar de Segovia (AGM). Escrito de la Sección de Sanidad a la Subsecretaría del Ministerio de la Guerra de 27 marzo 1917. Secc 2a , Div 14, Leg 99. Archivo General Militar de Segovia (AGM). Escrito del Director del Instituto de Higiene Militar al Ministro de la Guerra; Rf. Instituto de Higiene Militar, número 2268 de 2 de agosto 1922. Secc 2a , Div 14, Leg 99. Archivo del Instituto de Medicina Preventiva de la Defensa “Capitán Médico Ramón y Cajal”. Escrito del Jefe de la Sección de Sanidad, 2◦ Negociado n◦ 1989/2305 de 4 de agosto. ˜ XII Núm. 20. 15 de Variedades. Revista de Sanidad Militar. Ano octubre de 1922. Archivo General Militar de Segovia (AGM). Escrito de Intendencia General Militar 11 de octubre de 1922. Secc 2a , Div 14, Leg 99.