PASTEUR VACCINATIONS

PASTEUR VACCINATIONS, or anti-rabies vaccinations, are a preventive measure against rabies (see). As an antigen, fixed virus (virus fixe) (see Rabies) is used, which to this day has almost everywhere continued to be passaged from the virus originally obtained by Pasteur in Paris; in the USSR, some stations have already conducted over 2,000 such passages. Only the Kiev and Dnepropetrovsk Pasteur stations worked for a time with vaccine from a local virus. Since the causative agent of rabies is unknown in its pure form, it must be studied in the tissues (brain) of the organism. This makes the task technically difficult and sometimes does not ensure obtaining quite accurate and consistent results. Nevertheless, many of the properties of virus fixe have been established. It is known that a number of physical and chemical agents act on it weakeningly; these include sunlight, x-rays, radium, high temperature, oxygen, bile, gastric juice, sublimate, formalin, phenols, ether, etc. At low temperatures, virus fixe is preserved for a very long time, putrefaction acts on it weakly, and it is well preserved in glycerin. All these data have great practical significance, and many of the mentioned means have been used to weaken the virus, to develop methods for its longer preservation, etc. The most virulent part in the brain is the gray matter, and the infectious agent is contained in greater quantity in the medulla oblongata, in the cerebral cortex, and in the Ammon's horn. The saliva of rabid animals is undoubtedly virulent, and practically bites by dogs should be considered dangerous 10-12-15 days before the appearance of obvious signs of the disease; the question of whether the saliva of a person suffering from hydrophobia is virulent remains unresolved; the question regarding the virulence of the blood of rabid animals and their milk also remains questionable. Virus fixe is influenced by the breed of animals through which it is passaged, climate, conditions, etc. Naturally, decades of passage (since 1885) of the virus in different places, in different climates, on different animals, with different technical methods, etc., must have influenced it, and indeed its biological properties at the present time differ significantly from those known to Pasteur. Such observations exist abroad (Fermi, Kraus, Remlinger, etc.), and Pasteur stations in the USSR (Dubrovinsky) also have such data. The virus has become, compared to Pasteur's original data, more virulent for rabbits (shortening of the incubation period and time of death after infection) and less virulent for humans, less resistant to external influences, etc. These circumstances played a major role in anti-rabies vaccinations and their application methods. Despite the indicated deviations, virus fixe still basically retains its constant features, by which it can be distinguished from the street virus. According to a number of authors (Gerlach, Kraus, Schweinburg), these differences come down to the following (Table 1): Speed of multiplication in the central nervous system Pasteur (see) built the method of anti-rabies vaccinations on the same principle on which he proposed preventive vaccinations also for other infectious diseases (chicken cholera, anthrax, etc.). Since the causative agent of rabies is unknown in its pure form, one has to use brain tissue of an infected animal to make the vaccine, in which this virus is contained in large quantities. At the same time, it is necessary to take such an animal in which this virus develops with a certain strength, but differs in weak virulence for humans. Before Pasteur, there were only scattered data on this question, namely, that rabbits are susceptible to rabies and suitable for experimentation, that the virus is contained in greater quantity in the brain, that in the saliva of an animal sick with rabies, rabies poison is contained, and that it is possible to cause insusceptibility of animals to this disease by introducing infected saliva. Through the work of Pasteur and his students (Roux, Chamberland, Thuillier), it was established that 1) the rabies virus is localized in the central nervous system; through prolonged passages through the rabbit organism, the virus acquires maximum toxicity for this animal, i.e., becomes a fixed poison; 2) when using the subdural method of rabies infection, it ensures the possibility of proper experimentation and study of the properties of virus fixe, and thereby creates possibilities for using this substance for preventive treatment purposes; 3) when drying the spinal cord above caustic potash infected with virus fixe, it systematically weakens and only after 13-15 days when kept at a temperature of 20-24° it completely loses its virulence; 4) if when vaccinating with brains from rabbits sick with rabies, one starts vaccination with non-virulent vaccine and systematically strengthens them until the use of completely fresh brains, one can confer insusceptibility to rabies on both animals and humans; such vaccination is safe; 5) due to the length of the incubation period in rabies (usually not less than 20-30 days in humans), preventive treatment is possible, calculated for the duration of the incubation period. - The method proposed by Pasteur basically comes down to the following: the spinal cord, extracted from a rabbit that died or was killed during agony, infected with virus fixe, is dried in a jar above caustic potash at a temperature of 20-24°. Pasteur's original scheme provided for treatment in which injection began with brains dried for 14 days; gradually reducing the drying time, Pasteur reached a vaccine dried for 3 days. Pasteur believed that drying leads to the weakening of virus fixe, but that in the brain tissue another substance (matiere vaccinale) is preserved, which is capable of causing immunity upon vaccination. Depending on the severity of bites, Pasteur proposed a series of treatment schemes. In mild cases (traitement simple), treatment continued for 15 days; in cases of moderate severity - for 18 days; in severe cases (traitement intense) - for 21 days. According to the last scheme, brains dried for 2 days were introduced. In all cases, 2-3 cm³, and sometimes 1 cm³ of emulsion (in 3 cm³ of emulsion there were 2 linear millimeters of spinal cord) was introduced. Over time, it had to be established that in a certain number of cases, vaccinations did not give the desired effect. Under the influence of these failures, even Pasteur himself began to systematically switch to a more intensive method of vaccinations, using a more virulent vaccine by shortening the drying time of the brains. Pasteur believed that a rapid transition to little-dried, i.e., still virulent, brains is dangerous for humans (Rage attenuee), but in severe cases he went for this out of fear that with such bites a short incubation period might be possible and therefore it is necessary to more quickly confer immunity to rabies on the organism. The intensification of Pasteur's method continued at the Paris Pasteur Institute even after Pasteur's death; starting from 1912, the following scheme has been used here (3 cm³ of emulsion per vaccination) (Table 2). Pasteur stations in other countries went further in their modifications of Pasteur's method in the direction of its intensification. Thus, in the Pasteur Department of the Koch Institute for Infectious Diseases in Berlin, 2 cm³ of spinal cord emulsion was introduced daily for 21 days. The emulsion was prepared at the rate of 2 cm of spinal cord per 10 cm³ of physiological solution. In severe cases, the dosage was increased.

Treatment was extended to 4-6 weeks, and after a month, additional treatment was performed. Due to the increasing number of paralysis cases among patients treated by this method, the Koch Institute was forced in 1916-17 to adopt a milder scheme, under which treatment began with brains dried for five days and in cases of ordinary severity did not go below brains dried for three days. Russian Pasteur stations, where the original Pasteur method had been applied since 1886, also gradually intensified their initial schemes over time. The Moscow station, followed by a significant number of other stations, starting from 1923, excluded brains dried for four days. Until 1929, the Moscow station adhered to the following scheme (Table 3). (The emulsion was prepared from 1 mg of brain per 1 g of physiological solution without the addition of any preservative substances.) In very severe cases in Moscow, two-day brains were sometimes replaced by one-day brains, but this was done with great caution due to the fear of complications from vaccinations in the form of paralysis. In these cases, additional treatment was also applied after two weeks from the end of the first course of treatment (the first 15 vaccinations according to the main scheme). In Leningrad, from 1920, treatment was applied with brains dried for three and two days. In Odessa until recent years, brains dried for four and one day were used. In Samara, as early as 1914, treatment began with brains dried for five days and was carried up to one-day brains; a scheme was introduced under which treatment began with brains dried for three days and was carried to fresh brains. Here, therefore, they moved faster than in other places along the line of intensification. The objective necessity to intensify P. p. and the accumulation of facts about the harmlessness of fresh virus fixe for humans when administered subcutaneously naturally led to the fact that stations gradually transitioned from the Pasteur method to other methods. Some of them are based on the principle of applying fresh virus fixe; others use phenol, ether, etc. for weakening the virus, which makes it easier to determine the dosage. These methods are also more economical and allow for more sterile work. Dilution methods. Hogyes' method. Hogyes began to apply his original method in Budapest in 1887. He justifies his method with the position that the degree of weakening of the brain when dried over caustic potash depends on the remaining amount of live virus, that immunizing substances are not separable from virus fixe, and that one can without danger to the animal and human organism begin vaccination by introducing fresh virus in small doses. Based on the fact that by diluting the brain one can obtain such amounts of virus that correspond in content to rabies-causing agents dried over KOH for specific periods, Hogyes developed his dilution method for the preventive treatment of humans. He began with vaccinations in a dilution of 1:10,000; systematically increasing the dose, he brought it up to 1:100. At each vaccination, 1 to 3 cm³ of emulsion was administered. Depending on the severity of bites, the amount of virus administered was correspondingly changed. In mild cases, the treatment course lasted 14 days with two vaccinations daily—in the morning and evening, while in severe cases the number of vaccinations was daily increased to 3-4, and treatment continued for 20 days. For the same reasons as the Pasteur method, the Hogyes method was subsequently correspondingly strengthened. At present, in the Budapest Institute, vaccinations are applied according to the scheme proposed by Szekely. He begins treatment with a dilution of 1:2,000, quickly increases the dosage and brings the dilution to 1:100. He introduced 1-2-3-day pauses, so that his treatment, which actually lasted only 13 days, ends only after 21 days from the start of vaccinations. In addition, he provides for an additional treatment course. Building their schemes on the Pasteur principle, Hogyes and his followers provide depending on the severity of cases 3 schemes, and in each of them the dosage is correspondingly increased both in the main and in the additional treatment course. The amount of brain tissue administered according to Hogyes' original method amounted to 50.6 to 93.4 mg, and according to Szekely correspondingly 127-195 mg plus for the additional course 50 to 100 mg. The Hogyes method is applied besides Budapest and in a number of other stations where it was found necessary either to replace the Pasteur method with it or to apply it in severe cases as an additional course to the Pasteur method. Such stations include stations in Madrid, Belferden (on Java), in Vienna and other places. Among Soviet stations, this method, considerably modified, was first applied in 1920 in Astrakhan, in 1921 in Tomsk and received relatively rapid spread in those places (Siberia, Caucasus) where one has to deal with severe wolf bites, which most frequently give failures in vaccinations and consequently require more intensive methods. Philipps' method is one of the modifications of the Hogyes method. According to this method, the brain is ground in anhydrous glycerin in the ratio of 15 mg of brain to 0.1 cm³ of glycerin. This emulsion, when kept at a temperature of 2-9° in dark vessels in an oxygen-free space, retains its virulence for several months. For injection, 0.1 cm³ of this emulsion (therefore 15 mg of brain) is taken and 2 cm³¹/₂% carbolic acid is added to it. Depending on the severity of bites, from 11 to 19 vaccinations are applied. To vaccinations with fresh brains, Philipps proceeds only after 3 vaccinations from material previously killed by heating in a 0.5% solution of carbolic acid at 37° for 24 hours. At each such vaccination, 60 mg of brain is administered. This method was first applied by Philipps in Colombia (America) with good results both in experiment and on humans. The main difference of Philipps' method from Hogyes' method lies in that the vaccine can be preserved for a long time, and therefore there is no need to prepare it ex tempore, as is required in the Hogyes method; in addition, vaccinations are not started with live but with killed virus; this makes Philipps' method especially convenient. In 1923, when rabies epizootics intensified in Germany and the demand for vaccinations significantly increased, the Pasteur station at the Koch Institute in Berlin (Baecker) began to use a vaccine prepared according to the Philipps principle, but the dosage was built according to the Hogyes method. Here a basic glycerin emulsion is prepared from brain and spinal cord in a dilution of 1:10. This basic emulsion is preserved in reserve and when used is diluted 1:25. Vaccinations are carried out according to the following scheme (Table 4): Table 4. Day of treatment Amount of vaccine in cm³ Day of treatment Amount of vaccine in cm³ 1 2 a 4 5 0.25 0.5 0.75 0.75 1.25 1.25 2.0 0.75 0.75 0.75 11 12 13 14 15 16 17 18 19 20 1.25 1.25 1.25 2.0 0.75 0.75 1.25 1.25 1.25 2.5 1 A total of 90 mg of fresh brain is administered according to this scheme. Treatment is carried out according to a similar scheme in Breslau. From the same 1923, Berlin began to use the indicated vaccine for dispatch to branches, which were then created in Germany in 10 places. The Philipps-Baecker method, like the original Philipps method, gives quite satisfactory results, it is economical, the dosage is simple with it, it is convenient both for vaccinations on site and for dispatch. The latter is the main reason why it received relatively rapid spread on stations in the USSR. In 1930, the largest station in the USSR—the Moscow station—also switched to the Philipps-Baecker method. Fermi's method. It uses a 5% emulsion of brain in a 1% solution of carbolic acid. Vaccinations are performed over 15-21-25 days with 5.0-6.0 cm³ for each vaccination. Correspondingly smaller doses are dispensed for children. The author considers that his vaccine, being avirulent, retains its antigenicity at the same time, which fully fits into the principle of Pasteur's original theory about matiere vaccinale. The works of Babes, Puntoni, Polovandov and Weinberg, Nikolaeva and others indicate that a 1% solution of carbolic acid in the first days does not completely kill the virus, but only weakens it or reduces its quantity, which is also observed with other physical-chemical effects, such as heating, drying over KOH, etc. Fermi's method, like Hogyes' method, is applied in different places in Europe, America and Africa with good results. A number of authors have made significant changes to it. In the USSR, this method was first applied by Nikolaeva in Ufa in 1921, and then in Omsk. At present, it is receiving wide distribution on Pasteur stations in the USSR.

It is most widely used for distribution to Pasteur points due to the possibility of preserving the emulsion in a sterile state and the ease of dosing. The disadvantage of this method is that it requires large quantities of brain tissue and that when used, the first vaccinations often begin with a virus that is less attenuated in carbolic acid, i.e., more virulent than in subsequent vaccinations. In this regard, Puntoni made a very significant correction. He begins treatment with brains attenuated in a 1% solution of carbolic acid for 10 days, and gradually transitions to less attenuated ones, bringing the treatment to brains exposed to carbolic acid for one day. In Puntoni's method, 'the principles of Pasteur are restored, i.e., he begins with a weaker and ends with a stronger vaccine.' The methods listed, as already noted, are systematically displacing the classic Pasteur method at stations in the USSR, as can be seen from Table 5. There are attempts at various stations, especially where severe bites occur, to introduce accelerated treatment methods. Among these is the Remlinger method (Paris, Constantinople), which aims to complete vaccinations in a five-day period, administering 4-6 vaccinations per day according to the following schedule (Table 6):

Pasteur method....... » Form........ » Gédés or Filips » Pasteur-Fermi . . . » Filips-Fermi . . . ~~ 1930. Fatal cases among those treated 1927 ! 1928 1929 1 ! 1930 0,20 0,11 0,05 0,09 0,16 0,07 0,12 0,12 0,12 0,10 0,11 0,06 0,33 0,60 0,10 0,12 - 0,10 0,20 vaccinated, but they still indicate that vaccinations against rabies, in which the living poison from the brain tissue of a sick animal is introduced into the human body, should not be considered indifferent to humans, and in cases where vaccination is absolutely unnecessary, it should not be prescribed. At most stations in the USSR, the Panisset and Verge scheme has been adopted, which establishes indications for vaccination (see Rabies). Mortality from rabies among vaccinated and unvaccinated. Since the main task of Pasteur stations is to prevent disease among those bitten by rabid animals through vaccinations, the effectiveness of the vaccinations can be judged by the mortality from hydrophobia among the treated, on the one hand, and the untreated-on the other. Combined treatment is usually used in severe cases, which explains the slightly increased mortality with it. The data from USSR stations in general speak in favor of the cultivation methods. They also speak in favor of the work of anti-rabies points, since the methods of Fermy and Gédés-Filips are predominantly used there. True, at points b.ch. people who received non-severe bites are treated, since those with severe bites are as a rule sent for treatment to Pasteur stations. Preventive vaccinations for animals. From Pasteur's first experiments (and even before him from the work of Gaitier), it is known that preventive vaccinations can prevent rabies in animals infected with this disease. For the purpose of preventive immunization of animals, Pasteur's methods and cultivation methods (Aujeszky) were used. Attempts were made to protect animals from laboratory rabies by introducing the vaccine into the abdominal cavity (Gelman, and then Marx, Pokhishevsky and others), intravenously (Galtier, and then Rou, Babes and others) and by introducing intravenously material heated to 37° and filtered (Krasnitsky, and then Remlinger and others); serovaccination was also used (Marie, Remlinger and others). All these experiments did not always give satisfactory results. Immunity is more stable when large amounts of active virus are introduced, but this in turn causes the immunized animal to contract laboratory rabies. This circumstance, as well as the fact that anti-rabies vaccinations are expensive, time-consuming and sometimes complicated, prevented them from being put into practice on animals. The recently so-called Japanese method (Umeno, Doi) (see Rabies) is free from a number of shortcomings that have hindered the use of anti-rabies vaccinations on animals until now: it uses killed material, thus avoiding the danger of direct infection, the treatment is short-term and provides good protection against further street rabies. This method has been tested in various places and gives very encouraging results. This is evidenced by the large amount of material from Japanese (Hata and others) and Americans (Eichhorn and Lyon), covering a total of about 200,000 dogs, as well as experimental data from a number of authors. In the literature, there are also objections to this method (Fermy). There is no doubt that to eliminate rabies, the only correct method at present, as before, remains the extermination of wolves, destruction of sick animals and veterinary-sanitary and police supervision of carriers of this virus—dogs (see Rabies).