Popular Science Monthly/Volume 28/January 1886/Inoculation Against Hydrophobia
|INOCULATION AGAINST HYDROPHOBIA.|
By M. LOUIS PASTEUR.
THE prevention of rabies, as I have described it, in my own name and the names of my collaborators, in previous notes, certainly constitutes a real progress in the study of that malady, a progress which was, however, more scientific than practical. Its application was precarious. Of twenty dogs that I had then treated, I could not assert that I had made more than fifteen or sixteen proof against rabies.
It was expedient, on the other hand, to finish the treatment by a final exceedingly virulent inoculation, with virus of control, in order to confirm and strengthen the refractory state. Finally, prudence made it necessary to keep the dogs under observation for a longer time than the period of incubation of the disease produced by the direct inoculation of the last virus; and it thus required an interval not less, perhaps, than three or four months to be assured of a fully refractory condition. These necessities considerably limited the application of the method. The method, also, did not accommodate itself readily to contingencies, which were always immediate, growing out of the accidental and sudden character of the bites of rabid animals. It was therefore necessary to obtain, if possible, a more rapid method, and one more capable of giving a security which might be considered perfect over dogs. Besides, how, before reaching that stage of progress, could we venture to make an experiment on man?
After almost innumerable experiments I obtained a preventive method, practical and prompt, of which sufficiently numerous and assured successes have been gained upon dogs to give me confidence in its general applicability to all animals, and to man himself. This method is based essentially upon the following facts:
Inoculation of a rabbit, by trepanning, under the dura mater, with the poisonous marrow of a mad dog, always gives rabies to the animal after a mean period of incubation of about fifteen days. If the virus is passed from this first rabbit to a second, from this one to a third, and so on, by the same method of inoculation, there is shortly manifested a more and more marked tendency toward a shortening of the period of incubation in the rabbits successively inoculated. After from twenty to twenty-five passages from rabbit to rabbit, we arrive at a period of incubation of eight days, which is maintained during a new series of from twenty to twenty-five passages. Then we have a period of incubation of seven days, which occurs with striking regularity during a new series of passages rising to the ninetieth. At least that is the number I have now reached without having hardly yet observed a tendency to a slight further shortening of the period.
The experiments of this character, which I began in November, 1882, have already been continued for three years without the series having been interrupted, or without my having used any other virus than that from rabbits which successively died rabid. Nothing, therefore, is more easy than to have at one's disposition, during considerable intervals of time, a virus of perfect purity, always identical, or nearly so. This is the practical point of the method.
The marrows of these rabbits are infected with rabies of constant virulence in their whole extent. If we detach from them pieces a few centimetres long, taking the greatest possible precautions to insure their purity, and suspend them in dry air, the virulence of the rabies in them will slowly pass away, till it is quite extinguished. The duration of the process varies somewhat with the thickness of the marrow, but depends chiefly on the exterior temperature: the lower the temperature the longer the virulence lasts. These results constitute the scientific point of the method.
These facts being substantiated, we have the following method of making a dog, within a reasonably short time, proof against rabies.
In a series of flasks, the air of which is kept dry by pieces of potash in the bottom, we suspend each day a piece of freshly infected marrow from a rabbit that has died of rabies, developed after seven days of incubation. Every day, at the same time, we inoculate under the skin of a dog a Pravaz syringeful of sterilized broth, in which has been soaked a small piece of one of the marrows we are keeping in desiccation, beginning with one of those which we have prepared several days before our operation is performed, so as to be sure that it is not of full strength. On that subject we have informed ourselves by previous experiments. We operate in the same manner on the following days with more recent marrows, separated from one another by, say, two days of age, till we come at last to a very recent one, which has been in the flask for only one or two days. The dog is then found to be made proof against rabies. We can inoculate him under the skin, or even, by trepanning, under the surface of the brain, without the disease showing itself.
By the application of this method I had succeeded in getting fifty dogs, of various ages and races, proof against rabies without having had a single failure, when, on the 6th of July last, three persons from Alsace unexpectedly presented themselves at my laboratory: Theodore Vone, a grocer of Meissengott, near Schelstadt, who had been bitten in the arm on the 4th of July by his own dog, become mad; Joseph Meister, nine years of age, who had been bitten by the same dog at eight o'clock in the morning of the same day, and who, thrown to the ground by the dog, bore the marks of numerous bites on his hand, legs, and thighs, some of them so deep as to make walking hard for him. The more serious wounds had been cauterized only twelve hours after the accident, or at eight o'clock in the evening of the same day, with phenic acid, by Dr. Weber, of Villé; the third person, who had not been bitten, was the mother of Joseph Meister.
At the autopsy of the dog, which had been killed by its master, we found its stomach filled with hay, straw, and pieces of wood. It was certainly mad. Joseph Meister had been picked up from under it covered with froth and blood. M, Vone had marked bruises on his arms, but he assured me that the dog's teeth had not gone through his shirt. As he had nothing to fear, I told him he might go back to Alsace the same day, and he did so; but I kept little Meister and his mother.
The weekly meeting of the Academy of Sciences took place on the 6th of July. I saw our associate, Dr. Vulpian, there, and told him what had passed. lie and Dr. Grancher, professor in the École de, had the kindness to come and see little Joseph Meister at once, and ascertain his condition and the number of his wounds, of which there were no less than fourteen. The opinion of these two physicians was that, in consequence of the severity and number of the bites upon him, Joseph Meister was almost certain to have hydrophobia. I then informed them of the new results which I had obtained in the study of rabies since the address I had delivered at Copenhagen a year previously. The death of this child seeming inevitable, I decided, not without considerable and deep anxiety, as you may imagine, to try upon him the method with which I had had constant success on dogs.
It is true that my fifty dogs had not been bitten before I found them to have been made proof against rabies. But I felt that I might dismiss all anxiety on this point, because I had already obtained a similar condition on a large number of dogs after they had been bitten. Thus, on the 6th of July, at eight o'clock in the evening, sixty hours after he had been bitten on the 4th, in the presence of Drs. Vulpian and Grancher, we inoculated under a crease made in the skin of the hypochondrium of little Meister a half-syringe Pravaz of marrow of a rabbit that had died of rabies on the 21st of June, which had been kept since that time, or for fifteen days, in a flask of dry air.
New inoculations were made, always in the hypochrondres, under conditions of which a table is here given:
A HALF-SYRINGE PRAVAZ.
|July||7,||9 a. m.,||marrow of June||23,||14||days old.|
|"||7,||6 p. m.,||""||25,||12||"|
|"||8,||9 a. m.,||""||27,||11||"|
|"||8,||6 p. m.,||""||29,||9||"|
|"||9,||11 a. m.,||"July||1,||8||"|
|"||10,||11 a. m.,||""||3,||7||"|
|"||11,||11 a. m.,||""||5,||6||"|
|"||12,||11 a. m.,||""||7,||5||"|
|"||13,||11 a. m.,||""||9,||4||"|
|"||14,||11 a. m.,||""||11,||3||"|
|"||15,||11 a. m.,||""||13,||2||"|
|"||16,||11 a. m.,||""||15,||1||day old.|
I thus made the number of inoculations thirteen, and the number of days of treatment ten, I would say, furthermore, that a smaller number of inoculations would have been sufficient. But it is easily conceivable that in this first trial I should have acted with particular caution.
We also inoculated, by trepanning, two new rabbits with each of the several marrows employed, in order to test their states of virulence. The observations on these rabbits permit me to assert that the marrows used on the 6th, 7th, 8th, 9th, and 10th of July were not virulent, for they did not make the rabbits mad. Those of the 11th, 12th, 14th, 15th, and 16th of July were all virulent, in proportion as the marrow was fresher. Rabies declared itself after seven days of incubation in the rabbits of the 15th and 16th of July; after eight days in those of the 12th and 14th; and after fifteen days in those of the 11th of July.
I had thus in the last days inoculated Joseph Meister with the most virulent virus, that of the dog strengthened by several passages from rabbits to rabbits; it was a virus that gave rabies after seven days of incubation to these animals, after eight or ten days to dogs. I was justified in venturing on this experiment by what had taken place with the fifty dogs of which I have spoken. When the state of immunity is reached, we can, without inconvenience, inoculate with the most virulent virus, and in any quantity; and it has seemed to me that this had no other effect than further to confirm the condition of refractoriness against rabies. Joseph Meister, then, has escaped, not only the rabies which his bites would have developed, but also that with which I inoculated him in order to confirm the immunity secured by the treatment—a more virulent rabies than that of the mad dog. The final extremely virulent inoculation had also the advantage of putting a term to the duration of the apprehensions we might entertain as to the consequences of the bites. If rabies was to break out, it would declare itself more speedily with a more virulent virus than that of the bites. From the middle of August I regarded the future of the health of Joseph Meister with confidence; and now, after three months and three weeks have passed since the accident, his health leaves nothing to be desired.
What interpretation shall we give to the new method which I have just described for preventing rabies after being bitten? I do not intend to consider this question in full to-day; but will limit myself to a few preliminary details, such as may help to comprehend the significance of the experiments which I prosecuted for the purpose of directing attention to the best of the possible interpretations.
Recurring to the methods of progressive attenuation of mortal viruses, and the prophylaxy that may be deduced from it, and the influence of the air in the attenuation being given on the other side, the first thought that occurs in trying to account for the effects is that the continued presence of rabies-infected marrows in contact with dry air progressively diminishes the intensity of their virulence till it is rendered nil. We are, therefore, led to believe that the prophylactic method under consideration rests upon the employment at first of virus without appreciable activity; then of weak viruses, and then of those of greater and greater virulence. I shall show, further on, that the facts are in disaccord with this view. I shall prove that the increase in the length of the periods of incubation of the rabies, communicated day after day to rabbits, as I have just said, to test the condition of virulence of our marrows, dried in contact with the air, is an effect of impoverishment in the quantity of the virus contained in the marrows, and not an effect of its impoverishment in virulence.
We may suppose that inoculation with a virus of virulence constantly identical in itself may lead to a condition proof against rabies by the process of employing very small but daily increasing quantities. This interpretation of the facts of the new method I have studied experimentally. . . .
I need not remark, in conclusion, that the most serious of the questions to be resolved now is perhaps that of the interval that should be observed between the time when the patient is bitten and that at which the treatment should be begun. In the case of Joseph Meister, the interval was two days and a half. But there is reason to suppose that it may sometimes be much longer. On Tuesday last, the 20th of October, with the obliging assistance of Drs. Vulpian and Grancher, I began to treat a young man fifteen years old, who had been bitten six days before, in both hands, and whose condition was exceptionally grave.
The Academy will perhaps not be uninterested to bear the story of this young man's courage and presence of mind. He is a shepherd, named Jean-Baptiste Jupille, of Villers Farlay in the Jura, who, seeing a large dog of suspicious appearance rush at a group of six of his comrades, all younger than himself, sprang, whip in hand, in front of the animal. The dog seized Jupille by the left hand. Jupille then knocked the dog down, held it under himself, opened its jaw with his right hand to relieve his left, not without receiving several new bites, and then, with the thong of his whip tied up its muzzle, and, taking off one of his wooden shoes, dispatched the dog with it.
I shall promptly make known to the Academy the outcome of this new experiment.
[After the reading of M. Pasteur's paper, M. Vulpian remarked that the Academy should not be surprised to see one of the members of the Section of Medicine and Surgery take the floor to express the feelings of admiration which the communication had inspired in him. These feelings, he continued, "will be shared, I am convinced, by the whole medical profession. A remedy has at last been found for rabies, that terrible malady, against which all therapeutic measures had miscarried till now. M. Pasteur, who has had no precursor in this road, has been led, by a series of researches pursued uninterruptedly for years, to create a method of treatment that enables him surely to prevent the development of hydrophobia in a man who has been bitten by a mad dog: I say surely, because, after what I have seen in M. Pasteur's laboratory, I do not doubt the constant success of this treatment whenever it is put in practice in its completeness within a few days after the rabid bite has been inflicted. It becomes henceforth necessary to take into consideration the organization of a service for the treatment of hydrophobia by M. Pasteur's method. Every person bitten by a mad dog must be made able to enjoy the benefit of this great discovery, which affixes the seal to the glory of our illustrious associate, and which will shed an incomparable luster upon our dear country." On motion of Baron Larrey, a prize was proposed for young Jupille, in recognition of his bravery and devotion.
The President of the Academy, M. Bouley, expressed his full sympathy with the feelings which the Academy had just manifested by its applause. The date of the 20th of October, 1885, he said, would be marked as a great day among the festivals of French biology and medicine, and among the festivals of the medicine of the whole world. He would ask M. Pasteur whether, if, during the course of the preventive inoculations, an inoculated dog should bite a person or other animals in play, it would communicate rabies to them. M. Pasteur replied that no experiments bearing on that point had yet been made.
On the 30th of October four other persons came from Arcachon to place themselves under M. Pasteur's care; so that, if success is gained in these cases also, six demonstrations will have been obtained from human subjects of the efficacy of the inoculation treatment. In an interview with a correspondent of the London "Times," M. Pasteur explained the philosophy of his treatment by stating that the virus acted very slowly, and, while he was making the body refractory to it by repeated inoculations, the virus deposited by the bite localized itself in the region of the wound. Whatever this region, that virus becomes digested during the year and a half which he has found by experiment the inoculation lasts, and will no longer exist in the body. As the propagation of the virus, which has always an ascending tendency and directs itself to the brain, takes place so slowly that the minimum of the total inoculation with it is thirty days, the whole question consists in inoculating the patient soon enough to prevent the propagation of the virus through the wound from spreading. In the case of Jupille, after the lapse of six days, the virus through the wounds had not yet left the hands. Consequently, it had not yet penetrated into any of the regions where its presence causes an outbreak of rabies. It will remain cooped up, till after some months it will have been digested and expelled.
There would be no need to dwell on the value of M. Pasteur's discovery, the "Times" suggestively remarks, "were it not for the strange perversity of those who will only see in the whole story a fresh ground for attacking physiological experiment. Such people, as we know from long experience, will lose all sight of the thousands and tens of thousands of animals whom M. Pasteur liberates from the curse, and of the multitudes of human beings freed from torture and death, when they think of the twenty or fifty rabbits in his laboratory. They forget, in the contemplation of a few cases of immediate suffering, the innumerable animals, friends of man, whom the discovery will set free. "With these excellent people it is impossible to argue; but men whose sympathies are wider and whose sight is truer than theirs will unite in paying homage to the man who, if what he tells us is confirmed, has worked so patiently and so wisely to so noble and beneficent an end."—Editor of "The Popular Science Monthly."]
- A paper read in the French Academy of Sciences, October 26, 1885.
- If the infected marrow is protected from the air, and is kept moist in carbonic acid, the virulence will last, for several months at least, without change in intensity, provided it be guarded against the attack of microbes from without.