XI. Vaccinations against tetanus. Tetanus unlike plague is not a contagious disease, nor is it capable of becoming epidemic. It constitutes, however, a very formidable disease against which all therapeutic methods have only a very limited effect. This is a further reason for drawing the whole attention of medical and veterinary men to the prevention of tetanus by vaccinal injections. Tetanus is a disease in which the intoxication plays an altogether dominant part. The tetanus bacilli do not develop, at the point where they are introduced into the body, unless favoured by auxiliary conditions, such as the multiplication of other micro-organisms. Even then the organism of tetanus reproduces itself with difficulty, and without becoming generalised throughout the body. The poison which it secretes is however sufficient to produce a very grave intoxication, ending most frequently in death. In certain countries tetanus, as a sequel to various wounds, is very frequently met with in man and in certain domestic animals, such as the horse, donkey, pig, etc.

It is only since the discovery by von Behring and Kitasato of an effective method of immunisation against tetanus that it has been possible to consider the practical application of antitetanus vaccinations. These observers demonstrated that the tetanus poison, when treated with trichloride of iodine, had its toxic action weakened and was transformed into an effective vaccine. Roux and Vaillard found that the addition of Lugol’s iodo-iodurated solution to the tetanus poison renders it capable of vaccinating all kinds of susceptible animals. It was shown later, that even with modified active tetanus toxin, we can still obtain good results when care is taken to inject the poison with great circumspection.

But it is not these vaccines obtained from tetanus cultures that have come to be used in practice. The best results are obtained by the use of antitetanus serums. After von Behring and Kitasato’s discovery of the power of the serum of animals immunised against tetanus to neutralise the action of the tetanus poison, very numerous experiments were made on the same subject. It has now become possible by treating horses with large quantities of tetanus toxin to obtain specific serums of extraordinary activity. Thus several serums are capable of preserving mice against a lethal dose of tetanus poison if we inject into them a quantity of serum equal to the one-thousand-millionth of their weight.

Serums of this strength protect domestic animals against tetanus. We know that many operations on horses, sheep, goats, pigs, and other mammals are very often followed by a tetanus which is usually fatal. Castration, amputation of the tail, the ablation of proud flesh or tumours, the operation for cryptorchitis or hernias, etc. are often complicated by tetanus. Moreover, tetanus may frequently appear in horses that have received wounds in the foot or in the lower parts of the limbs, “Clous de rue,” farrier’s punctures, wire-heels, blows, etc.

With the object of remedying this state of things Nocard^[819] distributed to veterinarians about 70 litres of antitetanus serum to be employed for protective purposes. The majority of the animals treated (horses, donkeys, mules, bulls, rams, lambs, and pigs) received two injections of serum at an interval of 10–12 days, 20 c.c. for large animals and 6–10 c.c. for sheep and pigs. Of 3088 animals which received the first injection of serum immediately after the operation not a single one contracted tetanus. Of 400 animals which received the first injection at a later period, 1–4 days and more after the accidental wound of which they had been the victims, one horse only, treated five days after the accident (farrier’s puncture), was seized with mild tetanus, but it soon recovered. In the same localities where the results of the vaccination were so brilliant, 314 cases of grave and fatal tetanus occurred amongst animals operated upon or injured that were not submitted to the serum treatment.

It may be readily understood with these facts before us why the practice of protective vaccinations of animals against tetanus should have spread so rapidly amongst veterinarians. The demand for antitetanus serum from the Pasteur Institute of Paris for veterinary use increases every year at a great ratio. Thus in 1896 there were sent out only 1511 bottles of 10 c.c. each, in 1898 the number rose to 24,959 bottles, in 1900 it exceeded 43,000.

The efficacy of the antitetanus serum employed as a protective agent can no longer be questioned, but it must not be forgotten that its injection does not render the treatment of the wounds unnecessary. These wounds should receive a rigorous antiseptic cleansing. All foreign bodies should be carefully extracted; otherwise the prolonged presence of tetanus spores might set up a late tetanus after the disappearance of the transient immunity due to the serum.

The protective injections of antitetanus serum into men likely to contract tetanus are also beginning to spread. It often happens that bicyclists, in falling, receive injuries which are contaminated by horse-dung or other matters which may contain the spores of tetanus. In these cases, as in many other forms of injury, vaccination with antitetanus serum is indicated. Thus it happens from time to time at the Pasteur Institute that injured persons come and ask for a protective injection of serum. Several medical men and surgeons are now accustomed to vaccinate such of their patients as have had their wounds contaminated by earth or dung. All the cases of this treatment which have come to our knowledge have been followed by very good results.

XII. Vaccinations against diphtheria. Antidiphtheria vaccinations have been the subject of much discussion since the discovery of the antidiphtheria serum and its introduction into routine practice. A large number of works were published for and against the application of serum in protective treatment against diphtheria, especially in the early years of its use. Later the controversy has subsided somewhat, and at present very few writers are found who continue to decry antidiphtheria vaccinations.

The antidiphtheria serum was discovered in 1890 by von Behring working in collaboration with Kitasato; these observers demonstrated in laboratory animals its neutralising action upon the diphtheria toxin. A little later von Behring began to apply it in the treatment of diphtheria, but the early results were far from satisfactory, and von Behring soon recognised that it was necessary to obtain much more active serum. Along with Ehrlich of the Institute for Infective Diseases at Berlin he set to work to study this problem. In collaboration with several investigators, among whom I may cite Wernicke, Wassermann, and Kossel, he succeeded in obtaining very encouraging results as regards the antitoxic strength of the serums and their therapeutic action on children attacked by diphtheria.

At this time, also, Roux in Paris began, assisted by Martin and Chaillou, to study the same question. These observers prepared serums which for that period were very active and made a very effective application of them upon more than 300 diphtheria patients.

From the year 1894 the use of serum began to spread in all countries, and it was then that an attempt was made to apply it to the protection of children in good health, but who had been specially exposed to contagion.

It was necessary to have at command large supplies of antidiphtheria serum; this was prepared by injecting into horses repeated doses of the toxin manufactured by the diphtheria bacillus. The serums thus obtained were first tested as to their protective, antitoxic, and curative action on guinea-pigs, animals very susceptible to diphtheria. The necessity of finding some means of measuring the strength of the serum soon arose. Von Behring and Wernicke at first standardised it on the basis of the number of grammes of guinea-pig which could be protected by one gramme of serum. Later, von Behring^[820] introduced the principle of the “normal serum,” that is to say, a serum of which 0·1 c.c., mixed with 10 lethal doses of diphtheria toxin, is capable of preventing every morbid symptom in a guinea-pig weighing 300 to 400 grammes.

Ehrlich^[821] perfected this method in the following way: to tubes, each containing 10 lethal doses of a standard toxin, are added different amounts of serum. These mixtures are brought to the same volume of 4 c.c. by the addition of physiological saline solution, and each is immediately injected below the skin of a guinea-pig. If 0·1 c.c. of a serum completely neutralises the 10 lethal doses of toxin, the serum retains its name of normal serum; in the case where 0·05 c.c. is sufficient to bring about the same result the serum is designated double normal serum. When 0·001 c.c. gives the same results, a hundred times normal serum, and so on. A cubic centimetre of normal serum (that is to say a dose capable of neutralising 100 lethal doses of standard toxin) constitutes an “immunising unit” (Immunisirungseinheit (I.E.) of Ehrlich). As it was soon recognised that toxins, even when kept under the best conditions, lose more or less of their toxic power, Ehrlich had to modify his method of standardising serum. He now makes use of a standard antidiphtheria serum, kept in a dry condition, which is much more constant than are the toxins. Solutions of this standard serum are prepared and compared with the serum whose strength has to be determined. Ehrlich has given a detailed description of the method of procedure required to obtain exact results.

At the Pasteur Institute Ehrlich’s method has been adopted, supplemented however by another test for the estimation of the strength of antidiphtheria serums, a method allied to von Behring’s old method. Various doses of the serum to be examined are injected subcutaneously into guinea-pigs, and 24 hours later these guinea-pigs receive a quantity of a living culture of diphtheria bacilli which kills control animals in 30 hours. The protective power of the serum in relation to the weight of the animal is thus determined. For example, a serum which is said to be active at 1/100,000 has the power, in a quantity equal to 1/100,000th of the weight of the inoculated guinea-pig, of preventing a fatal result. It was thought, at first, that the protective power, measured in this way, would be proportional to the antitoxic property determined according to Ehrlich’s method. But as the results given by these two methods were often widely different, it was resolved at the Pasteur Institute to examine by both methods all the serums intended for use in practice. This led to the conclusion formulated by Roux^[822], in his report communicated to the International Congress of Hygiene, held at Paris in 1900, that a serum possessing a very high protective power (against the living diphtheria bacillus) might be only feebly antitoxic, and vice versâ.

This result is explained by the fact that the antidiphtheria serums are very complex fluids, containing several superposed properties of very variable strength. Marx^[823], of the Frankfort-on-Main Institute, tried to shake Roux’s conclusions, bringing forward his experiments made on guinea-pigs and rabbits injected with antidiphtheria serum into the peritoneal cavity and into the veins. He wished in this way to avoid the introduction of the serum into the subcutaneous tissues, whence the absorption of the antitoxin must take place in a very irregular fashion. In Marx’s experiments, thus carried out, the protective power of the serums was always found to run parallel with their antitoxic power, from which he concluded that Roux’s view was incorrect. It must not be forgotten, however, that this view was founded on experiments in which the antitoxin had been injected into the subcutaneous tissue before or simultaneously with the toxin or the diphtheria bacillus. Under these conditions the protective power is often found to be altogether disproportionate to the antitoxic power. This fact has been observed so carefully and with such exactness that it is impossible to deny it. Now it is undoubted that the conditions of the experiments upon which Roux relies correspond much more closely with those that are realised in vaccination of man against diphtheria than with the conditions met with in Marx’s experiments. In these vaccinations antidiphtheria serum is injected below the skin of persons whom it is wished to protect against the action of the diphtheria bacillus.

With the object of bringing about a unification of the methods of estimating serums used in different countries the International Congress of Hygiene, held at Madrid in 1898, appointed a special Commission to settle this problem. But when the Congress met again at Paris in 1900 this Commission had not completed the task allotted to it. The representatives of the various methods had exchanged ideas, but in applying the same method the results obtained in various places and by various observers presented differences too great to allow of any understanding being arrived at. It is evident that we have here a very complicated problem. The serums are tested on living animals in which of course nothing like the constancy of a chemical reaction can be obtained.

Possibly the methods of breeding and the races of the same animals in the different countries may be quite sufficient to explain the divergencies in the results obtained. Whatever may be the reason the unification of serum estimation has not yet been obtained, and it is difficult to anticipate that any better result is to be arrived at.

From all this we may draw the conclusion that the possibility of attaining a too rigorous precision in the standardisation of serum has been exaggerated. Our object must be to obtain results as favourable as possible in the application of the antidiphtheria serums, and for that purpose it is necessary to inject greater quantities than those which may be indicated by any method of estimation. This rule is applied as far as is possible at the Pasteur Institute.

As regards vaccination against diphtheria of persons who are in good health but are especially exposed to infection, the question must be accepted as settled in the affirmative.

From the commencement of our attempt to cure diphtheria by means of a specific serum, the necessity was seen of protecting children who were in contact with the sick persons against this disease. Small quantities of serum were injected into such children for protective purposes. The first results communicated in 1894 by Roux to the Congress at Budapest being very encouraging, an attempt was made to give the greatest possible extension to the system of vaccination by antidiphtheria serum. In the following year, 1895, fairly numerous statistics had been collected, and Torday^[824] at Budapest, Kurth^[825] at Bremen, and Rubens^[826] at Gelsenkirchen were able to publish a number of favourable statistics. Soon afterwards, however, a fatal case occurred in the family of a well-known Berlin doctor, Langerhans^[827], an accident that started a violent controversy and stirred up an active campaign against serum. Langerhans’s son, a boy aged 2 years, in good health, was inoculated with a small dose (1·2 c.c. of this serum) and succumbed about a quarter of an hour afterwards with symptoms of suffocation. The post-mortem examination made by Strassman^[828] showed the cause of death to be suffocation in consequence of the aspiration of food into the respiratory passages during the act of vomiting. An examination of the serum used by Langerhans did not reveal any toxic action on animals or any contamination by micro-organisms. All to no purpose, the serum was held answerable for the death of the child, and an attempt was made to demonstrate at almost any cost that its use in human practice was extremely dangerous. Gottstein^[829] joined in chorus with the over-excited opinion and published a denunciation of vaccinations by antidiphtheria serum. He collected from the literature of both hemispheres four cases, in all, in which death had occurred some time after the injection of this serum into children not suffering from diphtheria. A perusal of the description of these cases is sufficient to convince one that the death could in no sense be attributed to the serum, and that it could be explained much more easily by the fatal action of the streptococcus, the cause of the non-diphtheritic affections of the children that died.

The ineptitude of this denunciation must have done much to calm public opinion, and in September of the same year, 1896, C. Fränkel^[830], in a report presented to the German Association of Public Hygiene, was able to give a review of the state of the question of vaccination against diphtheria, summing up in favour of the use of the specific serum. “Taking into consideration the data collected,” he remarks, “it is scarcely possible to doubt the value of immunisation by serum, so that we may say positively that we are now treading a path which will lead us to great and important results.” This very favourable opinion was due in great measure to the vaccinations carried out in the wards of Heubner’s Clinic at Berlin^[831]. At first, injection of the antidiphtheria serum as a protective into patients who were found in the immediate vicinity of the children attacked with diphtheria (contacts) was deemed to be sufficient: but in consequence of the results obtained by this method it was decided (starting from January, 1896) to inject all children who came into the hospital. During the first period there still occurred a few cases of diphtheria contracted in hospital, but from the moment systematic and general vaccinations were introduced not a single new case occurred.

The immune condition of the vaccinated children is maintained for three to four weeks. After this lapse of time some of them contracted diphtheria. But it was sufficient to introduce revaccination at the end of this period to prevent the outbreak of any further case of diphtheria in Heubner’s wards. Results quite as favourable and as convincing were obtained in the department for children attacked by scarlet fever.

The amount of serum injected varied, but it was usually given in doses of 1 c.c. containing from 200 to 250 I.E. (immunising units of Ehrlich). The serum was always found to be innocuous except in certain cases where it set up erythemata of greater or less extension. In 460 injections 20 cases of these exanthemata were produced, that is to say 4·34%. The frequency of these complications was not proportional to the amount of serum injected. According to the figures communicated by Löhr the largest doses of the serum employed did not produce exanthemata more frequently than did the smaller quantities. Thus 117 injections of 1 c.c. only were followed in five cases by these erythemata, which corresponds to 4·27 per cent. The hope of diminishing the frequency of the exanthemata by diminishing the amount of serum injected was therefore not realised. This fact lends support to the conclusion above formulated as to the exaggeration of the importance of the measurement of serum. If it could be established that small quantities of serum rich in antitoxin caused cutaneous eruptions less frequently than did stronger doses there would certainly be a great advantage in using serums containing a very large number of immunising units for vaccination. Perhaps serums having a great antimicrobial power but of comparatively low antitoxic potency might even render great service in protective treatment. Future researches undertaken in this direction alone can give us information on this subject.

In 1896 the vaccinations in Heubner’s wards were discontinued, but the reappearance of diphtheria in 1897^[832] rendered their recommencement necessary. 500 children were vaccinated each with 200 immunising units. Following this no case of diphtheria broke out. The eruptions were rare and slight.

The increasing extension of the use of antidiphtheria serum for the cure of the disease after it has broken out has led to a greater development in its use as a preventive measure. Thus, in the countries where diphtheria is endemic, vaccinations by serum are now practised very extensively. In Russia, which is one of the great hotbeds of this disease, vaccinations by antidiphtheria serum are frequently practised.

At the Congress of Russian doctors at Kasan in 1896, Vissotsky communicated the result of 2,185 vaccinations which gave a morbidity of 1·3%, a morbidity that must be regarded as very low indeed. A well-known Russian physician for children’s diseases, Rauchfuss^[833], who cites these figures, has collected several other facts concerning the prophylactic injections of antidiphtheria serum followed by good results. In the government of Woronetz, according to the statements of Ouspensky^[834], out of 738 vaccinated persons diphtheria occurred in 2·2 per cent., which again may be considered a favourable result, especially if we take into account the great extension of diphtheria in this country. In Podolia, out of 537 children vaccinated in 1895, only four cases of diphtheria occurred, a morbidity of 0·74%. In the government of Kherson, one of the great centres of diphtheria in southern Russia, the results appear to be less favourable: out of 543 children which received a protective inoculation, 21 contracted the disease (or 4·6 per cent.), of which five died. If we study these statistics more closely^[835] it will be seen that these results are far from being unfavourable. The protective inoculations were made only once and with somewhat small doses, nevertheless many of the cases of diphtheria broke out only at a late period, sometimes more than nine months after the injections had been made. Now, it is proved that these injections, although very efficacious, produce their action for a very short time only, for a few weeks at most. Of the five fatal cases, four did not occur until 2, 4½, 6, and 9½ months respectively after the protective inoculation. It is impossible to look upon these statistics as affording proof of the inefficacy of the serum. The fifth case is the only one that occurred within a short time (15 days) of the injection, and in this instance only 150 immunising units had been injected.

A detailed study of the other examples of antidiphtheria inoculations in the government of Kherson leaves a very favourable impression. Out of 90 children inoculated by Wecker^[836] in the district of Elisabetgrad not a single one contracted diphtheria, which is the more remarkable as at the time of the inoculations there existed in the same families 14 cases of diphtheria; the chances of contamination were thus great.

Recently, on the occasion of the outbreak of a great epidemic in Paris, the question of vaccinations by serum was again raised and earnestly discussed at the Paris Hospitals Medical Society and at the Society for the Study of Children’s Diseases. Voisin and Guinon^[837] communicated the history of an epidemic amongst the staff at the Salpêtrière Hospital in the wards of idiot children, “against which protective serum treatment was remarkably effective and absolutely innocuous.” The serum was injected, in the case of children more than 10 years of age, in 10 c.c. doses, and into the rest in 6 c.c. doses. This measure brought about first an abatement and then cessation of the epidemic. The immunity after a single injection lasted from two to three weeks, and the few cases of diphtheria which broke out amongst the infected children were distinguished by their great mildness. Erythemata and other post-injection complications were insignificant, so that the protective use of the serum was fully justified. Only a small minority of the medical men who took part in the discussion spoke against the antidiphtheria vaccinations; once, indeed, a reference was made to the case of Langerhans’s child, although its death was certainly not due to the serum. It is true that in families where it is possible to keep the children under careful observation and to intervene at the appearance of the first symptoms of diphtheria, the preventive injections may be dispensed with, but in practice these favourable conditions are rarely realised, and the prophylactic serum treatment is then of great service in preventing the outbreak of the disease.

Netter^[838] communicated to the Society of Pediatrics a summary of 32,484 observations on the prophylactic injection of antidiphtheria serum. Of this number 192 cases were noted in which the diphtheria broke out in spite of the injections, corresponding to 0·6 per cent. of those treated. These figures, however, included all cases of the disease which occurred up to thirty days after the injection. Now, the immunity is often less durable than this, and it may disappear more or less completely twenty days and sometimes even fifteen days after vaccination.

Netter himself made great use of antidiphtheria vaccination. It was his custom to propose to the parents either a protective inoculation at once or a systematic precautionary bacteriological examination of the throats of the children not yet attacked. He regards the first method as preferable. According to the latest statistics which he was kind enough to communicate to me, of 152 children (in 50 families), 91 of whom received protective inoculations, not one contracted diphtheria: whilst in 239 other families where the children had not been inoculated there were 52 cases of diphtheria, with 10 deaths. Many practitioners in Paris have now pronounced themselves in favour of protective injections of the serum, and the Society of Pediatrics, at its meeting on 11th June, 1901, concluded the discussion of this question by proposing the following resolution: “The Society of Pediatrics, affirming that protective inoculations present no serious danger and confer a very considerable amount of immunity for some weeks, recommend their use when children are gathered together in numbers, and in families where a scientific supervision cannot be maintained.”

The large amount of evidence collected on this question leaves no doubt as to the real efficacy of vaccinations by antidiphtheria serum.

The summary of the results obtained by vaccination in the 12 diseases of man and of animals I have just placed before my readers cannot pretend to serve as a detailed guide to prophylactic practice. My object has been merely to concentrate into one chapter the principal data upon which this very important question rests, to bear witness to the progress which has already been realised, and at the same time to show that the scientific study of immunity is in very intimate relation with its practical application. It is evident that the road is far from traversed to its terminus, for there are many infective diseases in which vaccinations cannot be employed, but it is none the less certain that the path which has led to so many important and useful results should still be followed in studying problems which up to the present we have been unable to solve.