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The principles of preventive inoculation and their practical application
PREVENTIVE
THE PRINCIPLES INOCULATION AND APPLICATION.
INOCULATION.
OF PREVENTIVE THEIR PRACTICAL
BY
ALLAN ~ACI~'ADYEN, M.D., B.Sc.
IN the annals of medical science there is no name more worthy of being honoured and revered than that of Edward Jenner. The epoch-making discovery of the principle of vaccination which we owe to him has stood the test of time and experience. T h e hundredth anniversary of Jenner's vaccination experiments has now come, a n d the principles that he advocated and put into practice still remain the one efficient means of protection against the most dreaded of diseases. T h e lives that Jenner's work has been instrumental in saving are the most eloquent tribute to his memory, and the brilliant discoveries that have since been made in the field of protective inoculation render his name imperishable. Indeed, after one hundred years, medical science seems once more to be on the threshold of discoveries as great and as momentous. It will be:the object of this paper to trace succinctly the achievements that have been obtained through the application of the principles of vaccination by those who followed Jenner and worked in his spirit. It is an old observation that individuals after recovery from a given disease are generally protected for a time or permanently against a return of the same malady. In other words, they have acquired an immunity to that disease. T h e important observ~ation was also made that a mild attack of a disease likewise conferred protection. Thus, a mild attack of smallpox could equally protect an individual against a severe attack of that disease. T h e attempt was made to utilise this act of nature as a means of protection. I n its crudest form this consisted in exposing children to infection, for instance, with measles in a mild form in order to protect them against the severer forms of the disease. A vague appreciation of the principles of immunity ex,sted in such methods. At the beginning of the ~Sth century it was customary to inoculate healthy people with the virus of human small-pox as a means of protection. This method, though extensively used, was attended with danger. T h e disease so induced did not always run a mild course, and those vaccinated formed a source of infection to others. Jenner observed that people infected with cow-pox were protected against the virus of human small-pox, and that the inoculation of cow-pox in man was a trustworthy protection from the latter disease. Jenner, by inoculating the infectious material of cow-pox, lessened the susceptibility of the human organism to the contagion of smalt-pox. T h e vaccinated person, if attacked, acquired a mild form of the disease. T h e conclusion deduced from this was that vaccinia was a milder form of small-pox, due to the growth in the
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body of the attenuated virus o f small-pox. T h e important modification introduced by Jenner wa~ that he used the mild virus of cow-pox as a means of protection against the virulent virus of small-pox. T h e recovery from a mild attack of cow-pox rendered those inoculated proof against small-pox. One need hardly dwell upon the subsequent development and practical application of Jenner's discovery as regards small-pox. Many years elapsed before the attempt was made to apply the principles of vaccination to other diseases. T h e experiments were conducted on essentially similar lines, viz., to produce a mild attack of a disease by means of an attenuated virus, in order to render the organism proof against the virulent virus of the same disease. T h e fresh starting point was furnished by Pasteur's demonstration of the fact that not only fermentative but also disease processes were due to the action of bacteria. T h e demonstration of the parasitic nature o f infectious diseases culminated in the classical researches of Koch. T h e methods of cultivating pathogenic bacteria outside the body were brought by him to a high degree of perfection. I n this way a systematic study of the cause o f a disease became possible, and the means of combating its action could be determined by experiment. Further, the problems connected with immunity could be studied on a scientific, instead of an empirical, basis. Pasteur proved that it was possible to modify the virulence of a pathogenic organism b y artificial means so that it no lOnger produced fatal results, and that this attenuated virus protected against the fatal form of the disease. T h e experiments upon which these conclusions were based were made by Pasteur in 188% whilst studying the disease known as " F o w l Cholera." I n the same way he was able to attenuate the virulence o f anthrax bacilli by growing them at high temperatures. These results led to similar attempts in the case of other diseases, and fresh light was thrown on the subject of immunity and the methods by which it could artificially be brought about. These methods, however successful in the laboratory, have not always h~td the same success in practice, and in this respect cannot be compared with Jenner's method of vaccination. I n recent years other views have come to the front with regard to the nature of immunity and the means of rendering the animal organism proof against disease. I n a sense, a return has been made t o the Jennerian system of utilising the lower animals. for the preparation of the protective agents. I t has been proved that pathogenic bacteria by their growth in the body produce certain poisons to which are due the characteristic symptoms of the disease. These bacteria also oroduce the same poisons when cultivated on a suitable soil outside the body. The poisons or toxins so obtained, when freed from the bacteria that produced them, will, on inoculation into a susceptible animal, give
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rise to the same morbid symptoms. The assumption has been made that the cells of the body, as an act of self-defenee, secrete certain bodies that are capable of neutralising the action of the toxins (Alexmes, antitoxins). I f these protective bodies are present in sufficient amount they neutralise the toxins of the specific microbe, and recovery takes place; if present in excess, they are capable of neutralising new toxins that may be subsequently formed. In this way they can bring about a temporary or permanent immunity, If, therefore, the toxins of a given microbe be obtained from its cultures and inoculated into an animal in increasing doses, one may hope to favour the production of large quantities of protective bodies in its system. I f these protective bodies or antitoxins be obtained from the secretions or blood of the animal, they may be used to render other animal immune to the same disease. The antitoxins are present in largest quantity in the blood, and, consequently, the blood, or, better still, the blood serum of the artificially immunised animal, is utilised for the purpose of protective inoculation. This is the basis of the modern blood serum therapeutics, for which we are indebted to the investigations of Behring and his fellow-workers. With these prefatory remarks, we may now proceed to consider the principles of preventive inoculation and their practical application in a more detailed fashion. In the first instance, a few words must be devoted to the subject of immunity. The body is provided with certain external protections against the invasion of pathogenic bacteria. For example, the mouth and nasal cavity receive quite a number of bacteria, and yet infection occurs relatively seldom at these points. And in the digestive tract the invasion of microbes is to a certain extent combated, as, for instance, in the stomach, by means of the acidity of its contents. The internal agents at work are of still greater importance in protecting the organism. There is a natural immunity peculiar to individuals and species of animals whereby they are naturally resistent to forms of infection t o which others succumb. Certain diseases affect only man, whilst the lower animals have diseases peculiar to themselves. There is also an acquired immunity which takes place after recovery from a disease, e.g., small-pox. Immunity may be artificially produced by the in~oculation of attenuated vaccines, or by the injection of the blood serum of an immunised animal into another animal. In the latter instance, the immunity is artificially transferred. Many theories have been brought forward to explain the pl~enomena of natural and artificial immunity. The t'asteur-Klebs theory assumed that in the course of a given disease, the pabulum necessary for the specific organism is consumed, so that in the event of another attack, the bacte/'ia do not find the necessary nutriment. Chauveau supposed that the poisonous metabolic products of the
INOCULATION. bacteria formed in the system prevent their further development, bringing about a crisis in the disease. They also impregnated the system, and prevented a further invasion by the same organism. Another theory was based~ upon the results of small-pox vaccination. It was suggested that in the pustule the weakest celt elements succumbed ; the more vigorous, on the other hand, remained. After a first attack, only the more resistent cells survived, from which the new tissue elements were formed. This property was hereditary, and consequently subsequent generations of cells were equally endowed with a heightened power of resistance. These hypotheses are now mainly of historical interest. At present, the three following are the most favoured. The first is a cellular theory, and is associated with the name of Metschnikoff. The phagocytes or wandering cells of the body are capable of taking up and digesting foreign bodies. This phenomenon was observed by him in the case of bacteria, e.g., anthrax bacilli in the frog. The bacteria were taken up and digested by the wandering cells. Metschnikoff believes that the bacteria are ingested and disposed of by the cells whilst still in full vitality. H e finds special support for his theory in the fact that bacteria will multiply even in an immune animal, if they are protected from the attack of the phagocytes. Natural immunity depends on the fact that the leucocytes are capable of quickly ingesting and destroying the invading microbes, whilst in susceptible animals the microbes remain free. In the immunity that occurs after recovery from a disease the phagocytes have acquired the power of exercising their destructive properties more certainly and quickly. The second is a humoral theory of immunity which has found a special advocate in Buchner. The fact has been experimentally proved that the cell-free blood plasma and serum of warm-blooded animals possess marked bactericidal properities towards certain organisms. Nuttall found that not only the blood but also the pericardial fluid of dogs and rabbits could destroy anthrax bacilli. The cell-free blood serum exercised the bactericidal property. Behring observed that the blood serum of white rats immune to anthrax was not a good soil for the bacilli ; whilst they grew well in the blood serum of animals susceptible to the disease. Behring believes that the degree of alkalinity of the blood has something to do with this action. It was also found that a given serum was only fatal to certain bacteria, others it did not affect. The substances upon which the bactericidal action of the serum depends were termed "Alexines." Little is known with regard to the nature of these protective substances, except that they are very sensitive to external agents and quickly lose their properties outside the body. The third theory is one which occupies an inter-
P R E V E N T I V E INOCULATION. mediate position between the cellular and humoral theories. It grants the existence of the alexines, but regards them as being produced by the leucocytes. The bactericidal action of an exudation containing leucocytes is therefore due to the presence of soluble bodies which have been secreted by the cells. The bactericidal action of the blood plasma does not depend upon the direct destruction of the bacteria by the cells, but upon soluble bodies which have passed into the plasma from the cells. Kossel found that the nuclei of the lymph cells contain nucleic acid, which has a destructive action on cholera, typhoid and pus organisms. Vaughan by the subcutaneous inoculation of nucleic acid immunised animals to a subsequent infection with pneumocoeci. If an exudation rich in leucocytes is frozer~, phagocytosis is completely inhibited but the action of the alexines is not destroyed. (Buchner). The bactericidal action of the exudation is therefore probably due not to the phagocytes, but to dissolved substances derived from them. The leueocytes play a secondary not a primary rote in the process. There is no theory which can harmonise all views on the subject of immunity. We must patiently wait for the results that further investigation will brin~. Metschnikoff states that all investigations hitherto made point to the living cells as the active agents in the production of immunity, and to the phagocytes as the primary agents in the process. As already stated, immunity may be acquired by recovery from ar/attack of a given disease, and that this fact led to early attempts to produce immunity by exposing healthy individuals to infection during a mild outbreak of a disease. Further, recovery from a mild disease like cow-pox afforded an equal protection against small-pox as an attack of the same. The scientific development of the possibilities underlying this observation is the work of comparatively recent years, and dates from the discovery of the causal relation of bacteria to disease processes. The first endeavours were made by Pasteur who sought to render animals proof against a di.ease by inoculating the naturally or artificially attenuated virus, e,g., fowlcholera, anthrax. If he attenuated the virulence of the organisms and inoculated them into an animal, the animal was protected against infection with the fully virulent bacilli. Anthrax bacilli grown at 43 ° C. for varying lengths of time were modified in their virulence and yielded a protective vaccine. The virus of swine erysipelas on being passed through the body of a less susceptible ~nimal became similarly modified by natural means. The methods introduced by Pasteur for the treatment of hydrophobia likewise depend upon an artificial attenuation of the virus. A virulent stable virus was first obtained by inoculating rabbits and this virus was then attenuated. The virulent spinal cord of the animal was
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dried in the presence of caustic potash. In this way various grades of attenuation were obtained. A cord dried x--4 days produced the symptoms of rabies in seven days, and if dried for a fortnight it became innocuous. An emulsion was made of the virus which had been dried for varying lengths of time, and accordingly possessed varying degrees of virulence. These emulsions were inoculated into dogs, proceeding from the weaker to the stronger virus. The result was that the animals became insusceptible to infection with the fully virulent virus of rabies. The same method has been successfully applied to the human subject, and is in daily use at the Pasteur Institute. Another method of protective inoculation was tried by utilising the metabolic products of the specific organism. Pasteur proved that cultivations of fowl eholera bacilli, when freed from living bacteria, still produced all the toxic symptoms of the disease. In other diseases it was also shown that the symptoms were due not to the bacteria, but to their toxic products, e.g., diphtheria (Roux and Yersin) and tetanus (Kitasato). These recta. bolic products can be used for immunising purposes. Salmon and Smith conducted successful immunising experiments in the case of American swine plague. Experiments of a similar nature made with other organisms such as bac. pyoeyaneus, streptococci, pneumococci, &c., gave successful results in the lower animals. Beumer and Peiper attempted to immunise against typhoid by the rejection of cultures which h a d previously been heated to 55--6o ° C. The most of the experiments in this direction, whilst successful in the laboratory, cannot be so successfully utilised on a larger and more extensive scale. These instances may suffice of the attempts made to utilise directly the metabolic products of the bacteria as immunising agents. A large number of experiments have also been made with the bacterial proteins. These bacterial proteins are derived from the cells by extraction methods or by prolonged boiling, and are of a stable character. The most familiar example is Koch's tuberculin, which is an extract of the tubercle bacilli. According to many obseE-cers its action is not specific, and it cannot confer a specific immunity to tuberculosis. The medical profession have almost entirely abandoned its use as a therapeutic agent. It is of extreme value as a diagnostic agent for tuberculosis in the lower animals. By its aid tubercular cows can be eliminated from a dairy, and in this way the danger of infection for the human subject lessened. Mallein is prepared in the same way as tuberculin, from the glanders bacilli. It is an invaluable agent in the diagaosis of glanders. It now remains to. consider the present-day methods of producing an artificial immunity, and their practical application under the name o f blood serum therapeutics. In this ease neither the
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attenuated organisms nor their metabolic products are directly used in the prevention or cure of a disease. A n intermediary is used in the shape of an animal which has been artificially immunised to a high degree, so that its system contains an excess of the protective bodies or antitoxins. These antitoxins are utilised to supply any deficiency of the same protective bodies that may exist in the body of another animal during an attack of the same disease. I f an adequate amount of antitoxins be prc~ent in the system, the animal will be enabled to overcome the specific disease~ because the specific toxins formed in its course will be neutraliscd. This protective action takes place if the serum is inoculated after infection has occurred. F r o m this it will be seen that the inoculation o f the serum has a curative action, and that it may be used in the same way as a drug (Heilserum). Ehflich distinguishes an active immunity, such as occurs , for example, after an attack of an infectious disease, and a~assive immunity d u e to the transference of the immunismg agent from the blood of one animal to another. The blood serum therapeutics would come under the latter category. Experimental research has shown that animals possessing a natural immunity to an infectious disease cannot transfer that immunity by means of their blood to other animals. But the blood o f an animal artificially immunised to a disease has protective properties which can be transferred to other animals, Behring and Kitasato published in I89O a series of important investigations with regard to this subject. They came to the conclusion that the immunity of rabbits and mice which have been rendered immune to tetanus depends upon the capacity of the celt-free blood plasma to render innocuous the toxins of the tetanus bacillus. Cultures of the tetanus and diphtheria bacilli contain specific toxic bodies, which produce the same effect upon an animal as pure cultures of these organisms. Behring and Kitasato found that rabbits, artificially immunised to tetanus, were protected against infection either with the bacteria or their toxic products. The blood of these rabbits protected other rabbits against the bacilli and their toxins. T h e blood serum was therefore curative, as it acted when injected after infection. According to Behring and Kitasato, this protective and curative effect is due to a destructive action of the blood serum upon the toxins. They drew the following conclusions : - - ( i ) The blood of a rabbit immune to tetanus exercises a destructive action upon the tetanus poison. (2) This property can be detected in the extravascular blood, and in the cell-free serum obtained from it. (3) This property is of so ,lasting a nature that it remains potent in the systems of other animals. A marked therapeutic action can. therefore be obtained by transfusion of the blood or serum. (4) The destructive action on the tetanus poison is wanting in the blood of animals that are not
INOCULATION. immune to tetanus. The tetanus poison inoculated into such animals can be detected in their blood and tissues after death. I n the course of further research, Behring found that the blood serum of animals, artificially immunised to diphtheria, can protect other animals against otherwise fatal doses of the diphtheria poison. By these investigations, the general law was established that the blood and the blood serum of animals, which have been immunised against a given infectious disease, can confer the special immunity on other animals. This was found to obtain in other diseases besides diphtheria and tetanus, e.g'., pneumonia~ typhoid, swine erysipelas, etc. T h e specific nature of the antitoxins is the view at present most generally held. . T h e antitoxins are likewise found in the blood of human beings, after recovery from an infectious disease, e.g., pneumonia, diphtheria. The methods adopted to produce the artificial immunity proceeded on the following lines : - - T h e animal to be immunised was inoculated with gradually increasing doses of the virulent material. The result was that a certain tolerance was established in course of time, so that the animal was able to withstand otherwise fatal doses of the toxins. T h e injections produced a temporary reaction, viz., rise of temperature, alterations in body weight and general condition. This is connected with the production of the antitoxins in its system. In this way a highly active serum, rich in antitoxins, was obtained. The curative action of the serum was supposed to depend upon a neutralisation of the specific toxins in the body. T h e matter is, however, too complicated to be dealt with here. We know so little about the chemistry of these proteid bodies, that a long time must elapse before anything definite can be said respecting their nature and mode of action. I t has been supposed that the antitoxins are products of the animal cells, and that the toxins act as a stimulant on the ceils producing them. It may be that the active immunising agent is not in the serum, but is the result of a tissue reaction following its injection. T h e suggestion has also been made that the antitoxins are modified products derived from the specific micro-organisms. T h e diphtheria and tetanus serum in some way lead to the destruction of the toxins produced by the bacteria in the tissues. The action is not bactericidal, it is antitoxic. It has been proved that the antitoxins can pass into the milk, and that immunity to a disease can thus be transferred from the mother to the child. T h e use that has been made of serum therapeutics in the treatment of disease will best be illustrated by a few typical examples. At present, it is the only method of protective inoculation that promises to rival the success obtained by vaccination, and its development has taken place on strictly scientific lines. T h e results have been obtained by accurate observation and accurate
PREVENTIVE experiment. T h e careful investigations of Vaillard and Vincent and others proved that in the case of Tetanus t h e symptoms of the disease were due to poisonous bodies formed by the bacilli in the system. These specific toxins reproduced in animals the morbid symptoms of the disease. When injected in increasing doses, beginning with with non-fatal amounts, a tolerance and ultimately a resistance to the poisons was established in the system. The animal became immune even to many times the fatal dose. T h e immunising agent was present in largest quantity in the blood. The blood, when transIerred to another animal in sufficient quantity, rendered it proof against infection with tetanus. It was necessary to obtain large quantities of the antitoxie serum in order to successfully treat the diseases on the human subject, and in this respect the horse proved the most useful animal. After immunisation large quantities of blood could be obtained without sacrificing the life of the animal. Horses are therefore generally used for the preparation of antitoxic serum on a large scale. Although the tetanus serum gave such brilliant results in the lower animals, its success was not so striking in the case of man. I n acute cases it was generally used too late, the intoxication of the system having gone too far. T h e earlier a serum is injected in the course of a disease the better chance it has of producing a favourable effect. T h e tetanus sermn can undoubtedly favourably influence the course of the disease if injected in good time, as well as in the less acute cases. I n countries where tetanus is common, its powers as a prophylactic agent can be freely tested, and, it is to be hoped, with the best results. Behring and Wernicke, in i892, successfully immunised animals to the 1)[~htkeria poison. The immunising and curative properties of the serum could be transferred to other animals. The animals used were sheep and, eventually, horses. T h e largest quantity of the immunising agent was present in the separated blood serum. Larger doses of the serum were required for curative than for simply immunising purposes. T h e later after injection it was used, the larger was the dose necessary to save life. This applies not only to the lower animals, but also to the human subject. T h e influence of the serum on the course of the disease was shown by experiments on guinea-pigs. I f a guinea-pig is inoculated with a fatal dose of a diphtheria culture, and then after a lapse of twenty-four hours with the serum, the local changes are s t o p p e d and the animal slowly recovers. I n later stages of the infection the serum injection does not generally avert death, though it postpones the fatal issue. I n the first instance, the antitoxin was able to affect favourably the local symptoms, and also to render innocuous the poison circulating in the body. In the other case, the intoxication
INOCULATION.
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had gone too far, so that the antitoxin could not completely counteract its effects. T h e serum is not able to repair any m i s c h i e f that has already occurred. Its action is not bactereidal, it is antitoxic. T h e infection, if taken in time, is locatised, and the general intoxication of the system due to the diphtheria poison is neutralised. Animals which had been previously inoculated with the serum were protected against a subsequent infection with diphtheria, showing that the serum can exercise a prophylactic action. The toxins used for immunising the animals are obtained by cultivating the diphtheria bacilli in a nutrient broth. I f the cultures are filtered after a time, the filtrate contains the soluble toxins freed from the bacilli. On the addition of a small quantity of carbolic acid the toxins preserve their activity for a long time. T h e injections are commenced with very feeble doses of the toxins, and they are gradually increased as tolerance is established. T h e injections produce a local and general reaction, which passes off. T h e injections are continued until the animal has attained a high degree of immunity, characterized by an excess of antitoxins in its blood. Roux found that it was easier to immunise the horse, and that it tolerates repeated dosing with the toxins. It is easier to bleed, and the blood yields a clear serum. T h e serum per se of the horse is innocuous in large doses, and it is quickly absorbed after subcutaneous inoculation. To preserve theserum, carbolic acid, tricresol, or camphor is added. T h e serum before being sent out is standardised, and its exact immunising value is determined and the necessary dose estimated. T h e serum, when bottled, should be kept in a cool and dark place. T h e horses before being used are carefully tested with tuberculin and mallein, and thus the assurance given that infective agents are e x c l u d e d . No serious effects have been found to follow the use of the serum. T h e consensus of opinion at present is that the use o f the serum has a striking effect in lessening the mortality from diphtheria. As time goes on we shall be in possession of still fuller statistics, which will decide the matter conclusively as to the value of the serum treatment. T h e bacteriological diagnosis) which can be easily made, will at once decide whether a case is one of genuine diphtheria or not. T h e specific action of the serum is more certain the earlier the treatment begins. In this respect the practitioner has a better opportunity than the hospital physician of starting an early treatment of a case and of giving his patient the best possible ,chance. T h e mortality is less when the injections are commenced at once, i.e., on the first or second day. Further, treatment is easier in the earlier stages of the disease before complications have occurred against which the antitoxic serum may be powerless. T h e serum is not so effectual in cases of mixed infection. I n conclusion, it u
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V A C C I N A T I O N OR S A N I T A T I O N ?
may be mentioned that favourable reports exist regarding the us%of the serum as a prophylactic agent where persons are exposed to the diphtheritic contagion. Many experiments are being carried on at present, with a view of immunising animals to other diseases, in the hope of obtaining a curative serum. One must be especially mentioned as of great promise, viz., the streptococcus serum. Marmorek has succeeded in immunising large animals (sheep, donkey, horse) against infection with the streptococcus pyogenes. T h e highly virulent cultures of the streptococci are inoculated subcutaneously. The doses are repeated and, gradually increased. A very violent readtion occurs in the animals, but without causing death. As a result an active antitoxic serum is obtained, which protects animals against fatal doses of the streptococci. T h e serum is obtained from the horse as in the case of diphtheria and tetanus. The importance of these results will be understood, when we consider how many diseases of the human subject there are in which streptococci play an important role--e.g., erysipelas, wound infections, puerperal septicmmia, &c. They also occur as a frequent complication in other diseases, and add to the severity of the symptoms, e.g., diphtheria, influenza, scarlet fever, tubercle, &c. Successful results are said to have been obtained in septic~emia, diphtheria, &c., and in erysipelas a striking fall in the temperature and abatement of the local symptoms has occurred. It has also been remarked that in cases of diphtheria, complicated b y t h e presence of streptococci, an injection of the diphtheria and streptococcus antitoxins had a good effect. The attempt has also been made to immunise the horse to both diphtheria and streptococcus toxins, with a view of utilising the serum in those cases of mixed infection we have referred to. In other directions research is equally active, but as the investigations are not beyond the experimental stage they hardly come within the scope of this paper. Behring is confident that the treatment of Asiatic cholera on antitoxic principles is within reach of accomplishment. I n similar fashion it is hoped that an antitoxic serum may be obtained for the treatment of typhoid fever, pneumonia, rabies, etc. There is no disease in which a reliable means of treatment is more ardently to be wished for than consumption. Behring states that he has found in the blood of animals rendered resistant to the action of tuberculin a substance which neutralises its effects, to which he has applied the name antituberculin. The promising investigations of Camette and Fraser with regard to a snake poison antitoxin must also be mentioned. It may also be that in vaccinia the blood contains certain antitoxic principles, and that in Jenner's great discovery lay the germ of serum therapeutics.
V A C C I N A T I O N OR S A N I T A T I O N ? BY JOHN C. MCVAIL,M.D., D.P.H. 1I" is one of the commonest allegations of those who assert that vaccination is not a preventive of small-pox, that diminution of small-pox prevalence attributed to vaccination, is wholly or largely due to sanitation. It is argued that as certain other infectious diseases have also diminished, and that as their diminution is acknowledged to be due to sanitation, the diminution in small-pox should be similarly attributed. In this line of argument no cognisance is taken of the fact, that for one infectious disease sanitation means one thing, and for another infectious disease another thing. For example, the preventive measures which have had most influence against typhoid fever, are not those which have been most powerful against typhus, and the causes which have made cholera almost unknown among us, have had no similar influence on whooping cough; nor are diarrhcea, and rabies, and erysipelas, and anthrax, and diphtheria to be dealt with by identical sanitary procedures. As regards small-pox, neither drainage, nor water supply, nor increased air space, nor improved cleanliness, can account for the remark. able changes which have taken place in the age incidence of the disease, can explain the fact that small-pox w a s formerly a disease of infancy, but that now-a-days it has been transferred to more advanced periods of life ; to periods of life at which some preventive cause operative among infants and juveniles, would appear to have lost much of its power. It is obvious that neither sanitation as a whole, nor any of the individual measures above noted can account for this remarkable phenomenon. Fresh air, and good drainage, and good water, and general cleanliness are healthful, not only for children, but for adults. I n addition, ho~'ever, to such obvious considerations as these, it may be well to call attention to what may be looked on as an experiment carried out on a huge scale to test the effect of vaccination on small-pox, in the absence of sanitation. The City of Glasgow, at the beginning of the present century furnishes the facts. Those relating to the influence of vaccination on small-pox were put on record by Dr. Robert Watt, of Glasgow, in 1813, and those relating to the sanitary condition of the City in the early part of the century are to be found most conveniently in Dr. Russell's recent monograph on the sanitary history of Glasgow. The population of Glasgow increased very rapidly from about the year 1780 onwards. In that year it was 42,832 ; in 1791 it was 66,578. I n t8ol it h a d increase d to 83,00o ; in i 8 i i to 11%ooo; in 182i to x47,ooo ; in i83r to 2o2,ooo, and so on. The area occupied by these populations was very small, the people living layer upon layer in high tenement houses closely built together. The date of the earliest description of the sanitary condition of the
THE PRINCIPLES INOCULATION AND APPLICATION.
INOCULATION.
OF PREVENTIVE THEIR PRACTICAL
BY
ALLAN ~ACI~'ADYEN, M.D., B.Sc.
IN the annals of medical science there is no name more worthy of being honoured and revered than that of Edward Jenner. The epoch-making discovery of the principle of vaccination which we owe to him has stood the test of time and experience. T h e hundredth anniversary of Jenner's vaccination experiments has now come, a n d the principles that he advocated and put into practice still remain the one efficient means of protection against the most dreaded of diseases. T h e lives that Jenner's work has been instrumental in saving are the most eloquent tribute to his memory, and the brilliant discoveries that have since been made in the field of protective inoculation render his name imperishable. Indeed, after one hundred years, medical science seems once more to be on the threshold of discoveries as great and as momentous. It will be:the object of this paper to trace succinctly the achievements that have been obtained through the application of the principles of vaccination by those who followed Jenner and worked in his spirit. It is an old observation that individuals after recovery from a given disease are generally protected for a time or permanently against a return of the same malady. In other words, they have acquired an immunity to that disease. T h e important observ~ation was also made that a mild attack of a disease likewise conferred protection. Thus, a mild attack of smallpox could equally protect an individual against a severe attack of that disease. T h e attempt was made to utilise this act of nature as a means of protection. I n its crudest form this consisted in exposing children to infection, for instance, with measles in a mild form in order to protect them against the severer forms of the disease. A vague appreciation of the principles of immunity ex,sted in such methods. At the beginning of the ~Sth century it was customary to inoculate healthy people with the virus of human small-pox as a means of protection. This method, though extensively used, was attended with danger. T h e disease so induced did not always run a mild course, and those vaccinated formed a source of infection to others. Jenner observed that people infected with cow-pox were protected against the virus of human small-pox, and that the inoculation of cow-pox in man was a trustworthy protection from the latter disease. Jenner, by inoculating the infectious material of cow-pox, lessened the susceptibility of the human organism to the contagion of smalt-pox. T h e vaccinated person, if attacked, acquired a mild form of the disease. T h e conclusion deduced from this was that vaccinia was a milder form of small-pox, due to the growth in the
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body of the attenuated virus o f small-pox. T h e important modification introduced by Jenner wa~ that he used the mild virus of cow-pox as a means of protection against the virulent virus of small-pox. T h e recovery from a mild attack of cow-pox rendered those inoculated proof against small-pox. One need hardly dwell upon the subsequent development and practical application of Jenner's discovery as regards small-pox. Many years elapsed before the attempt was made to apply the principles of vaccination to other diseases. T h e experiments were conducted on essentially similar lines, viz., to produce a mild attack of a disease by means of an attenuated virus, in order to render the organism proof against the virulent virus of the same disease. T h e fresh starting point was furnished by Pasteur's demonstration of the fact that not only fermentative but also disease processes were due to the action of bacteria. T h e demonstration of the parasitic nature o f infectious diseases culminated in the classical researches of Koch. T h e methods of cultivating pathogenic bacteria outside the body were brought by him to a high degree of perfection. I n this way a systematic study of the cause o f a disease became possible, and the means of combating its action could be determined by experiment. Further, the problems connected with immunity could be studied on a scientific, instead of an empirical, basis. Pasteur proved that it was possible to modify the virulence of a pathogenic organism b y artificial means so that it no lOnger produced fatal results, and that this attenuated virus protected against the fatal form of the disease. T h e experiments upon which these conclusions were based were made by Pasteur in 188% whilst studying the disease known as " F o w l Cholera." I n the same way he was able to attenuate the virulence o f anthrax bacilli by growing them at high temperatures. These results led to similar attempts in the case of other diseases, and fresh light was thrown on the subject of immunity and the methods by which it could artificially be brought about. These methods, however successful in the laboratory, have not always h~td the same success in practice, and in this respect cannot be compared with Jenner's method of vaccination. I n recent years other views have come to the front with regard to the nature of immunity and the means of rendering the animal organism proof against disease. I n a sense, a return has been made t o the Jennerian system of utilising the lower animals. for the preparation of the protective agents. I t has been proved that pathogenic bacteria by their growth in the body produce certain poisons to which are due the characteristic symptoms of the disease. These bacteria also oroduce the same poisons when cultivated on a suitable soil outside the body. The poisons or toxins so obtained, when freed from the bacteria that produced them, will, on inoculation into a susceptible animal, give
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rise to the same morbid symptoms. The assumption has been made that the cells of the body, as an act of self-defenee, secrete certain bodies that are capable of neutralising the action of the toxins (Alexmes, antitoxins). I f these protective bodies are present in sufficient amount they neutralise the toxins of the specific microbe, and recovery takes place; if present in excess, they are capable of neutralising new toxins that may be subsequently formed. In this way they can bring about a temporary or permanent immunity, If, therefore, the toxins of a given microbe be obtained from its cultures and inoculated into an animal in increasing doses, one may hope to favour the production of large quantities of protective bodies in its system. I f these protective bodies or antitoxins be obtained from the secretions or blood of the animal, they may be used to render other animal immune to the same disease. The antitoxins are present in largest quantity in the blood, and, consequently, the blood, or, better still, the blood serum of the artificially immunised animal, is utilised for the purpose of protective inoculation. This is the basis of the modern blood serum therapeutics, for which we are indebted to the investigations of Behring and his fellow-workers. With these prefatory remarks, we may now proceed to consider the principles of preventive inoculation and their practical application in a more detailed fashion. In the first instance, a few words must be devoted to the subject of immunity. The body is provided with certain external protections against the invasion of pathogenic bacteria. For example, the mouth and nasal cavity receive quite a number of bacteria, and yet infection occurs relatively seldom at these points. And in the digestive tract the invasion of microbes is to a certain extent combated, as, for instance, in the stomach, by means of the acidity of its contents. The internal agents at work are of still greater importance in protecting the organism. There is a natural immunity peculiar to individuals and species of animals whereby they are naturally resistent to forms of infection t o which others succumb. Certain diseases affect only man, whilst the lower animals have diseases peculiar to themselves. There is also an acquired immunity which takes place after recovery from a disease, e.g., small-pox. Immunity may be artificially produced by the in~oculation of attenuated vaccines, or by the injection of the blood serum of an immunised animal into another animal. In the latter instance, the immunity is artificially transferred. Many theories have been brought forward to explain the pl~enomena of natural and artificial immunity. The t'asteur-Klebs theory assumed that in the course of a given disease, the pabulum necessary for the specific organism is consumed, so that in the event of another attack, the bacte/'ia do not find the necessary nutriment. Chauveau supposed that the poisonous metabolic products of the
INOCULATION. bacteria formed in the system prevent their further development, bringing about a crisis in the disease. They also impregnated the system, and prevented a further invasion by the same organism. Another theory was based~ upon the results of small-pox vaccination. It was suggested that in the pustule the weakest celt elements succumbed ; the more vigorous, on the other hand, remained. After a first attack, only the more resistent cells survived, from which the new tissue elements were formed. This property was hereditary, and consequently subsequent generations of cells were equally endowed with a heightened power of resistance. These hypotheses are now mainly of historical interest. At present, the three following are the most favoured. The first is a cellular theory, and is associated with the name of Metschnikoff. The phagocytes or wandering cells of the body are capable of taking up and digesting foreign bodies. This phenomenon was observed by him in the case of bacteria, e.g., anthrax bacilli in the frog. The bacteria were taken up and digested by the wandering cells. Metschnikoff believes that the bacteria are ingested and disposed of by the cells whilst still in full vitality. H e finds special support for his theory in the fact that bacteria will multiply even in an immune animal, if they are protected from the attack of the phagocytes. Natural immunity depends on the fact that the leucocytes are capable of quickly ingesting and destroying the invading microbes, whilst in susceptible animals the microbes remain free. In the immunity that occurs after recovery from a disease the phagocytes have acquired the power of exercising their destructive properties more certainly and quickly. The second is a humoral theory of immunity which has found a special advocate in Buchner. The fact has been experimentally proved that the cell-free blood plasma and serum of warm-blooded animals possess marked bactericidal properities towards certain organisms. Nuttall found that not only the blood but also the pericardial fluid of dogs and rabbits could destroy anthrax bacilli. The cell-free blood serum exercised the bactericidal property. Behring observed that the blood serum of white rats immune to anthrax was not a good soil for the bacilli ; whilst they grew well in the blood serum of animals susceptible to the disease. Behring believes that the degree of alkalinity of the blood has something to do with this action. It was also found that a given serum was only fatal to certain bacteria, others it did not affect. The substances upon which the bactericidal action of the serum depends were termed "Alexines." Little is known with regard to the nature of these protective substances, except that they are very sensitive to external agents and quickly lose their properties outside the body. The third theory is one which occupies an inter-
P R E V E N T I V E INOCULATION. mediate position between the cellular and humoral theories. It grants the existence of the alexines, but regards them as being produced by the leucocytes. The bactericidal action of an exudation containing leucocytes is therefore due to the presence of soluble bodies which have been secreted by the cells. The bactericidal action of the blood plasma does not depend upon the direct destruction of the bacteria by the cells, but upon soluble bodies which have passed into the plasma from the cells. Kossel found that the nuclei of the lymph cells contain nucleic acid, which has a destructive action on cholera, typhoid and pus organisms. Vaughan by the subcutaneous inoculation of nucleic acid immunised animals to a subsequent infection with pneumocoeci. If an exudation rich in leucocytes is frozer~, phagocytosis is completely inhibited but the action of the alexines is not destroyed. (Buchner). The bactericidal action of the exudation is therefore probably due not to the phagocytes, but to dissolved substances derived from them. The leueocytes play a secondary not a primary rote in the process. There is no theory which can harmonise all views on the subject of immunity. We must patiently wait for the results that further investigation will brin~. Metschnikoff states that all investigations hitherto made point to the living cells as the active agents in the production of immunity, and to the phagocytes as the primary agents in the process. As already stated, immunity may be acquired by recovery from ar/attack of a given disease, and that this fact led to early attempts to produce immunity by exposing healthy individuals to infection during a mild outbreak of a disease. Further, recovery from a mild disease like cow-pox afforded an equal protection against small-pox as an attack of the same. The scientific development of the possibilities underlying this observation is the work of comparatively recent years, and dates from the discovery of the causal relation of bacteria to disease processes. The first endeavours were made by Pasteur who sought to render animals proof against a di.ease by inoculating the naturally or artificially attenuated virus, e,g., fowlcholera, anthrax. If he attenuated the virulence of the organisms and inoculated them into an animal, the animal was protected against infection with the fully virulent bacilli. Anthrax bacilli grown at 43 ° C. for varying lengths of time were modified in their virulence and yielded a protective vaccine. The virus of swine erysipelas on being passed through the body of a less susceptible ~nimal became similarly modified by natural means. The methods introduced by Pasteur for the treatment of hydrophobia likewise depend upon an artificial attenuation of the virus. A virulent stable virus was first obtained by inoculating rabbits and this virus was then attenuated. The virulent spinal cord of the animal was
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dried in the presence of caustic potash. In this way various grades of attenuation were obtained. A cord dried x--4 days produced the symptoms of rabies in seven days, and if dried for a fortnight it became innocuous. An emulsion was made of the virus which had been dried for varying lengths of time, and accordingly possessed varying degrees of virulence. These emulsions were inoculated into dogs, proceeding from the weaker to the stronger virus. The result was that the animals became insusceptible to infection with the fully virulent virus of rabies. The same method has been successfully applied to the human subject, and is in daily use at the Pasteur Institute. Another method of protective inoculation was tried by utilising the metabolic products of the specific organism. Pasteur proved that cultivations of fowl eholera bacilli, when freed from living bacteria, still produced all the toxic symptoms of the disease. In other diseases it was also shown that the symptoms were due not to the bacteria, but to their toxic products, e.g., diphtheria (Roux and Yersin) and tetanus (Kitasato). These recta. bolic products can be used for immunising purposes. Salmon and Smith conducted successful immunising experiments in the case of American swine plague. Experiments of a similar nature made with other organisms such as bac. pyoeyaneus, streptococci, pneumococci, &c., gave successful results in the lower animals. Beumer and Peiper attempted to immunise against typhoid by the rejection of cultures which h a d previously been heated to 55--6o ° C. The most of the experiments in this direction, whilst successful in the laboratory, cannot be so successfully utilised on a larger and more extensive scale. These instances may suffice of the attempts made to utilise directly the metabolic products of the bacteria as immunising agents. A large number of experiments have also been made with the bacterial proteins. These bacterial proteins are derived from the cells by extraction methods or by prolonged boiling, and are of a stable character. The most familiar example is Koch's tuberculin, which is an extract of the tubercle bacilli. According to many obseE-cers its action is not specific, and it cannot confer a specific immunity to tuberculosis. The medical profession have almost entirely abandoned its use as a therapeutic agent. It is of extreme value as a diagnostic agent for tuberculosis in the lower animals. By its aid tubercular cows can be eliminated from a dairy, and in this way the danger of infection for the human subject lessened. Mallein is prepared in the same way as tuberculin, from the glanders bacilli. It is an invaluable agent in the diagaosis of glanders. It now remains to. consider the present-day methods of producing an artificial immunity, and their practical application under the name o f blood serum therapeutics. In this ease neither the
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attenuated organisms nor their metabolic products are directly used in the prevention or cure of a disease. A n intermediary is used in the shape of an animal which has been artificially immunised to a high degree, so that its system contains an excess of the protective bodies or antitoxins. These antitoxins are utilised to supply any deficiency of the same protective bodies that may exist in the body of another animal during an attack of the same disease. I f an adequate amount of antitoxins be prc~ent in the system, the animal will be enabled to overcome the specific disease~ because the specific toxins formed in its course will be neutraliscd. This protective action takes place if the serum is inoculated after infection has occurred. F r o m this it will be seen that the inoculation o f the serum has a curative action, and that it may be used in the same way as a drug (Heilserum). Ehflich distinguishes an active immunity, such as occurs , for example, after an attack of an infectious disease, and a~assive immunity d u e to the transference of the immunismg agent from the blood of one animal to another. The blood serum therapeutics would come under the latter category. Experimental research has shown that animals possessing a natural immunity to an infectious disease cannot transfer that immunity by means of their blood to other animals. But the blood o f an animal artificially immunised to a disease has protective properties which can be transferred to other animals, Behring and Kitasato published in I89O a series of important investigations with regard to this subject. They came to the conclusion that the immunity of rabbits and mice which have been rendered immune to tetanus depends upon the capacity of the celt-free blood plasma to render innocuous the toxins of the tetanus bacillus. Cultures of the tetanus and diphtheria bacilli contain specific toxic bodies, which produce the same effect upon an animal as pure cultures of these organisms. Behring and Kitasato found that rabbits, artificially immunised to tetanus, were protected against infection either with the bacteria or their toxic products. The blood of these rabbits protected other rabbits against the bacilli and their toxins. T h e blood serum was therefore curative, as it acted when injected after infection. According to Behring and Kitasato, this protective and curative effect is due to a destructive action of the blood serum upon the toxins. They drew the following conclusions : - - ( i ) The blood of a rabbit immune to tetanus exercises a destructive action upon the tetanus poison. (2) This property can be detected in the extravascular blood, and in the cell-free serum obtained from it. (3) This property is of so ,lasting a nature that it remains potent in the systems of other animals. A marked therapeutic action can. therefore be obtained by transfusion of the blood or serum. (4) The destructive action on the tetanus poison is wanting in the blood of animals that are not
INOCULATION. immune to tetanus. The tetanus poison inoculated into such animals can be detected in their blood and tissues after death. I n the course of further research, Behring found that the blood serum of animals, artificially immunised to diphtheria, can protect other animals against otherwise fatal doses of the diphtheria poison. By these investigations, the general law was established that the blood and the blood serum of animals, which have been immunised against a given infectious disease, can confer the special immunity on other animals. This was found to obtain in other diseases besides diphtheria and tetanus, e.g'., pneumonia~ typhoid, swine erysipelas, etc. T h e specific nature of the antitoxins is the view at present most generally held. . T h e antitoxins are likewise found in the blood of human beings, after recovery from an infectious disease, e.g., pneumonia, diphtheria. The methods adopted to produce the artificial immunity proceeded on the following lines : - - T h e animal to be immunised was inoculated with gradually increasing doses of the virulent material. The result was that a certain tolerance was established in course of time, so that the animal was able to withstand otherwise fatal doses of the toxins. T h e injections produced a temporary reaction, viz., rise of temperature, alterations in body weight and general condition. This is connected with the production of the antitoxins in its system. In this way a highly active serum, rich in antitoxins, was obtained. The curative action of the serum was supposed to depend upon a neutralisation of the specific toxins in the body. T h e matter is, however, too complicated to be dealt with here. We know so little about the chemistry of these proteid bodies, that a long time must elapse before anything definite can be said respecting their nature and mode of action. I t has been supposed that the antitoxins are products of the animal cells, and that the toxins act as a stimulant on the ceils producing them. It may be that the active immunising agent is not in the serum, but is the result of a tissue reaction following its injection. T h e suggestion has also been made that the antitoxins are modified products derived from the specific micro-organisms. T h e diphtheria and tetanus serum in some way lead to the destruction of the toxins produced by the bacteria in the tissues. The action is not bactericidal, it is antitoxic. It has been proved that the antitoxins can pass into the milk, and that immunity to a disease can thus be transferred from the mother to the child. T h e use that has been made of serum therapeutics in the treatment of disease will best be illustrated by a few typical examples. At present, it is the only method of protective inoculation that promises to rival the success obtained by vaccination, and its development has taken place on strictly scientific lines. T h e results have been obtained by accurate observation and accurate
PREVENTIVE experiment. T h e careful investigations of Vaillard and Vincent and others proved that in the case of Tetanus t h e symptoms of the disease were due to poisonous bodies formed by the bacilli in the system. These specific toxins reproduced in animals the morbid symptoms of the disease. When injected in increasing doses, beginning with with non-fatal amounts, a tolerance and ultimately a resistance to the poisons was established in the system. The animal became immune even to many times the fatal dose. T h e immunising agent was present in largest quantity in the blood. The blood, when transIerred to another animal in sufficient quantity, rendered it proof against infection with tetanus. It was necessary to obtain large quantities of the antitoxie serum in order to successfully treat the diseases on the human subject, and in this respect the horse proved the most useful animal. After immunisation large quantities of blood could be obtained without sacrificing the life of the animal. Horses are therefore generally used for the preparation of antitoxic serum on a large scale. Although the tetanus serum gave such brilliant results in the lower animals, its success was not so striking in the case of man. I n acute cases it was generally used too late, the intoxication of the system having gone too far. T h e earlier a serum is injected in the course of a disease the better chance it has of producing a favourable effect. T h e tetanus sermn can undoubtedly favourably influence the course of the disease if injected in good time, as well as in the less acute cases. I n countries where tetanus is common, its powers as a prophylactic agent can be freely tested, and, it is to be hoped, with the best results. Behring and Wernicke, in i892, successfully immunised animals to the 1)[~htkeria poison. The immunising and curative properties of the serum could be transferred to other animals. The animals used were sheep and, eventually, horses. T h e largest quantity of the immunising agent was present in the separated blood serum. Larger doses of the serum were required for curative than for simply immunising purposes. T h e later after injection it was used, the larger was the dose necessary to save life. This applies not only to the lower animals, but also to the human subject. T h e influence of the serum on the course of the disease was shown by experiments on guinea-pigs. I f a guinea-pig is inoculated with a fatal dose of a diphtheria culture, and then after a lapse of twenty-four hours with the serum, the local changes are s t o p p e d and the animal slowly recovers. I n later stages of the infection the serum injection does not generally avert death, though it postpones the fatal issue. I n the first instance, the antitoxin was able to affect favourably the local symptoms, and also to render innocuous the poison circulating in the body. In the other case, the intoxication
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had gone too far, so that the antitoxin could not completely counteract its effects. T h e serum is not able to repair any m i s c h i e f that has already occurred. Its action is not bactereidal, it is antitoxic. T h e infection, if taken in time, is locatised, and the general intoxication of the system due to the diphtheria poison is neutralised. Animals which had been previously inoculated with the serum were protected against a subsequent infection with diphtheria, showing that the serum can exercise a prophylactic action. The toxins used for immunising the animals are obtained by cultivating the diphtheria bacilli in a nutrient broth. I f the cultures are filtered after a time, the filtrate contains the soluble toxins freed from the bacilli. On the addition of a small quantity of carbolic acid the toxins preserve their activity for a long time. T h e injections are commenced with very feeble doses of the toxins, and they are gradually increased as tolerance is established. T h e injections produce a local and general reaction, which passes off. T h e injections are continued until the animal has attained a high degree of immunity, characterized by an excess of antitoxins in its blood. Roux found that it was easier to immunise the horse, and that it tolerates repeated dosing with the toxins. It is easier to bleed, and the blood yields a clear serum. T h e serum per se of the horse is innocuous in large doses, and it is quickly absorbed after subcutaneous inoculation. To preserve theserum, carbolic acid, tricresol, or camphor is added. T h e serum before being sent out is standardised, and its exact immunising value is determined and the necessary dose estimated. T h e serum, when bottled, should be kept in a cool and dark place. T h e horses before being used are carefully tested with tuberculin and mallein, and thus the assurance given that infective agents are e x c l u d e d . No serious effects have been found to follow the use of the serum. T h e consensus of opinion at present is that the use o f the serum has a striking effect in lessening the mortality from diphtheria. As time goes on we shall be in possession of still fuller statistics, which will decide the matter conclusively as to the value of the serum treatment. T h e bacteriological diagnosis) which can be easily made, will at once decide whether a case is one of genuine diphtheria or not. T h e specific action of the serum is more certain the earlier the treatment begins. In this respect the practitioner has a better opportunity than the hospital physician of starting an early treatment of a case and of giving his patient the best possible ,chance. T h e mortality is less when the injections are commenced at once, i.e., on the first or second day. Further, treatment is easier in the earlier stages of the disease before complications have occurred against which the antitoxic serum may be powerless. T h e serum is not so effectual in cases of mixed infection. I n conclusion, it u
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may be mentioned that favourable reports exist regarding the us%of the serum as a prophylactic agent where persons are exposed to the diphtheritic contagion. Many experiments are being carried on at present, with a view of immunising animals to other diseases, in the hope of obtaining a curative serum. One must be especially mentioned as of great promise, viz., the streptococcus serum. Marmorek has succeeded in immunising large animals (sheep, donkey, horse) against infection with the streptococcus pyogenes. T h e highly virulent cultures of the streptococci are inoculated subcutaneously. The doses are repeated and, gradually increased. A very violent readtion occurs in the animals, but without causing death. As a result an active antitoxic serum is obtained, which protects animals against fatal doses of the streptococci. T h e serum is obtained from the horse as in the case of diphtheria and tetanus. The importance of these results will be understood, when we consider how many diseases of the human subject there are in which streptococci play an important role--e.g., erysipelas, wound infections, puerperal septicmmia, &c. They also occur as a frequent complication in other diseases, and add to the severity of the symptoms, e.g., diphtheria, influenza, scarlet fever, tubercle, &c. Successful results are said to have been obtained in septic~emia, diphtheria, &c., and in erysipelas a striking fall in the temperature and abatement of the local symptoms has occurred. It has also been remarked that in cases of diphtheria, complicated b y t h e presence of streptococci, an injection of the diphtheria and streptococcus antitoxins had a good effect. The attempt has also been made to immunise the horse to both diphtheria and streptococcus toxins, with a view of utilising the serum in those cases of mixed infection we have referred to. In other directions research is equally active, but as the investigations are not beyond the experimental stage they hardly come within the scope of this paper. Behring is confident that the treatment of Asiatic cholera on antitoxic principles is within reach of accomplishment. I n similar fashion it is hoped that an antitoxic serum may be obtained for the treatment of typhoid fever, pneumonia, rabies, etc. There is no disease in which a reliable means of treatment is more ardently to be wished for than consumption. Behring states that he has found in the blood of animals rendered resistant to the action of tuberculin a substance which neutralises its effects, to which he has applied the name antituberculin. The promising investigations of Camette and Fraser with regard to a snake poison antitoxin must also be mentioned. It may also be that in vaccinia the blood contains certain antitoxic principles, and that in Jenner's great discovery lay the germ of serum therapeutics.
V A C C I N A T I O N OR S A N I T A T I O N ? BY JOHN C. MCVAIL,M.D., D.P.H. 1I" is one of the commonest allegations of those who assert that vaccination is not a preventive of small-pox, that diminution of small-pox prevalence attributed to vaccination, is wholly or largely due to sanitation. It is argued that as certain other infectious diseases have also diminished, and that as their diminution is acknowledged to be due to sanitation, the diminution in small-pox should be similarly attributed. In this line of argument no cognisance is taken of the fact, that for one infectious disease sanitation means one thing, and for another infectious disease another thing. For example, the preventive measures which have had most influence against typhoid fever, are not those which have been most powerful against typhus, and the causes which have made cholera almost unknown among us, have had no similar influence on whooping cough; nor are diarrhcea, and rabies, and erysipelas, and anthrax, and diphtheria to be dealt with by identical sanitary procedures. As regards small-pox, neither drainage, nor water supply, nor increased air space, nor improved cleanliness, can account for the remark. able changes which have taken place in the age incidence of the disease, can explain the fact that small-pox w a s formerly a disease of infancy, but that now-a-days it has been transferred to more advanced periods of life ; to periods of life at which some preventive cause operative among infants and juveniles, would appear to have lost much of its power. It is obvious that neither sanitation as a whole, nor any of the individual measures above noted can account for this remarkable phenomenon. Fresh air, and good drainage, and good water, and general cleanliness are healthful, not only for children, but for adults. I n addition, ho~'ever, to such obvious considerations as these, it may be well to call attention to what may be looked on as an experiment carried out on a huge scale to test the effect of vaccination on small-pox, in the absence of sanitation. The City of Glasgow, at the beginning of the present century furnishes the facts. Those relating to the influence of vaccination on small-pox were put on record by Dr. Robert Watt, of Glasgow, in 1813, and those relating to the sanitary condition of the City in the early part of the century are to be found most conveniently in Dr. Russell's recent monograph on the sanitary history of Glasgow. The population of Glasgow increased very rapidly from about the year 1780 onwards. In that year it was 42,832 ; in 1791 it was 66,578. I n t8ol it h a d increase d to 83,00o ; in i 8 i i to 11%ooo; in 182i to x47,ooo ; in i83r to 2o2,ooo, and so on. The area occupied by these populations was very small, the people living layer upon layer in high tenement houses closely built together. The date of the earliest description of the sanitary condition of the