Popular Science Monthly/Volume 57/July 1900/Preventive Inoculation II

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PREVENTIVE INOCULATION. (II.)
By Dr. W. M. HAFFKINE,

DIRECTOR-IN-CHIEF, GOVERNMENT PLAGUE RESEARCH LABORATORY, BOMBAY.

ON a previous paper I reviewed briefly the history of preventive inoculation and described the results of my attempts to secure a 'virus fixé' in the case of cholera. It will be remembered that the two vaccines finally obtained protected guinea pigs successfully against all possible forms of cholera infection.

It was now necessary to ascertain whether the same protection could be given to man which was observed in animals. For this purpose it was essential to first of all prove the perfect harmlessness of the operation. This was established by very careful observations of medical men and scientists who were inoculated in Europe soon after the results of the above investigations were published. The inoculation causes a rise of temperature and general discomfort, which lasts one or two days, and some pain at the seat of the injection, which disappears in a few days. The fever and discomfort induced are, on the whole, shorter in duration, though often more intense, than those caused by vaccination against smallpox. The effect disappears within a few days and the individual returns to his usual condition of health.

The next and all-important stage was to devise an experiment or a series of experiments on man so as to test the efficiency of the method against cholera attacks. This part of the investigation could only be done in a cholera-stricken country, where opportunities would arise of comparing the incidence of the disease in inoculated and uninoculated. Such opportunities are limited. Except in certain parts of India and China, cholera appears in localities unexpectedly and does not last long. In the places where the disease is endemic the cases are scattered over large areas. These features rendered the demonstration of the effect of the vaccine a matter of particular difficulty. In 1893 I went to India, and in the course of a year inoculated some twenty-three thousand people in the northern parts of the country; but no cholera appeared in their midst to show whether the vaccine was of value or not. In the spring of 1894 the inoculations were introduced into Bengal, and, with the assistance and co-operation of Prof. W. J. Simpson, of King's College, London, at that time Health Officer of Calcutta, and of his staff, efforts were made to induce the inhabitants of the bustees of Calcutta to get themselves inoculated. These bustees are isolated villages consisting of groups of mud huts inhabited by the poorer class. Owing to the consumption of water from the ponds or tanks belonging to these villages, the inhabitants of the bustees are subject to periodic visitations of cholera. It was in one of these bustees that the first observation was made as to the effect of the cholera vaccines.

The spring is essentially the cholera season in Calcutta. About the end of March two fatal cases of cholera and two cases of choleraic diarrhoea occurred in Katal Bagan Bustee, in a population grouped around two tanks. This outbreak led to the inoculation of one hundred and sixteen persons in the bustee out of about two hundred. After the inoculation there occurred nine more cases of cholera, seven of which proved fatal, and one case of choleraic diarrhoea. All the ten cases occurred among the uninoculated portion of the inhabitants, which formed the minority, none of the inoculated suffering. The results were more interesting when analyzed in detail. Some of the cases had occurred in families in which some of the members had been inoculated and others not, and the disease selected the non-inoculated members, sparing the inoculated. Thus, in one house six members out of eight had been inoculated. The attack, a fatal one, occurred in one of the remaining two. In another house eleven members out of eighteen were inoculated. The eleven members remained free while four out of seven not inoculated were attacked.

Upon these observations the Calcutta municipality felt encouraged to vote funds for the continuance of the inoculations in an experimental farm, and appointed for that purpose a special staff. In 1896 the result of two years' observations were embodied by the health officer in a report to the Calcutta Municipal Corporation. It recorded a most satisfactory state of affairs. During the time under observation some eight thousand persons were inoculated. Cases of cholera occurred in seventy-seven huts in which some members of the family had been previously inoculated and others not. Comparing the incidence of the disease in the two groups, a striking advantage was found to be with the inoculated. I made an analysis of the cases according to the time which had elapsed between inoculation in each of these huts and the occurrence of cholera in them, and the following results were found. During the first four days after inoculation, apparently before the vaccine had time to produce its full protective effect, there were proportionately 1.86 times fewer deaths among the inoculated than among the non-inoculated members of the families. In a second period, extending from the fifth to the four hundred and twenty-ninth day—i. e., for fourteen months—there were 22.62 times fewer deaths among the inoculated; while in the last period—that is, between the four hundred and thirtieth and seven hundred and twenty-eighth day after the inoculation—there were only 1.54 fewer deaths among the inoculated, the immunity having evidently gradually disappeared. The net result was that for two years after inoculation, including the periods of incomplete protection, there was a reduction in mortality of 72.47 per cent among the inoculated; or in other words, in houses in which inoculations were performed and in which cholera subsequently occurred there were, even from the day of inoculation, before the full effect of it could be produced, eleven deaths among the non-inoculated to only three among the inoculated. Eight lives out of every eleven were saved.

At the end of my first cholera campaign, in August, 1895, there were altogether 31,056 natives of India, 125 Eurasians, 869 Europeans of the civil population, 6,627 native officers and sepoys, and 291 officers with 3,206 men of the British troops stationed in India, in all 41,787 people, who had submitted to inoculation. Observations instituted among them, especially among prisoners, soldiers and coolies in tea estates, with regard to whom detailed records could be kept, went to confirm the results as detailed above. In order to lengthen, if possible, the period of immunity, the plan was formed of inoculating stronger vaccines and in higher doses. The inoculations are now carried on in a Government laboratory, in Purulia, Bengal, chiefly among the people emigrating to the cholera districts of Assam, and there is no doubt that in the course of time a marked effect upon the prevalence of cholera in those districts will be produced and valuable theoretical data will be obtained.

 

There was one noticeable feature about the results of the inoculation against cholera which early attracted my attention, and this was that while the number of attacks and the absolute number of deaths was strikingly influenced by the operation, the" proportion of deaths to those attacked did not appear to be changed. The case incidence was effectively checked, but the 'case mortality' was not reduced. The inoculation diminished the chances of an attack of cholera—that is, the chances of the cholera virus penetrating into the tissues of a man; but if it so happened that the patient was attacked and the virus found an entrance and started growing in the system notwithstanding the inoculation, the latter would not assist in mitigating the severity of the symptoms or reducing the fatality of the disease. In analyzing this result further, it seemed to me permissible to assume that the vaccine protected against the cholera microbes themselves, but did not protect against their poisonous products, which are the cause of the actual symptoms.

This interpretation of the facts found support in a-set of laboratory experiments by Professor Pfeiffer and Dr. Kolle, of Koch's Institute, in Berlin, who showed that the" blood serum of animals and persons inoculated with the cholera vaccine, as practiced in India, acquired an intense power of destroying cholera microbes, but exhibited no properties capable of counteracting the effect of their toxic products—no 'antitoxic properties.' Combined with those of previous experimenters these results tended to prove that two kinds of immunity could be produced separately, and it became incumbent to devise a plan which would secure not only a lowering of susceptibility to the disease, but also a reduction in the case mortality.

For that purpose it seemed rational to attempt the treatment with a vaccine containing a combination of bodies of microbes, together with their toxic products. I intended to test this plan experimentally in the cholera districts; but, plague having broken out in Bombay, the Government of India commissioned me to inquire into the bacteriology of that disease, and I determined that the knowledge gained in the cholera inoculations should be applied and tested in the preparation of a prophylactic against the new epidemic.

The experiments I had in view involved manufacturing a material on a large scale, and operating on it for weeks continuously. To do this it was essential to find a way of recognizing plague growth with certainty, so as to enable the officers engaged in the manufacture to control the process and know exactly when they were handling the proper stuff, and when an admixture and invasion of extraneous growth took place. When this was solved, a drug was prepared by cultivating the plague microbe in sterilized broth, to which a small quantity of clarified butter or of cocoanut oil had been added. The plague bacilli attach themselves to the drops of butter or oil floating on the surface, and grow down into the depth of the liquid, forming a peculiar threadlike appearance. While doing so they secrete toxic matter, which is gradually accumulated in the liquid; at the same time a large amount of microbial growth comes gradually down from the surface of the liquid and collects at the bottom of the flask. When shaken up the whole represents the desired combination of the bodies of microbes and of their toxic products. The process is continued for a period of five to six weeks. As the microbes of plague had been very little studied before, and as their exact effect on the human system was unknown, I decided not to use for the treatment living microbes, but to use at least at first 'carbolized' vaccines, though the result of the treatment might be less favorable or less lasting than that which could be expected from living vaccines. The microbes in the above plague growth were accordingly killed by heating them at a temperature ranging from 65° to 70° C, and then mixed with a small proportion of carbolic acid, to prevent the drug from subsequent contamination and decomposition. The dose of the prophylactic was regulated by measuring up the quantity to be injected. The requisite amount is determined by the degree of fever which it produces. The febrile reaction varies in different individuals, but a temperature reaching 102° and above in at least thirty per cent of those inoculated has been found to indicate a good material. In the cholera, rabies and smallpox vaccines, the microbes being employed in a living state, it was essential to fix the strength of the vaccine, for otherwise it was impossible to predict the behavior of the microbe when injected into the system. In the case of the plague prophylactic the activity of the microbes is arrested before it is inoculated, and the effect can be regulated, as mentioned above, by simply measuring up the doses in the same way as is done with any chemical drug.

The expectation formed when devising the plan for the plague prophylactic has been very fortunately justified, and an advance on the results from the cholera vaccines was obtained; but I can not yet say certainly whether this favorable result is indeed due to the particular provisions which I had made for obtaining it.

The effect of the plague prophylactic was first tested at the Byculla Jail, in Bombay, when the epidemic reached that establishment. From the first day after the inoculation till the end of the outbreak there were in the jail twelve cases and six deaths among one hundred and seventy-two uninoculated inmates, and two cases, with no deaths, among one hundred and forty-seven inoculated. A year later, almost exactly a similar result was observed when the plague attacked the so-called Umarkhadi Common Jail, in Bombay. In this case after the inoculation i here were ten cases and six deaths among one hundred and twenty-seven uninoculated inmates, and three cases, with no deaths, among one hundred and forty-seven inoculated. These and other observations show that the vaccine for the plague begins to exercise its effect within some twenty-four, hours after inoculation; that it is useful even in the case of persons already infected; that it is therefore applicable at any stage of an epidemic. Numerous* further observations were soon collected on the working of the system.

At the small village of Uudhera, of the Baroda feudatory state, where plague broke out, inoculation was applied to a half of each family, the other half remaining uninoculated. After that there were twenty-seven cases and twenty-six deaths among sixty-four uninoculated, and eight cases, with three deaths, among seventy-one inoculated of the same households, the proportionate difference in mortality being over eighty-nine per cent. There followed observations on a far larger scale, demonstrating that the mortality of the inoculated, compared to that of the non-inoculated, was on an average between eighty and ninety per cent less. Sometimes this reduction reached ninety per cent. In the Punjaub, in a village called Bunga, there occurred, in two hundred and eighty-one not inoculated, ninety-seven cases of plague and sixty-five deaths, while among seventy-four inoculated there were six cases, but no deaths. In Bangalore, among 80,285 of the inhabitants not inoculated, there were 2,208 deaths from plague, while among 23,537 inoculated there were only 108. The observations at Lanowli, Kirkee, Daman, Hubli, Dharwar, Gadag, in the Bombay Presidency, gave the same results. At Hubli over forty-two thousand inhabitants out of some fifty thousand were inoculated. In Bombay city, out of a population of 821,764, 157,256 have now undergone the i n< 'dilation. The work proceeds here at present at the rate of one thousand to eleven hundred inoculations a day.

From plague hospitals the returns show that among those of the attacked who were previously inoculated the mortality is reduced to less than one half of that among patients who were not inoculated. The property of reducing the case mortality thus appears to belong to the plague prophylactic in an unmistakable degree.

 

By the anti-cholera and anti-plague inoculation the methods of preventive treatment by means of cultivated bacteria and their products have been rendered, so to say, a part of the daily policy in human medicine. The usefulness and practicability of those methods have become clearly apparent, and steps have been taken to extend further the field of their application. On the ground of the experiments made with the typhoid bacillus in the Pasteur Institute in 1889-'93, and of the results obtained from the anticholera inoculation in India, I was able to induce Professor Wright, of the Pathological Laboratory in Net ley. whom I initiated in 1892 in the principles and technique of anti-cholera inoculation, to start a campaign of similar operations against typhoid among the British troops. The latter are stationed at different times of their service very nearly in all parts of the world, and yearly pay a very heavy tribute to that disease. The medical officers in charge of these troops pass through a course of training at Netley, and Professor Wright had rendered excellent services in connection with the cholera inoculations, by disseminating the knowledge of them among the probationers of the school. It seemed to me expedient, therefore, to start the typhoid inoculation also through the staff and pupils of that school. The following plan as to the preparation of the vaccine, and the way of carrying out the inoculation, was laid before Professor Wright. The typhoid bacillus was to be brought to a fixed stage of virulence by the inoculation in the peritoneal cavity of Guinea pigs, according to the exact rules prescribed for the anti-cholera inoculation. Once the virus was fixed, it was to be cultivated for twenty-four hours on a solid medium, and a first vaccine prepared by carbolizing that virus. As, however, the durability of the effect of carbolized vaccine alone was not known, this was to be followed up by the injection of a dose of the fixed living virus.

The inoculation was first to be made on volunteers among the physicians on probation at Netley; then on volunteers among the young officers of the army on the eve of their departure for the tropics; and then, with the approval of the military authorities, on volunteers among private soldiers. At the end of 1895, during my visit to England, I obtained from Sir William Mackinnon, then Director-General of the Army Medical Department, permission for Professor Wright to start the work upon the plan above detailed; and the first inoculations, in the way described above, were done in the middle of 1896. Soon after that, Pfeiffer and Kolle, recognizing the same similarity between the cholera and typhoid microbes, and pointing out that the results obtained by us in India were likely to be repeated when applying the method to typhoid, proposed and started a similar series of inoculations.

When the inoculation against plague was begun, and observation showed that dead vaccines alone were apparently sufficient to produce satisfactory results, a second inoculation with living virus appeared less urgently necessary; and as the effect of such an inoculation, which Professor Wright very courageously tried first on himself, seemed troublesome, it was decided to do for the time being the second inoculation also with the carbolized virus. Similarly, the plan which was adopted for the plague inoculation, of cultivating the vaccine in a liquid, instead of a solid medium, and of using cultures of several weeks' duration, has been subsequently adopted in the typhoid inoculation also.

Many thousands of British soldiers and civilians have already undergone the inoculation in question. The latter was done partly with vaccines cultivated on a solid medium, according to the older plan, and partly with vaccines prepared according to the plague inoculation method. The results so far observed are encouraging, and, I hope, will shortly be improved considerably. At the last Harveian dinner in London, Surgeon-General Jameson, Director-General of the Army Medical Department, summarized the results of the observations in India, where, among several thousands of young soldiers, the most prone to the disease, the incidence of typhoid since their inoculation was 0.7 per mille, while among the older, more resistant, not inoculated soldiers, the incidence was during the same period just double that. A large proportion of the force now on service in the South African campaign have been inoculated, some before embarking and others on their way out.

 

Such is the position of preventive inoculation, as applied, so far, to human communities. The very success of these operations is now apt to create some sort of feigned or earnest alarm, and one meets at present with the question, What is going to happen to our poor body if we are to be inoculated against all diseases? and with this other one, How do you expect us to make a living if you try to keep all of us alive? The humorous form of these questions usually permits of their dropping out of the conversation without a reply. The earnest answers are, however, obvious. The efforts of the bacteriologists in combating diseases are at present directed to a twofold aim: their prevention, by a prophylactic treatment, and their cure. The advantage of a curative treatment is that it is to be applied to a relatively small number of persons, to those who actually fall victims to an attack; while that of the preventive treatment is in the greater certainty with which safety and protection are secured by it. The relative position of the two treatments will, in practice, differ in different diseases—namely, according to the prevalence and fatality of a given disease, and according to the merits of the two treatments as they stand at the time. In diseases in which the risks of being attacked are smaller, or the consequences of an attack less serious, or for which a very effective and sure curative treatment has been discovered, the majority of people will prefer lo M r ait for an actual attack rather than to undergo the discomfort of a preventive treatment; in diseases, on the contrary, in which the chances of being attacked are great, or in which the fatality is higher, the sequels of an attack more serious, and for which a successful and not very troublesome preventive treatment has been found, large numbers will undergo preventive inoculation. But, even in the latter case, a mutual co-operation between the two methods will exist always, as there will always be a number of people, either among those who have neglected to protect themselves by inoculation, or among those in whom the inoculation has proved unsuccessful, who will fall victims to an attack and require the benefits of a curative treatment, be those at the time little or great.

The answer to the second question is of course to be expected rather from the politico-economist, the wise administrator, the civilian, than from the bacteriologist. In any case it is clear already that if we are ever to be told that we must thin our ranks, we shall prefer not to leave the task in the hands of the indiscriminating microbe, but to have some voice in the matter ourselves. Inoculation marks only the conquest of another force which henceforth we shall be glad to control.

Bombay, India, March, 1900.