Chapter VIII: Part II (3)

Pasteur's study of rabies began in 1880; and the date of the first case treated--Joseph Meister, a shepherd-boy of Alsace--is July 1885. The first part of the work was spent in a prolonged search for the specific microbe of rabies. It was not found: its existence is a matter of inference, but not of observation.[24] In his earlier inoculations, Pasteur made use of the saliva of rabid animals; and M. Valléry-Radot tells the story, how Pasteur took him on one of his expeditions:--

"The rabid beast was in this case a huge bull-dog, foaming at
the mouth and howling in his cage. All attempts to induce the
animal to bite, and so infect one of the rabbits, failed. 'But
we _must_,' said Pasteur, 'inoculate the rabbits with the
saliva.' Accordingly a noose was made and thrown, the dog
secured and dragged to the edge of the cage, and his jaws tied
together. Choking with rage, the eyes bloodshot, and the body
convulsed by a violent spasm, the animal was stretched on a
table, and kept motionless, while Pasteur, leaning over his
foaming head, sucked up into a narrow glass tube some drops of
the saliva."

[24] This sentence was written before the publication of Professor
Negri's observations (see _Medical Annual_, 1906, p. 418).

But these inoculations of saliva sometimes failed to produce the disease; and, when they succeeded, the incubation-period was wholly uncertain: it might be some months before the disease appeared. Thus Pasteur was led to use, instead of the saliva, an emulsion of the brain or spinal cord; because, as Dr. Duboué had suggested, the central nervous system is the chief seat, the _locus electionis_, of the virus of rabies. But these inoculations also were not always successful, nor did they give a definite incubation-period.

Therefore he followed with rabies the method that he had followed with anthrax. As he had cultivated the virus of anthrax, by putting it where its development could be watched and controlled, so he must put the virus of rabies in the place of its choice. It has a selective action on the cells of the central nervous system, a sort of affinity with them; they are, as it were, the natural home of rabies, the proper nutrient medium for the virus: therefore the virus must be inoculated not under the skin, but under the skull.

These sub-dural inoculations were the turning-point of Pasteur's discovery. The first inoculation was made by M. Roux:--

"Next day, when I informed Pasteur that the intracranial
inoculation offered no difficulty, he was moved with pity for
the dog. 'Poor beast, his brain is doubtless injured: he must be
paralysed.' Without reply I went down to the basement to fetch
it, and let it come into the laboratory. Pasteur did not like
dogs, but when he saw this one, full of life, inquisitively
rummaging about in all directions, he exhibited the greatest
delight, and lavished most charming words upon it."

Henceforth all uncertainty was at an end, and the way was clear ahead: Pasteur had now to deal with a virus that had a definite period of incubation, and a suitable medium for development. The central nervous system was to the virus of rabies what the test-tube was to the virus of fowl-cholera or anthrax. As he had controlled these diseases, had turned them this way and that, attenuated and intensified them, so he could control rabies. By transmitting it through a series of rabbits, by sub-dural inoculation of each rabbit with a minute quantity of nerve-tissue from the rabbit that had died before it, he was able to intensify the virus, to shorten its period of incubation, to fix it at six days. Thus he obtained a virus of exact strength, a definite standard of virulence, _virus fixe_: the next rabbit inoculated would have the disease in six days, neither more nor less.

As he was able to intensify the virus by transmission, so he was able to attenuate it by gradual drying of the tissues that contained it. The spinal cord, taken from a rabbit that has died of rabies, slowly loses virulence by simple drying. A cord dried for four days is less virulent than one that has been dried for three, and more virulent than one dried for five. A cord dried for a fortnight has lost all virulence: even a large dose of it will not produce the disease. By this method of drying, Pasteur was enabled to obtain the virus in all degrees of activity: he could always keep going one or more series of cords, of known and exactly graduated strengths, according to the length of time they had been dried--ranging from absolute non-virulence through every shade of virulence.

And, as with fowl-cholera and anthrax, so with rabies; a virus which has been attenuated till it has been rendered innocuous, can yet confer immunity against its more virulent forms: just as vaccination can protect against smallpox. A man, bitten by a rabid animal, has at least some weeks of respite before the disease can break out; and, during that time of respite, he can be immunised against the disease, while it is still dormant: he begins with a dose of virus attenuated past all power of doing harm, and advances day by day to more active doses, guarded each day by the dose of the day before, till he has manufactured within himself enough antitoxin to make him proof against any outbreak of the disease.

The cords used for treatment are removed from the bodies of the rabbits, by an aseptic method, and are cut into lengths and hung in glass jars, with some chloride of calcium in them, for drying. The jars are dated, and then kept in glass cases in a dark room at a constant temperature. To make sure that the cords are aseptic, a small portion of each cord is sown on nutrient jelly in a test-tube, and watched, to see that no bacteria occur in the tube. For each injection, a certain small quantity of cord is rubbed-up in sterilised fluid; and these subcutaneous injections give no pain or malaise worth considering.

Of course, the treatment is adjusted to the gravity of the case. A bite through naked skin is more grave than a bite through clothing; and bites on the head or face, and wolf-bites, are worst of all. The number and character of the scars are also taken into account. An excellent description of the treatment, by a patient, was published in the _Birmingham Medical Review_ of January 1898. It gives the following tables of treatment:--

1. _Ordinary Treatment._

Day of Days of Drying
Treatment. of Cord.
1 14 and 13
2 12 and 11
3 10 and 9
4 8 and 7
5 6
6 6
7 5
8 4
9 (1/2 dose) 3
10 (full dose) 5
11 5
12 4
13 4
14 (1/2 dose) 3
15 (full dose) 3

2. _Cases of Moderate Gravity._

Same treatment, up to 13th day.

Day of Days of Drying
Treatment. of Cord.
14 3
15 5
16 4
17 (1/2 dose) 3
18 (full dose) 3

3. _Grave Cases._

Same treatment, up to 10th day.

Day of Days of Drying
Treatment. of Cord.
11 4
12 3
13 5
14 5
15 4
16 4
17 (1/2 dose) 3
18 (full dose) 3
19 5
20 3
21 4
22 3

4. _Very Grave Cases._

Same treatment as 3, and in addition.

Day of Days of Drying
Treatment. of Cord.
23 5
24 4
25 (1/2 dose) 3
26 (full dose) 3

Furious criticism, unbelief, and flagrant misstatement of facts began at once, and lasted more than two years. Of Pasteur's opponents, the chief was M. Peter, who besought the Académie des Sciences, about once a week, that they should close Pasteur's laboratory, because he was not preventing hydrophobia but producing it. The value of M. Peter's judgment may be estimated by what he had said, a few years earlier, about bacteriology in general--"I do not much believe in that invasion of parasites which threatens us like an eleventh plague of Egypt. After so many laborious researches, nothing will be changed in medicine, there will only be a few more microbes. M. Pasteur's excuse is that he is a chemist, who has tried, out of a wish to be useful, to reform medicine, to which he is a complete stranger."

But it does not matter what was said twenty years ago. In England, the Report of the 1886 Committee, and the Mansion House meeting in July 1889, mark the decline and fall of all intelligent opposition to the work. Among so many thousand cases, during so many years, it would be a miracle indeed if not a single case had failed or gone amiss; but we are concerned here with the thousands. Take, to begin with, four reports from Athens, Palermo, Rio, and Paris. It is to be noted that the patients, alike at Paris and at other Institutes, are divided into three classes:--

"A. Bitten by animals proved to have been rabid by the
development of rabies in other animals inoculated from them.

"B. Bitten by animals proved to have been rabid by dissection of
their bodies by veterinary surgeons.

"C. Bitten by animals suspected to have been rabid."

It is to be noted also, as a fact proved beyond doubt, that the full benefit of the treatment is not obtained at once; the highest degree of immunity is reached about a fortnight after the discontinuance of the treatment. Those few cases, therefore, where hydrophobia has occurred, not only in spite of treatment, but within a fortnight of the last day of treatment, are counted as cases where the treatment came too late.

Finally, what was the risk from the bite of a rabid animal, in the days before 1885? It is a matter of guess-work. One writer, and one only, guessed it at 5 per cent.; another guessed it at 55, and a third came to the safe conclusion that it was "somewhere between these limits." Leblanc, who is probably the best guide, put it at 16; and Pasteur himself put it between 15 and 20. But suppose it were only 10; that, before Pasteur, out of every 100 men bitten by rabid animals, 90 would escape and only 10 would die of hydrophobia; then take this fact, that in one year, at one Institute alone, there were 142 patients in class A, bitten by animals that were proved, by the unanswerable test of inoculation, to have been rabid; and 1 death. And every year the same thing; and in all the twelve years together, 2872 such cases (A) and 20 deaths--a mortality not of 10 per cent., but of less than 1 per cent.

1. _Athens_

The _Annales de l'Institut Pasteur_, June 1898, contain Dr. Pampoukis' report of three years' work at the Hellenic Institute, from August 1894 to December 1897. During this period 797 cases were treated--590 male and 207 female. The animals that bit them were--dogs, 732; cats, 34; wolf, 1; other animals, 13; and the 17 other patients had been exposed to infection from the saliva of hydrophobic patients. Of the 797 cases, 245 were of class A, 112 B, and 440 C.

"Among the 797 persons treated, there are 2 deaths, one in class B and the other in class C. Thus the mortality has been 0.25 per cent. Besides these 2 who died of rabies there are 5 more, in whom the first signs of rabies showed themselves in less than fifteen days after the last inoculation.

"Finally, beside these 797 cases, there is 1 other case, bitten by a wolf, in which the treatment failed. If we reckon this last case in the statistics of mortality, we have 3 deaths in 798 cases = 0.37 per cent.

"Beside these 798 cases treated at the Institute, there have been others that have not undergone the antirabic treatment, having trusted the assurances of those who are called in Greece _empirics_. Among these non-treated cases there are 40 who have died of rabies."

2. _Palermo_

The _Annales_ for April 1896 give the report by Dr. de Blasi and Dr. Russo-Travali of the work of the Municipal Institute at Palermo during 8-1/2 years, from March 1887 to December 1895. The number of cases was 2221; in 1240 (class A), the animals were proved to have been rabid by the result of inoculations; in 981, there was reason to suspect rabies.

"Setting aside 5 patients who died during the course of the treatment, and 5 others who died less than fifteen days after the end of the treatment, we have had to deplore only 9 failures = 0.4 per cent. Even if we count against ourselves the 10 other cases, the mortality is still only 0.85."

3. _Rio de Janeiro_

The _Annales_ for August 1898 give Dr. Ferreira's report of ten years' work (February 1888 to April 1898) at the Pasteur Institute at Rio. The number of cases treated was 2647, of whom 1987 were male and 660 female. Beside these 2647 there were 1234 who were not treated, because it was ascertained that they were in no danger of rabies; 3 who were brought to the Institute, already suffering from the disease; and 59 who refused treatment.

Of the 2647 persons treated, 10 had pricked their hands at work in the laboratory, 3 had exposed chance scratches on their hands to the saliva of rabid animals, and 1 had been bitten by a rabid patient. Of the rest, 1886 had been bitten on the bare skin, and 747 through clothing.

In 236 cases the rabies of the animal had been proved by inoculation. In 1173 it had been recognised by the signs of the disease. In 1238 there was good reason to suspect that the animal had been rabid.

Of the 2647 patients, in 30 cases the treatment was stopped, because the animals were at last traced, after treatment was begun, and were found not to be rabid. In 65 cases the patients, after treatment was begun, refused to go on with it, and 3 of them died of rabies. In 6 cases rabies developed during treatment; 5 of them had been very badly bitten about the head, and 1 did not come for treatment till the twenty-first day after the bite, and was attacked by rabies two days later. And 5 cases died of other maladies that had nothing to do with rabies. Setting aside these 106 cases, there remain 2541 cases, with 20 deaths = 0.78 per cent. But, of these 20 deaths, 9 occurred within fifteen days of the end of treatment, before protection was fully established. If these 9 deaths be excluded, the figures stand at 2532 cases, with 11 deaths = 0.43 per cent.

4. _Paris_

Dr. Pottevin's report on the work of the Pasteur Institute (Paris) during 1897 (_Annales_, April 1898) must be given word for word, without abbreviation.

I

During 1897, 1521 patients received the anti-treatment at the Pasteur Institute: 8 died of rabies. The notes of their cases will be found at the end of this paper.

If we exclude 2 of these 8 cases--the cases of Heniquet and Morin, where death occurred before it was possible for the vaccinations to produce their effect--the results of the vaccinations in 1897 are

Patients treated 1519
Deaths 6
Mortality per cent. 0.39

In the following table these figures are compared with those of preceding years:--

+-------+----------+---------+-----------+
| Year. | Patients | Deaths. | Mortality |
| | treated. | | per cent. |
+-------+----------+---------+-----------+
| 1886 | 2671 | 25 | 0.94 |
| 1887 | 1770 | 14 | 0.79 |
| 1888 | 1622 | 9 | 0.55 |
| 1889 | 1830 | 7 | 0.38 |
| 1890 | 1540 | 5 | 0.32 |
| 1891 | 1559 | 4 | 0.25 |
| 1892 | 1790 | 4 | 0.22 |
| 1893 | 1648 | 6 | 0.36 |
| 1894 | 1387 | 7 | 0.50 |
| 1895 | 1520 | 5 | 0.33 |
| 1896 | 1308 | 4 | 0.30 |
| 1897 | 1521 | 6 | 0.39 |
+-------+----------+---------+-----------+

II

Patients treated at the Pasteur Institute are divided into three classes, as follows:--

A. The rabies of the animal was proved by experiment, by the development of rabies in animals inoculated with its bulb (the upper end of the spinal cord).[25]

[25] It is satisfactory to know that rabbits affected with rabies
do not suffer in the same way as dogs and some other animals, but
become subject to a painless kind of paralysis.

B. The rabies of the animal was proved by veterinary examination (dissection of its body).

C. The animal was suspected of rabies.

We give here the patients treated in 1897, under these three classes:--

+------------------+---------------+---------------+---------------+
| BITES OF THE | BITES ON THE | BITES OF THE | TOTAL. |
| HEAD. | HANDS. | LIMBS. | |
+--+-----+---+-----+-----+---+-----+-----+---+-----+-----+---+-----+
| | P | | M p | P | | M p | P | | M p | P | | M p |
| | a | D | o e | a | D | o e | a | D | o e | a | D | o e |
| | t | e | r r | t | e | r r | t | e | r r | t | e | r r |
| | i | a | t | i | a | t | i | a | t | i | a | t |
| | e | t | a c | e | t | a c | e | t | a c | e | t | a c |
| | n | h | l e | n | h | l e | n | h | l e | n | h | l e |
| | t | s | i n | t | s | i n | t | s | i n | t | s | i n |
| | s | . | t t | s | . | t t | s | . | t t | s | . | t t |
| | . | | y . | . | | y . | . | | y . | . | | y . |
+--+-----+---+-----+-----+---+-----+-----+---+-----+-----+---+-----+
| A| 15 | 0 | 0 | 81 | 0 | 0 | 46 | 1 | 2.1 | 142 | 1 | 0.7 |
| B| 106 | 0 | 0 | 539 | 4 | 0.74| 273 | 1 | 0.4 | 918 | 5 | 0.65|
| C| 30 | 0 | 0 | 244 | 0 | 0 | 187 | 0 | 0 | 461 | 0 | 0 |
+--+-----+---+-----+-----+---+-----+-----+---+-----+-----+---+-----+
| | 151 | 0 | 0 | 864 | 4 | 0.46| 506 | 2 | 0.4 |1521 | 6 | 0.39|
+--+-----+---+-----+-----+---+-----+-----+---+-----+-----+---+-----+

The following tables, giving the results obtained since the vaccinations were first used, show that the gravity of the bites varies with their position on the body, and that the mortality is always below 1 per cent. among patients bitten by dogs undoubtedly rabid:--

+-------------------+---------+-------+----------+
| |Patients.|Deaths.|Mortality.|
+-------------------+---------+-------+----------+
|Bites of the Head | 1,759 | 21 | 1.1 |
|Bites of the Hands | 11,118 | 53 | 0.47 |
|Bites of the Limbs | 7,289 | 22 | 0.30 |
+-------------------+---------+-------+----------+
| | 20,166 | 96 | 0.46 |
+-------------------+---------+-------+----------+

+---+---------+-------+----------+
| |Patients.|Deaths.|Mortality.|
+---+---------+-------+----------+
| A | 2,872 | 20 | 0.69 |
| B | 12,547 | 61 | 0.48 |
| C | 4,747 | 15 | 0.31 |
+---+---------+-------+----------+
| | 20,166 | 96 | 0.46 |
+---+---------+-------+----------+

III

In regard to their nationality, the 1521 patients treated at the Pasteur Institute in 1897 were as follows:--

Germany 8
England 83
Belgium 14
Egypt 2
United States 1
Greece 1
India 33
Switzerland 33

That is, 175 foreigners and 1346 French.

IV

Notes of the eight cases where the treatment failed:--

1. Camille Bourg, 26. Bitten 11th April; treated at the Pasteur Institute, 13th to 30th April; died of rabies at the Lariboisière Hospital, 26th May. Six penetrating bites on the ball of the left thumb. The dog was examined by M. Grenot, a veterinary surgeon at Paris, and the dissection gave evidence of rabies. Another person bitten and treated at the same time as Bourg is now in good health.

2. Louis Fiquet, 23. Bitten 22nd April; treated at the Pasteur Institute, 23rd April to 10th May; died of rabies at the Necker Hospital, 4th June. Five bites, two of them deep, round the right thumb. They had been cauterised five hours after infliction. The dog was examined by M. Caussé, a veterinary surgeon at Boulogne, and the dissection gave evidence of rabies. Another person bitten at the same time as Fiquet is now in good health.

3. Annette Beaufort, 19. Licked on the hands, which were chapped, on 15th April. The dog was killed next day, examined, and declared to have been rabid by M. Lachmann, a veterinary surgeon at Saint-Étienne. Treated at the Pasteur Institute, 20th April to 7th May. Died of rabies 14th October. Two other persons bitten by the same dog and treated at the Pasteur Institute are now in good health.

4. Julien Heniquet, 53. Bitten 11th March, by a dog that M. Jenvresse, veterinary surgeon at Beaumont-sur-Oise, declared after dissection to have been rabid. One bite had torn the lower lip, the wound had been sutured; three other wounds on the nose. The wounds had not been cauterised. Treated at the Pasteur Institute, 18th May to 5th June. First symptoms of rabies showed themselves 4th June, before the treatment was finished; died 7th June. As the disease had its onset during the course of the inoculations, this case should be excluded from the number of those who died of rabies after treatment.

5. Germain Segond, 7. Penetrating bite on the bare right fore-arm, 23rd May. Cauterised an hour later with a red-hot iron. Treated 26th May to 9th June; died of rabies 22nd July. The dog's bulb had been sent to the Pasteur Institute. A guinea-pig inoculated in the eye 26th May was seized with rabies 10th September.

6. Suzanne Richard, 8. Bitten 12th June on the left leg by a dog, found on dissection to have been rabid by M. Touret, veterinary surgeon at Sannois. The bite, penetrating 3 cm. long, had been sutured; it had been made through a cotton stocking, and had been cauterised in half-an-hour. Treated 13th to 30th June; died of rabies 2nd August. (Notes from M. le Dr. Margny, at Sannois.)

7. Joseph Vaudale, 33. Bitten on the left hand, 8th August. Six penetrating bites on the back of the hand; had not been cauterised. The dog was declared rabid by M. Verraert, veterinary surgeon at Ostend. Treated at the Pasteur Institute, 11th to 28th August; died of rabies 27th September.

8. Paul Morin, 38. Bitten 24th August on the left cheek, a single bite, 2 cm. long; no cauterisation. The dog was sent to the Alfort School, 25th August, and found to be rabid. Treated at the Pasteur Institute, 26th August to 15th September. Died of rabies some days after the end of treatment (three weeks after the bite, says a note sent to us). The interval between the end of the treatment and the onset of the disease being less than fourteen days, Morin must not be counted in the number of patients inoculated under conditions which permit successful inoculation.

* * * * *

We hardly need follow the work of the remaining years. The figures are as follows:--

+-------+----------+---------+-----------+
| Year. | Patients | Deaths. | Mortality |
| | treated. | | per cent. |
+-------+----------+---------+-----------+
| 1898 | 1465 | 3 | 0.2 |
| 1899 | 1614 | 4 | 0.25 |
| 1900 | 1420 | 4 | 0.28 |
| 1901 | 1318 | 5 | 0.38 |
| 1902 | 1105 | 2 | 0.18 |
| 1903 | 628 | 2 | 0.32 |
| 1904 | 755 | 3 | 0.39 |
+-------+----------+---------+-----------+

The falling off in the number of patients at the Paris Institute is related to the establishment of similar Institutes at Lyon, Marseilles, Bordeaux, Lille, and Montpellier. But is it not possible that a patient, after treatment at the Paris Institute, should die at home of rabies, and his death not be notified to the Institute? The answer is, that the Institute is very careful, so far as possible, to keep in touch with its old patients. For instance, in 1903, it recorded the case of a carpenter in a Welsh village, who had died of rabies nearly two years after treatment. And, of course, an Institute patient, wherever he was, would be of interest to his neighbours: and a death from rabies would excite attention, and would hardly fail to be reported.

It is not impossible that some sort of intensive modification of Pasteur's treatment may be found, not for the prevention, but for the cure of hydrophobia; and two successful cases of this kind have been reported in the _Annales_ of the Paris Institute. Apart from this faint hope, the _cure_ of hydrophobia is where it was in the days of the "Tonquin medicine" and the "Tanjore pills."

VII

CHOLERA

The study of cholera was the hardest of all the hard labours of bacteriology; it took years of work in all parts of the world, and the difficulty and disappointments over it are past all telling. Koch's discovery of the comma-bacillus (1883) raised a thousand questions that were solved only by infinite patience, international unity for science, and incessant research; and the Hamburg epidemic (1892) marks the time when the comma-bacillus was at last recognised as the cause of cholera. A mere list of the men who did the work would fill page after page; it was bacteriology _in excelsis_, often dangerous,[26] and always laborious.

[26] "In order to prove that this _vibrio_ is the cause of Asiatic
cholera, several tests upon themselves have been voluntarily made
by investigators in laboratories. These were carried out in Munich
and in Paris. The results to the experimenters were sufficiently
severe to indicate positively the pathogenic character of the
spirillum, and its capacity to produce cholera-like infections.
Such experimentation is, of course, to be deprecated; indeed, the
occurrence of accidental laboratory infections, one of which ended
fatally, furnished the necessary final proof of the specificity of
the cholera _vibrio_, and rendered unnecessary any exposure to the
risks belonging to voluntary inoculation." (Dr. Flexner, Stedman's
_Twentieth Century Practice_, vol. xix., 1900.)

There is the same heroic note in the story of the preventive treatment of cholera by Haffkine's method; one of the men in whom Pasteur seems to live again. He began in 1889, under Pasteur's guidance, to study the immunisation of animals against the cholera-bacillus. Other men, of course, were working on the same lines--Pfeiffer, Brieger, Metchnikoff, Fischer, Gamaleïa, Klein, Wassermann, and many more--and by 1892 the immunisation of animals was proved up to the hilt. Then came the advance from animals to men, from laboratories to Indian cities, villages, and cantonments; and here the honour is Haffkine's, and his alone. Ferran's inoculations (Spain, 1885) had failed. Haffkine, having tested his method on himself and his friends, went to India, with a commendatory letter from the British Government:--

"Researches on cholera, with special reference to inoculation,
were undertaken and carried on in my laboratory, in the Pasteur
Institute in Paris, between 1889 and 1893. The experiments
resulted in the elaboration of the present method, which when
tried on animals was found to render them resistant against
every form of cholera-poisoning otherwise fatal to them.

"The physiological and pathological effect on man was then
studied on some sixty persons, mostly medical and scientific men
interested in the solution of the problem. The effect was found
to be harmless to health. The next step was to transfer the
operations to the East." (Haffkine's _Report to the Government
of India_, 1895.)

He reached Calcutta in March 1893, and at the request of Mr. Hankin[27] was invited to Agra; here, in April, he vaccinated over 900 persons, including many English officers. From Agra to Aligarh; and from Aligarh he was asked to more places than he could visit. In 1895 his health failed, and no wonder; and he came back to Europe for a short time:--

"My actual work in India lasted twenty-nine months, between the
beginning of April 1893 and the end of July 1895. During this
period the anti-cholera vaccination has been applied to 294
British officers, 3206 British soldiers, 6629 native soldiers,
869 civil Europeans, 125 Eurasians, and 31,056 natives of India.
The inoculated people belonged to 98 localities in the
North-West Provinces and Oudh, in the Punjab, in Lower Bengal
and Behar, in the Brahmaputra Valley, and in Lower Assam. No
official pressure has been brought on the population, and only
those have been vaccinated who could be induced to do so by free
persuasion. In every locality, efforts were made to apply the
operation on parts of large bodies of people living together
under identical conditions, in order to compare their resistance
in outbreaks of cholera with that of non-inoculated people
belonging to the same unit of population. This object has been
obtained in 64 British and native regiments, in 9 gaols, in 45
tea-estates, in the fixed agricultural population of the
villages parallel to Hardwâr pilgrim road, in the _bustees_ of
Calcutta, in a certain number of boarding-schools, where the
parents agreed to the inoculation of their children, in
orphanages, etc. The vast majority of inoculated people lived
thus under direct observation of the sanitary and medical
authorities of India." (Haffkine, Lecture in London. _British
Medical Journal_, 21st Dec. 1895.)

[27] Mr. Hankin, whose name is had in remembrance by Cambridge
men, is Chemical Examiner and Bacteriologist to the North-West
Provinces and Oudh, and to the Central Provinces.

Altogether, upwards of 70,000 injections on 42,179 people--_without having to record a single instance of mishap or accident of any description produced by our vaccines_. Consider the colossal difficulties of this new treatment: the frequent running short of the vaccine, preventing a second injection; the absolute necessity, at first, of using very small doses of a weak vaccine, lest one disaster should occur; the impossibility of avoiding, now and again, some loss of strength in the vaccine; the impossibility of knowing how long the protection would last. Surely in all science there is nothing to beat this first voyage of adventure single-handed to fight the cholera in India.

Later than Haffkine's 1895 report, we have Dr. Simpson's 1896 report: "_Two Years of Anti-choleraic Inoculations in Calcutta._ W. J. Simpson, M.D., M.R.C.P., D.P.H., Health Officer, Calcutta." The date of this report is 8th July 1896; and it gives not only the Calcutta results, but all that are of any use for exact judgment:[28]--

"The results of Calcutta are fully confirmed by those obtained
in other parts of India, wherever it was possible to make all
the necessary observations with precision, and wherever the
cases were sufficiently numerous to show the effect of the
inoculation.

"Outside Calcutta, since the commencement of the inoculations in
India in April 1893, opportunities for an exact comparison of
the respective powers of resistance against cholera of
inoculated and non-inoculated persons presented themselves; (1)
in Lucknow, in the East Lancashire Regiment; (2) in Gaya, in the
jail; (3) in Cachar, among the tea-garden coolies; (4) in
Margherita, among coolies of the Assam-Burmah Railway Survey;
(5) in Durbhanga, in the jail; (6) in the coolie camp at
Bilaspur; (7) in Serampur, among the general population."

[28] For a summary of this report, see the _Lancet_, 8th August
1896. For more recent results, see Surgeon-Captain Vaughan and
Assistant-Surgeon Mukerji, in the thirtieth annual report of the
Sanitary Commissioner for Bengal (1897). Also the note published
by Surgeon-Captain Nott, in the _Indian Medical Gazette_, May
1898.

Here, then, in this 1896 report, are all the results that give an answer to the question, What will happen when cholera breaks out among a number of people living under the same conditions, of whom some have received preventive treatment, and the rest have been left to Nature?

I. _Calcutta_ (1894-1896)

"The number of people inoculated during the period under review
was 7690; of these, 5853 are Hindus, 1476 Mahomedans, and 361
other classes.... Considering that the system is a new one, that
the inoculations are purely voluntary, and everything connected
with them has to be explained before the confidence of the
people can be obtained, and considering how long new ideas are
in taking root among the general population--and in this case it
is not merely the acceptance of an idea, but such faith in it as
to consent to submit to an operation--the number is certainly
satisfactory for a beginning. The present problem can be
compared with the introduction of vaccination against smallpox
into Calcutta. It took 25 years before the number of
vaccinations reached an average of 2000; whereas the
inoculations against cholera have in two years nearly doubled
that average. This is a proof that, in spite of the difficulties
which every new movement naturally has to meet with, there are
large numbers of people anxious to avail themselves of the
protective effect of the inoculations.

"Although all sorts and conditions of individuals, weak and
strong, sickly and healthy, young and old, well nourished and
badly nourished, and often persons suffering from chronic
diseases, have been inoculated, in every instance, without
exception, the inoculations have proved perfectly harmless.

"The investigations on the effect of the inoculation are made
exclusively in those houses in which cholera has actually
occurred, the object being to ascertain and compare the
incidence of cholera on the inoculated and not inoculated in
those houses in which inoculations had been previously carried
out. _For this purpose, affected houses in which inoculations
have not been performed, and inoculated houses in which cholera
has not appeared, are excluded._"

Nature gave a demonstration in 77 houses. In one house, and one only, all the household had been inoculated; in 76, inoculated and non-inoculated were living together; but of these 76 houses, 6 are excluded from the table of results, because the inoculated in them were so few--less than one-tenth of the household--that their escape from cholera might be called chance. The cholera came, and left behind it this fact:--

654 uninoculated individuals had 71 deaths = 10.86 per cent.

402 inoculated in the same households had 12 deaths = 2.99 per
cent.

If we add the 6 houses which Dr. Simpson excludes, we find that in 77 houses there were 89 deaths from cholera, 77 being among the uninoculated and 12 among the inoculated.

Moreover, of these 12 deaths, 5 occurred during the first five days after inoculation--that is to say, during the period in which the protective influence of the vaccine was still incomplete. _Then came a period of more than a year, during which the uninoculated had 42 deaths, and the inoculated had one death._ The remaining 6 of the 12 deaths occurred more than a year after inoculation, and 5 of these 6 had received only one inoculation of the weak vaccine that was used early in 1894.

Take a good instance that came at the very beginning of the work:--

"A local epidemic took place around two tanks in Kattal Began
_bustee_, ward 19, occupied by about 200 people. In this _bustee_,
about the end of March, 2 fatal cases of cholera and 2 cases of
choleraic diarrhoea occurred. The outbreak led to the inoculation
of 116 persons in the _bustee_ out of the 200. Since then, 9 cases
of cholera, of which 7 were fatal, and 1 case of choleraic
diarrhoea have appeared in the _bustee_, and it is a very
extraordinary fact that all these 10 cases of cholera have occurred
exclusively among the uninoculated portion of the inhabitants,
which, as stated, forms the minority in the _bustee_; while none of
the inoculated have been affected." (_Cholera in Calcutta in 1894._
W. J. Simpson.)

2. _Lucknow_ (1893)

The story of the outbreak of cholera in the East Lancashire Regiment must be read carefully:--

"Rumour magnified the events connected with this outbreak, and
distorted the facts connected with the inoculations; and as a
result, the current of public opinion, which had previously been
in favour of inoculation, set in strongly in the opposite
direction. The advocates of anti-choleraic inoculations were
abused in no particularly measured terms, and the inoculations
were held up to be the source of every possible evil and danger
... of the most loathsome diseases, and of every ill which man
is heir to. The distrust engendered by these misrepresentations
and fulminations was, however, only of a temporary nature; and
when the exact circumstances came to be known and understood,
the confidence created by the Calcutta experience began to be
considerably restored. Inoculations were performed in May 1893,
in the East Lancashire, Royal Irish, 16th Lancers, 7th Bengal
Infantry, 7th Bengal Cavalry, and general populations in the
Civil Lines. In 1894, cholera appeared among the native
population of Lucknow, in the form of an epidemic distinguished
by its extreme virulence, patients succumbing in the course of
a few hours. It is stated that the epidemic was of a most
malignant type. In the latter part of July it entered the
cantonments, and attacked the East Lancashire, almost
exclusively confining its ravages to that regiment."

In the East Lancashire, 185 men were inoculated in May 1893. From the statistical returns obtained from the military authorities at Lucknow, it appears that at the time of the outbreak, in July 1894, the strength of the men, including those in hospital, was 773; and of these, 133 had been inoculated, as recorded in the inoculation register, and 640 had not been inoculated.

The following table shows the total number of attacks and deaths in not inoculated and inoculated:--

+---------------------+-------------+------------+
| | Attacks. | Deaths. |
+---------------------+-------------+------------+
| | Per cent. | Per cent. |
| Non-inoculated, 640 | 120 = 18.75 | 79 = 12.34 |
| Inoculated, 133 | 18 = 13.53 | 13 = 9.7 |
+---------------------+-------------+------------+

The men were moved into camp; but this movement seemed only to make things worse: "the epidemic in the camp appears to have been twice as severe as in the cantonment."[29]

[29] "The moving into camp, notwithstanding this example, is all
the same an excellent measure of defence, and would with reason be
adopted in every outbreak." (Simpson, _loc. cit._)

Lucknow came so early in the work of inoculation, that weak vaccines were used in small doses. The cholera, when it broke out, was "of a most malignant type, senior medical officers of long experience in the country stating that such a virulent cholera had not been seen by them for very many years past." More than a year had elapsed between the inoculations and the outbreak of the cholera. It is no wonder that the regiment was not well protected:--

"The small amount of protection which the inoculations afforded
in this case may have depended on the mild effects which the
injections produced on the men at the time of the operation in
1893, in comparison with the severity of the epidemic which
attacked the regiment. It is recorded in the Lucknow Inoculation
Registers that only in two men, out of the 185 inoculated in
1893, a marked febrile reaction was obtained; in 77 individuals
the vaccinal fever was only slight, while in 66 there was no
reaction: an effect which was due to the weakness of the
vaccines procurable at that period of work, and to the small
doses used. The influence of the vaccines was possibly further
reduced, at the time of the epidemic, by a lapse of fourteen to
fifteen months." (Haffkine, 1895 Report.)

3. _Gaya Jail_

On 9th July 1894, an outbreak of cholera occurred in the Gaya jail, and by 18th June there had been 6 cases and 5 deaths. On that day and the next day, 215 prisoners were inoculated. The average number of the prisoners during the outbreak was 207 inoculated, and 202 not inoculated. Surgeon-Major Macrae, superintendent of the jail, reports:--

"The inoculations being purely voluntary, no selection of
prisoners was possible, but all classes of the jail were
represented--male and female, old and young, habituals and less
frequent offenders, strong and weakly, convalescent and even
hospital patients sent their representatives; no difference of
any kind was made between inoculated and non-inoculated; they
were under absolutely identical conditions as regards food,
water, accommodation, etc., in fact in every possible respect."

Of course, the best results could hardly be obtained, because the cholera was already at work: it took about ten days for the 1894 vaccine to produce its full effect; and two inoculations were generally made, one five days after the other. This gradual action of the vaccine is well shown in Dr. Simpson's table:--

+-------------------------+------------------+------------------+
| | NON-INOCULATED, | INOCULATED, |
| | 202. | 207. |
+-------------------------+------------------+------------------+
| | Cases. | Deaths. | Cases. | Deaths. |
+-------------------------+--------+---------+--------+---------+
| During 5 days after 1st | 7 | 5 | 5 | 4 |
| inoculation | | | | |
| During 3 days after 2nd | 5 | 3 | 3 | 1 |
| inoculation | | | | |
| After 3 days after 2nd | 8 | 2 | 0 | 0 |
| inoculation | | | | |
+-------------------------+--------+---------+--------+---------+

Haffkine's comment on these figures must be noted here:--

"In the Gaya jail, the inoculations were _for the first time_
applied _in a prevalent epidemic_, and _very weak doses_ of a
relatively weak vaccine were used.... Far higher results have
been obtained by an application of stronger doses. In the
_bustees_ situated round the tanks in Calcutta, where cholera
exists in a permanent state, the disease occurred in 36 houses
with inoculated people. In each of these houses there was one
part of the family inoculated and another not. The observations
were continued for 459 days, with the following results:--

During the first period of 5 days, subsequent to the inoculation with first vaccine, cholera occurred in 8 houses.

75 non-inoculated had 5 cases, with 3 deaths. 52 inoculated had
3 cases, with 3 deaths.

During the second period of 5 days, subsequent to the second inoculation, cholera occurred in 2 houses.

8 non-inoculated had 2 cases, with 2 deaths. 17 inoculated had
no cases.

_After the 10 days necessary for the preventive treatment had expired, and up to the 459th day, the disease visited 26 houses._

_263 non-inoculated had 38 cases, with 34 deaths._

_137 inoculated had 1 case, with 1 death, in a child that had
not been brought up for the second inoculation."_

4. _Assam-Burmah Railway_

For a good instance of lives saved even during an outbreak, take the Assam-Burmah Railway coolies:--

_"Three hundred and fifty[30] Khassia Hill coolies had been
collected for the survey party of the Assam-Burmah Railway, and
put under the escort of a detachment of Goorkhas, when cholera
broke out amongst them. The largest part of the coolies
immediately submitted to the preventive inoculation, the rest
remained uninoculated. The result was that _among the
not-inoculated minority there were 34 cases, with 30 deaths;
whereas the inoculated had 4 fatal cases_." (Haffkine, 1895,
Lecture in London.)_

[30] The exact number is 355, of whom 196 were inoculated; the
coolies numbered 343, and the Goorkhas 12. (See Dr. Simpson's 1896
Report.)

5. _Durbhanga Jail_ (1896)

The figures in this instance are small: but Surgeon-Captain E. Harold Brown's report is very pleasant reading. Cholera broke out in the jail on 31st March 1896, and by 9th April there had been 8 cases. Next day, 172 prisoners were moved into camp 12 miles away; and 53 were left behind, the sick in the jail hospital, the patients in the cholera huts, with their attendants, the old and infirm, and a few cooks and sweepers. That day, 3 cases occurred in the camp, and 1 in the jail; and on the 11th, at 2 and 4 A.M., 2 more cases were reported in camp. At 7.30 A.M., Haffkine and Dr. Green came to the camp:--

"The prisoners were spoken to on the subject, and seemed to be
pleased with the idea, the word _tika_ (inoculation), which was
familiar to them from its association with smallpox, appearing
to appeal to them. They were accordingly arranged in four rows
facing the tent, in front of which Dr. Haffkine was about to
commence operations. I was the first subject to be inoculated;
and after me the jailor, assistant jailor, hospital assistant,
and three warders. The first prisoner in the front rank was next
brought up and submitted cheerfully; after which, every
alternate man was taken, so that no selection of cases was made,
until one-half of the total number were inoculated. Those who
had not been inoculated were far from pleased at having been
passed over; and, to our surprise, they rose almost to a man,
and begged to be inoculated; nor were they satisfied when told
that the medicine was exhausted."

The dose administered on this occasion (11th April 1896) was stronger than the Gaya jail dose (18th July 1894): it acted in a few hours, and the reaction was well marked.

"There were fresh cases of cholera that day at 12 (noon), 6, 7,
and 7.30 P.M., and at midnight, all in those who had not been
inoculated, and all terminating fatally, despite the greatest
care and the most prompt and assiduous treatment. On the 12th
two further cases occurred, both among the uninoculated, and
both died; there being thus eight cases in succession, all from
the men who were not inoculated, and all proving fatal."

The inoculations were made at 7.30 A.M. Surgeon-Captain Brown had pain within half-an-hour, and fever in three hours, with temperature 104°, _but this was probably due to the fact that I was not able to rest_. The prisoners, of course, went to bed: they all reacted before 4 P.M., but did not have so much trouble over it. The last case was on the 15th. The outbreak was a bad type of cholera; out of 30 cases 24 died, some of them in 1-1/2 to 4 hours. "To summarise the combined results of the camp and the jail, we find that of a daily average of 99 non-inoculated there were 11 cases, all fatal = 11.11 per cent.; of 110 inoculated there were 5 cases, with 3 deaths = 2.73 per cent."

6. _Bilaspur and Serampur_

Here again the figures are small, but worth noting. In a coolie camp at Bilaspur (Central Provinces) 100 non-inoculated had 5 deaths, and 150 inoculated had 1 death. In Serampur, among the general population, 51 non-inoculated had 5 cases and 3 deaths, and 42 inoculated had 2 cases and 1 death.

7. _The Cachar Tea-Gardens_ (1895)

This series of inoculations was begun in February 1895, for the protection of the coolies on various tea-estates. The results are excellent, and deal with large numbers.[31] The latest report from Dr. Arthur Powell, the Medical Officer, is quoted in Dr. Simpson's 1896 report:--

_At Kalain_--
1079 not inoculated had 50 cases, with 30 deaths.
1250 inoculated--3 cases, with 2 deaths.[32]

_At Kalaincherra_--
685 not inoculated had 10 cases, with 7 deaths.
155 inoculated--no cases.

_At Degubber_--
254 not inoculated had 12 cases, with 10 deaths.
407 inoculated--5 cases, all recovered.

_At Duna_--
121 not inoculated had 4 cases, with 2 deaths.
29 inoculated--no cases.

_At Sandura_--
454 not inoculated had 2 cases, with 1 death.
51 inoculated--2 cases, with 1 death.

_At Karkuri_--
198 not inoculated had 15 cases, with 9 deaths.
443 inoculated--3 cases, with 1 death.

_At Craig Park_--
185 not inoculated had 1 fatal case.
46 inoculated--no cases.

TOTAL.

Not inoculated, 2976, with 94 cases and 60 deaths. Inoculated,
2381, with 13 cases and 4 deaths.

[31] "As a field for testing the value of inoculation, the
tea-factories of India possess many advantages. The labourers
being under contract, the after-history of those inoculated is
easily followed up. Each morning the adults are paraded for
roll-call; and all sick must attend hospital, where a record is
made of their disease and treatment." (Dr. Powell, _Lancet_, 13th
July 1896.)

[32] "It is unfortunate that neither of the fatal cases among the
inoculated was seen by any medical man, not even an unqualified
doctor Babu." Dr. Powell does not think, from what was told him,
that one of them was cholera.

To the preceding instances, which are rather old now, must be added the following more recent report, from the _Indian Medical Gazette_, September 1901:--

"We are glad to see, from a paragraph in the Report of the
Sanitary Commissioner for Bengal (Major H. J. Dyson, I.M.S.,
F.R.C.S.), that an increased number of anti-cholera inoculations
were performed during the year 1900. Assistant-Surgeon G. C.
Mukerjee, who was in charge of this work, reports that in the
Puralia Coolie Depot no less than 13,291 persons were inoculated
against cholera, including over 1000 children. All these cases
of inoculation were among labour emigrants proceeding to the
tea-gardens of Assam and Cachar. The employers of labour are
beginning to realise the value of cholera inoculation. It is
unfortunately not always easy, or even possible, to follow up
the after-history of persons inoculated; but Major Dyson has
quoted a table, received from the Superintendent of Emigration,
which shows the number of cases among the inoculated and the
non-inoculated at Goalundo. From this table, it is seen that out
of 1527 non-inoculated coolies, who passed through Goalundo, 33,
or 2.09 per cent., got cholera; whereas of 873 inoculated
coolies, only 2, or 0.2 per cent., were attacked by the disease;
that is, the unprotected suffered about ten times as much as the
inoculated. Assistant-Surgeon Mukerjee also reports that during
his cold-weather tour he passed through some villages in the
Manbhum district, in which he had practised inoculation the
previous year: and, though there had been epidemics of cholera
in them, the inoculated persons escaped. They came to him in
numbers, stating that they owed their safety to the
inoculation."

Of course, the preventive treatment touches points only here and there on the map of India, with its 300,000,000 people. Probably it will never become so general in India as vaccination. Cholera in India recalls what Ambroise Paré, more than 400 years ago, wrote of the plague, "Here in Paris it is always with us." But, wherever preventive inoculation has been done, there it has done good.

The _Medical Annual_ for 1905 contains an account of some preventive inoculations recently made during an epidemic in Japan. Among the inoculated, the attack-rate was much lower than among the uninoculated; and the mortality was 45.5 per cent., as against 75 per cent.

Another most important result of the discovery of the cholera bacillus is its use in diagnosis. For example, if a case of suspected cholera is landed at a British port, the sanitary authority at once takes steps to ascertain whether the specific microbe is present; and, according to the answer given by bacteriology, either allows the patient to proceed on his journey, or adopts measures of isolation to prevent the spread of the disease to others. Thus, thanks to the insular position of Great Britain, this dreadful disease has for many years been prevented from invading her population.

VIII

PLAGUE

The _bacillus pestis_ was discovered by Kitasato and Yersin, working independently, in 1894. Yersin's discovery was made at Hong Kong, whither the French Government had sent him to study plague: an excellent account of his work is given in the _Annales de l'Institut Pasteur_, September 1894. The first experiments in preventive inoculation, in animals, were made by Yersin, Calmette, and Borrel, working conjointly, in 1895. They found that it was possible to confer on animals a certain degree of immunity, by the hypodermic injection of dead cultures of the bacillus. These experiments were made on rabbits and guinea-pigs.

Haffkine's fluid was first used on man in January 1897. It is a _bouillon_ containing no living bacilli, and nothing offensive to the religious beliefs of India.[33] He proved its efficacy on rabbits; and then, on 10th January 1897, inoculated himself with a large dose, four times as strong as the subsequent standard dose. A few days later, Lieut.-Col. Hatch, Principal of the Grant Medical College, Bombay, and other members of the College Staff, were inoculated. These first inoculations were described by Haffkine in a lecture (1901) at Poona:--