No. 3773.

DECEMBER 21, 1895.

A LecturePREVENTIVE INOCULATION AGAINST

CHOLERA IN INDIA.Delivered at the Examination, Hall, Victoria Embankment,

on Dec. 18th, 1895.

BY W. M. HAFFKINE, D.Sc.

LON Wednesday afternoon last Professor Haffkine, who isataying temporarily in England, acceded to a request from,the Royal College of Physicians of London and the RoyalCollege of Surgeons of England that he should deliver in the.Examination Hall of the Conjoint Board an account of hiswell-known work in India in the matter of the prevention of.cholera by inoculation. The chair was taken by SirJ. Russell Reynolds, Bart., President of the Royal College of,Physicians of London, and Professor Haffkine entered withthe President. Both gentlemen were received with cheersby an expectant audience, far below numerically, however,,what might have been expected. Professor Haffkine said :]The virulence of pathogenic bacilli varies greatly, and in

this fact is to be seen the explanation of mild and severe.epidemics ; and from this, no doubt, arose the practice ofpreventive inoculation ; when a mild epidemic occurred

everyone tried to take the disease, seeking close contactwith infected persons, and, later, the virus itself was applied,to give a mild attack; but, unfortunately, very often whatflocked like a mild form of the disease was really a severeTform occurring in a very resistant subject, hence very severe,epidemics arose, so that it has come to pass that legal pro-- ceedings are now taken against those who practise thismethod.

In small-pox, rabies, and syphilis, where the microbe istransferred directly from case to case, and leads no existence.outside the human body, great variations in the virulencemay be observed, but this is still more the case in thosebacteria which lead a saprophytic life; and there appearsto be no limit to the variations in virulence that may occur,.and not merely variations in virulence, but in shape and,size. Thus the cholera bacillus, as the field of investigationgrew larger, was found to vary from a comma to a straightbacillus, and from what was little more than a micrococcusrto a long, thin bacillus; usually it was harmless to birds,,but at times birds were affected by it. The position andnumber of cilia also varied. Metchnikoff has found that its’initial strength may be seventy-five times greater than when11;he virus has become weakened.- The terms used are

- employed as in small-pox. The infectious material from a

,patient affected with the disease is a virus, and the process-is called variolisation ; this was the Eastern practice. Oncthe other hand, the substance cultivated under conditionswhich will keep the microbe in a fixed state of viru-lence is a vaccine, and the process is vaccination.Jt is the difference between vaccination and variolisation’which distinguished the method I have employed in India-from that used in Spain by Dr. Ferran in 1885. Dr. 1’erran

,injected bacteria from cases of cholera, and the results wereso unfortunate that the method was forbidden by the Spanish.authorities, and similar disasters have led to the use of anyform of cholera inoculation being forbidden in Russia. Themethod which I have employed in India is on the same lines- on which Jenner and Pasteur worked-that is to say, the useof a modified virus. A great difference between the twoMethods is to be seen in the fact that Jenner’s methodhas survived a hundred years of trial. When Toussaint’began to inoculate against anthrax he used the unmodified’virus from cases suffering from the disease and the resultswere exceedingly disastrous, but Pasteur’s inoculation.against the same disease were with the modified virus, andwere eminently successful. In the case of rabies also,preventive inoculation by an attenuated virus had now beenlused for ten years, and had been applied to many thousand{people in France alone. I have abstained from usingsterilised cultures in all my inoculations in India, becauseYthe effect is very much more evanescent and less trust-worthy. The method which I have worked out is to

give two injections : 1 the first injection is of a mildform, and the second is one whose virulence has been

strengthened. This is given after an interval of five days.The full effect of each is not attained until five days haveelapaecl, so that the individual is not fully protected till tendays after the first inoculation. The microbe is cultivatedunder fixed and suitable conditions and its virulence is

known, so that it can be used with certainty and safety.One-twentieth of a culture tube has been adopted as th3standard dose. The amount of reaction is in direct propor-tion to the dose, and the amount of protection is in directproportion to the intensity of the symptoms produced. A

slight swelling and pain in the side are the usual localsigns, and there is a slight rise of temperature. The amountof pain and fever are in direct proportion to the intensity ofthe symptoms produced. It is a matter of vital importancethat the operator should be master of the strength of thevirus used and know exactly the amount of power containedin a given dose.And now we come to the record: 70,000 injections were

made on 42,179 individuals without a single instance of

mishap or accident of any description produced by ourvaccination. My work in India lasted twenty-nine months-from April, 1893, till the end of July, 1895. The Indiancholera vaccination was applied in ninety-eight localities inthe North-West Provinces and Oudh, in the Punjab, inLower Bengal and Behar, in the Brahmaputra Valley and inLower Assam, and during this time there were inoculated294 British officers, 3206 British soldiers, 6629 native officers,non-commissioned officers, and soldiers, 869 civil Europeans,125 Eurasians, and 31,056 natives of India. No official

pressure has been brought to bear upon the population, andpersuasion only has been used. In some localities effortshave been made to apply the inoculation to large partiesof people living under similar conditions in order that

comparison might be made between the inoculated and theuninoculated belonging to the same unit of population. Theinoculated people belonged to sixty-four British and nativeregiments, to nine civil gaols, to forty-five tea estates, to thefixed agricultural population parallel to the Hurdwar pilgrimroad, to the bustees of Calcutta, and to a certain number ofboarding schools, orphanages, &c., and in the vast majorityof cases the inoculated people lived under the direct observa-tion of the military and sanitary authorities of India. Cholerahas occurred in the inoculated localities from one to 459 daysafter the operation, and careful statistics have been imme-diately collected by the civil and military medical authoritiesin regard to both inoculated and uninoculated. The resultscan be grouped into three categories : (1) unsuccessfulresults, or those where any definite conclusion is impossible ;(2) results slightly favourable to the method : and (3) satis-factory results. To the first-class belong observations made ina certain number of tea estates in Assam. The coolie workerslive in very isolated bodies and remain unmixed with thegeneral population. The whole of the cases underwent thefirst part of the treatment only-that is, inoculation withthe maximal doe of the first vaccine. Cholera occurred infrom one to six months after vaccination. The secondinoculation was not made till after the cholera season.

At Adam Tila, of 657 non-vaccinated no cases of choleraoccurred, and of 318 vaccinated there were 2 cases (0’63per cent.) with 1 death (0 3t per cent.). At Kalacherra,of 520 non-vaccinated there were 4 cases (0’77 percent.) with 3 deaths (0’58 per cent.), and of 211 vaccinatedthere was 1 case (0’47 per cent.) with 1 death (0’47per cent.). At Chargola. of 1007 non-vaccinated, therewere 3 cases (0-30 per cent.) with 1 death (0’10 per cent.) ;and of 291 vaccinated there were no cases. At Pallarbund,of 1170 non-vaccinated there were 2 cases (0’17 per cent.),with 2 deaths (0’17 per cent.) ; of 451 vaccinated therewere no cases. At Lungla, of 2050 non-vaccinated, therewere 3 cases (0’15 per cent.) with 3 deaths (0’15 per cent.) ;of 421 vaccinated there were no cases. At Burnie Braes.Loobacherra, Kalaincherra, and Sandhura the number ofvaccinated is not stated, but 11 cases occurred with 5deaths. No cases are reported among the 677 vaccinated.To the second class belong observations made on cases

where the results are slightly favourable. The results aredivided into two groups. In the first maximal doses of thefirst vaccine only were used and cholera occurred in from

1 Professor Haffkine explained the method of preparing anti-choleraicvaccine in a former lecture delivered on Wednesday, Feb. 8th, 1893, andreported in THE LANCET of Feb. 11th, 1893.

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two to six days after vaccination in the Manchester Itegi-ment and three months and a half after in the case of the

Degubber tea estates. The statistics are as iollows: In the2nd Battalion Manchester Regiment, at Dinapore, of 729 non-vaccinated there were 6 cases (0’82 per cent.) with 3 deaths(0’41 per cent.) ; 193 were vaccinated and there were no cases.At Degubber tea estate in Assam, among the 228 non-vacei-nated 2 cases occurred (0’88 per cent.) and 1 death (0’44 percent.), and no cases were reported among the 387 vaccinated.The second group of observations were made on cases inocu-lated with weak doses of both vaccines, cholera occurringfrom 13 to 15 months after operation. Among the Britishtroops in Cawnpore, of 797 non-inoculated there were 19ca es (2’38 per cent.) with 13 deaths (1’63 per cent.), and nocases occurred among the 75 inoculated. In the East Lanca-shire Regiment at Lucknow, of 640 non-vaccinated therewere 120 cases (18 75 per cent.) with 79 deaths (1234 percent.), and of 133 vaccinated 18 cases (13 53 per cent.) with13 deaths (9’77 per cent.). The last class contains observa-tions with satisfactory results. These have been groupedinto four parts. In the first group maximal doses of thefirst vaccine only were given, cholera occurring in fromone to three months after vaccination. At the Karkurietea estate, of 203 non-vaccinated there were 5 cases

(2 46 per cent.) with 2 deaths (0’98 per cent.), and of the709 vaccinated 1 doubtful case (0’24 per cent.) with 1 death(0-24 per cent.). At Kalain tea estate there were 1375non-vaccinated with 23 cases (1’67 per cent.) and 11 deaths(0’8 per cent.) and of 681 vaccinated 2 cases (0’29 percent.) with 1 death (0’15 per cent.).The second group contains cases where small doses of both

vaccines were given, cholera being prevalent during vacci-nation. At Gaya gaol during the first period of five daysnecessary for the full effect of the first vaccine, of 210 non-vaccinated there were 7 cases (3 35 per cent.) with 5 deaths(2’38 per cent.), and of 212 vaccinated 5 cases (2’36 percent.) with 4 deaths (1-89 per cent.). During the secondperiod of five days necessary for the full effect of the secondvaccine, of 197 non-vaccinated there were 9 cases (4’57 percent.) with 4 deaths (2’03 per cent.), and of 206 vaccinated3 cases (1-46 per cent.) with 1 death (0 43 per cent.).During the last four clays of the epidemic, of 192 non-vaccinated there were 3 cases (1-56 per cent.) with 1 death(0’52 per cent.), but no cases amongst 201 vaccinated.The total shows 2-56 times fewer cases and2’05 times fewerdeaths amongst vaccinated than amongst non-vaccinated.The difference in the results in the Gaya gaol during thefirst five days is very slight, and points out the absolutesimilarity of conditions under which the inoculated and theuninoculatecl lived.The third group includes cases with medium doses

of both vaccines. The observations extended over 459dates after vaccination. In Calcutta the comparisonbetween the uninoculated and inoculated has been made

exclusively among members of the same families

living under the same conditions of life. Observa-tions during 459 days after vaccination were madein the bustees of Calcutta, and middle doses of one and ofboth vaccines were given. Of eight houses with inoculatedpeople affected during the first period of five days after thefirst injection there were 5 cases among 75 non-vaccinated(6’66 per cent.) with 3 deaths (4 per cent.) and 3 c[’ses

among 52 vaccinated (5 77 per cent.), with 3 deaths (5-77per cent.). Of two houses with inoculated people affectedduring the second period of five days necessary for secondvaccination there were 2 cases among 8 non-vaccinated(25 per cent.) with 2 deaths (25 per cent.), and no casesamong 17 vaccinated. Of twenty-six houses with inoculatedpeople affected between the llth and 459th day after vac-cination there were 38 cases among 263 non-vaccinated(14-45 per cent.) with 34 deaths (12-93 per cent.), and 1case (in a child which had not been brought up for the secondinoculation) among 134 vaccinated (0-75 per cent.) with 1death (075 per cent.).The last observation (the fourth group) came from Assam,

and was received only a few days ago. The full account hasnot yet reached me, but the preliminary note runs as follows.In Assam, Surgeon-Captain Hare, my co-worker, is continuingthese inoculations for the Assam Government, under whosedirection all coolies for the Assam-Burma Railway Surveyhave been collected and sent under an escort. Cholera hadbroken out amongst the coolies, and Surgeon-Captain Hareimmediately applied the inoculation. The result is as

follows : Amongst the uninoculated there were 34 cases with

30 deaths, while amongst the inoculated, which formed thelarger part, there were only 4 fatal cases.

It appears that in instances where cholera has made the-

largest number of victims, and where it has sufficientlyspread so as to make it probable that the whole populatioswere equally exposed, the result has been invariably favourable’to inoculation. Applied during the existence of the epidemic.it tends to reduce the mortality even during the first ten days.In Lucknow there was a difference in the number of casesattacked of between 18 and 13 per cent., and in the deaths ofbetween 12 and 9 per cent. The best method is probably twouse doses of both vaccines, the second one being kept at the-highest strength attainable. The evidence collected up to,now is decidedly in favour of inoculation, and my own con-viction is strengthened more and more. My responsibility,however, forces me to point out that the number of observa-tions is not yet very large, and that it is desirable tmhave the results confirmed by more and more information. Jhope you will pardon me if I quote the opinion of Koch,whose discovery was the starting point of our inoculation forcholera. He says " the demonstration is complete ; the pro-tective power of the method is established finally by theobservations collected in India up to now ; further perfec-.tions and simplifications may be possible, but the mainrquestion at issue, the chief part of the problem, is solved bythe facts recorded in your report to the Government ofIndia." I quote this by his permission. Many very inter-esting curative methods by serum injection have been intro-duced during my absence from England. Treatment by-antitoxins must be considered a decided success, but it can-not be used as a preventive treatment, as its effects on the-system are very rapidly worn out. Neither the anti-diph-theritic serum nor the anti-cholera serum lasts more than afew days. The treatment stands otherwise in regard to>

people affected already. On my return to India I intendto make an extensive trial in connexion with the physiciansof the country and with the help of Professor Pfeiffer ofBerlin, who has put at my disposal his experience on thesubject and a supply of antitoxic serum. In case it proves a,failure-and there is danger of the patient succumbing before-the antitoxin can have its effect-I intend to combine it withtransfusion of saline fluids. It is possible that the adminis-tration of antitoxic serum will mitigate the symptoms and’it is possible that its administration will diminish the active’protection afforded by the vaccines. A series of experi-ments have been undertaken in the Netley BacteriologicatLaboratory.On the day I came back from India I found Pasteur lying-

on his death-bed. Whatever might have been his appreciationof the work, I have only one desire-tbat the whole of the-honour that may come from my efforts should be referred to-his sacred memory. To the Government of India, theofficers of the India and Army Medical Staff in India, to-

Professor Hankin in Agra, to Dr. Powell of Cuchar, and to-Dr. Simpson, the well-known health officer of Calcutta, Iaddress my hearty expressions of gratitude for the assistance-they have given me in carrying out my work. I beg them to,accept this public acknowledgment that without their help Ishould never have been able to accomplish in India the

smallest part of what I have done. I also beg to thank thE>>chairman anB! the organisers of this meeting for having:given me this opportunity of making this communication.

[At the conclusion of the lecture Sir J. Russell Reynolds-said he could not let that lecture come to an end without

saying on behalf of his colleagues how deeply they wereindebted to Professor Haffkine for having done such goodwork, and for having come there and:given them such a lucidexposition of the way in which the work had been done.They congratulated him most heartily for the success whichhad attended his labours, and hoped that in the future astill greater amount of success would follow. He con-

gratulated the lecturer on another point. Before Professor-Haffkine entered the lecture theatre he had told him(Sir J. Russell Reynolds) that he could not speak English.After hearing Professor Haffkine deliver the lecture, however,he thought he had spoken it remarkably well.]

ROYAL COLLEGE OF SURGEONS IN IRELAND.-Professor Alexander Fraser, having passed the necessaryexaminations, has been admitted a Fellow of the College.Mr. Richard Keatinge, L.R.C.P.I. and L.S.A. Lond., havingpassed the necessary examination, has been admitted a.Licentiate to the College.