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777 THE FUTURE OF VACCINE THERAPY. THE LANCET. LONDON: SATURDAY, OCTOBER 12, 1929. THE modern practice of vaccine therapy rests in effect less on any theory of immunity than on JENNER’S success in protecting from subsequent infec- tion with small-pox those who had been vaccinated with material from cow-pox. Indeed, the word vaccine introduced to describe this specific virus is now used in ampler connotation to cover any virus or bacterial body, even any foreign protein, which evokes a response when introduced into an animal body by inoculation. A vaccine has come to be almost synonymous with an antigen. It was PASTEUR who saw in JENNER’s results the germ of a law of general validity-namely, that by causing an animal or inoculated person to undergo successfully a mild infection, protection is thereby obtained from a more severe infection of the same nature brought about naturally or artificially. The results of such active immunisation are essentially protective, and are specific for the virus inoculated. They are limited in applicability when a living virus is used, owing to the difficulty of finding one whose potency is naturally reduced, so that as a rule artificial ways of reducing the virulence must be adopted. Active immunisation by such attenuated viruses is used successfully in the treatment of rabies, and forms the foundation of the methods of producing immune sera in animals. For use in man any virus, however attenuated, which is still able to propagate itself and thus increase in the site of inoculation or spread throughout the body is dangerous. Bacteria for vaccines in human therapy are therefore at least killed, usually by heat ; the bacterial bodies may even be disintegrated chemically, as in detoxicated vaccines. Experiments with such bacterial vaccines, sometimes together with their soluble toxins, have been made in the treatment of human infections for a generation, but so far no therapeutic principles have been evolved that have received general acceptance. The choice of patients suitable for vaccine treatment, the methods of pre- paring the vaccinal material and of administering itt and the results that may reasonably be expected even the successes claimed for vaccine therapy, are still debated. Certain facts have, however, accumu- lated. The body responds to any parenteral intro- duction of foreign protein by a reaction which may be so violent as to constitute shock, with profound effect on the nervous system, the circulation, and the heat- regulating mechanism. The reaction may be a local one, limited to the site of inoculation, and sometimes a focal one at the site of infection. On the other hand, there may be no apparent reaction. A consideration of experimental work on animals, and of the methods used in fighting animal diseases on a large scale, throws some light on the way vaccines work in thera- peutics, if it be granted that the presence of anti- bodies in the blood gives an indication of the degree of immunity obtained, a proposition not yet estab- lished. In animals inoculation, especially intra- venous inoculation, on three or four successive days- produces a serum with high but evanescent content of antibodies. Vaccines at intervals of some weeks give sera with antibody of long duration. ALMROTH "TRIGHT’S opsonic work led to vaccine administration at intervals of several days to avoid a possible negative phase, and to the use of small doses of vaccinal material; his careful immunisation experiments were carried out with the control of the opsonic index. Since this method has lapsed into disuse, no real control is made in vaccine therapy applied to man, except that to avoid active and immediate harm to- the patient. Under rather than overdosage is the rule. The tendency, too, is to use less often the bacteria cultivated from the individual, and to depend rather upon stock vaccines. Indeed the specificity of the vaccine employed may be disregarded, as in the use of typhoid stock vaccine for many conditions. Substances other than bacterial bodies may be used, and vaccine therapy then becomes frankly a non- specific protein therapy, the dosage and results being decided empirically. Many laboratory workers refuse to see in the use of vaccines anything more than a specific protection against a reinfection. Patho- logists, however, working in close touch with clinicians and with the patient, seem to advocate vaccine treatment in a great number of infective processes. Meanwhile, the practitioner is in a quan-- dary, swayed to and fro by his inadequately controlled clinical impressions, and yet hesitating to omit from his means of treatment anything that is likely to benefit his patient. Theoretically it should be possible to divide cases of infective diseases into three groups. In the first the patient is doing well, the infecting forces are being dealt with adequately by the natural resistance, and no anxiety about the outcome need be felt. In the second group the infection is localised, but there is a state of unstable equilibrium between the resistance of the patient and the infection which at any time may be upset. Thirdly, there is the group in which the patient is doing badly and is being overwhelmed by the infection. The first group obviously needs no specific treatment in order to ensure recovery. In the third group a procedure bringing about further toxic effects is not to be contemplated lightly, and adding more poison may be actively harmful. It is probable that in the developments of the new chemotherapy there will be found a better means of treatment for such cases. It is only in the second group, where there is already some degree of resistance, that the possibility of stimulating that resistance and calling up further antibodies to the infecting germs by injecting vaccines should be considered. (In hydrophobia immunising treatment is begun after infection takes place, and completed before symptoms of the disease show themselves ; but this- is essentially prophylactic treatment, which is not now under discussion.) In this group of cases, where symptoms have already appeared but progress is delayed and resistance is inadequate, or is liable to break down at any time, medical vaccine therapy is. largely used in practice, and the success of this method of treatment has been assessed differently by various observers. The scientific basis for it has not been demonstrated ; the advocates of vaccines in treatment base their claims upon the evidence obtained by clinical- judgment. Evidence in support from the experi- mental side is wanting, but this may well be due to the fact that investigators of the problems of immunity have been working on other lines. Even the

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Page 1: THE FUTURE OF VACCINE THERAPY

777

THE FUTURE OF VACCINE THERAPY.

THE LANCET.

LONDON: SATURDAY, OCTOBER 12, 1929.

THE modern practice of vaccine therapy rests ineffect less on any theory of immunity than on

JENNER’S success in protecting from subsequent infec-tion with small-pox those who had been vaccinated

with material from cow-pox. Indeed, the word

vaccine introduced to describe this specific virus isnow used in ampler connotation to cover any virus

or bacterial body, even any foreign protein, whichevokes a response when introduced into an animalbody by inoculation. A vaccine has come to bealmost synonymous with an antigen. It was

PASTEUR who saw in JENNER’s results the germ of alaw of general validity-namely, that by causing ananimal or inoculated person to undergo successfullya mild infection, protection is thereby obtained froma more severe infection of the same nature broughtabout naturally or artificially. The results of suchactive immunisation are essentially protective, andare specific for the virus inoculated. They are

limited in applicability when a living virus is used,owing to the difficulty of finding one whose potencyis naturally reduced, so that as a rule artificial ways ofreducing the virulence must be adopted. Activeimmunisation by such attenuated viruses is usedsuccessfully in the treatment of rabies, and forms thefoundation of the methods of producing immune serain animals.For use in man any virus, however attenuated,

which is still able to propagate itself and thus increasein the site of inoculation or spread throughout thebody is dangerous. Bacteria for vaccines in human

therapy are therefore at least killed, usually by heat ;the bacterial bodies may even be disintegratedchemically, as in detoxicated vaccines. Experimentswith such bacterial vaccines, sometimes together withtheir soluble toxins, have been made in the treatmentof human infections for a generation, but so far notherapeutic principles have been evolved that havereceived general acceptance. The choice of patientssuitable for vaccine treatment, the methods of pre-paring the vaccinal material and of administering ittand the results that may reasonably be expectedeven the successes claimed for vaccine therapy, arestill debated. Certain facts have, however, accumu-lated. The body responds to any parenteral intro-duction of foreign protein by a reaction which may beso violent as to constitute shock, with profound effecton the nervous system, the circulation, and the heat-regulating mechanism. The reaction may be a localone, limited to the site of inoculation, and sometimesa focal one at the site of infection. On the other hand,there may be no apparent reaction. A considerationof experimental work on animals, and of the methodsused in fighting animal diseases on a large scale,throws some light on the way vaccines work in thera-peutics, if it be granted that the presence of anti-bodies in the blood gives an indication of the degree

of immunity obtained, a proposition not yet estab-lished. In animals inoculation, especially intra-venous inoculation, on three or four successive days-produces a serum with high but evanescent content ofantibodies. Vaccines at intervals of some weeks

give sera with antibody of long duration. ALMROTH"TRIGHT’S opsonic work led to vaccine administrationat intervals of several days to avoid a possible negativephase, and to the use of small doses of vaccinalmaterial; his careful immunisation experiments werecarried out with the control of the opsonic index.Since this method has lapsed into disuse, no realcontrol is made in vaccine therapy applied to man,except that to avoid active and immediate harm to-the patient. Under rather than overdosage is therule. The tendency, too, is to use less often thebacteria cultivated from the individual, and to dependrather upon stock vaccines. Indeed the specificityof the vaccine employed may be disregarded, as in theuse of typhoid stock vaccine for many conditions.Substances other than bacterial bodies may be used,and vaccine therapy then becomes frankly a non-specific protein therapy, the dosage and results beingdecided empirically. Many laboratory workers refuseto see in the use of vaccines anything more than aspecific protection against a reinfection. Patho-

logists, however, working in close touch withclinicians and with the patient, seem to advocatevaccine treatment in a great number of infectiveprocesses. Meanwhile, the practitioner is in a quan--dary, swayed to and fro by his inadequately controlledclinical impressions, and yet hesitating to omit fromhis means of treatment anything that is likely tobenefit his patient.

Theoretically it should be possible to divide cases ofinfective diseases into three groups. In the first thepatient is doing well, the infecting forces are beingdealt with adequately by the natural resistance, andno anxiety about the outcome need be felt. In thesecond group the infection is localised, but there is astate of unstable equilibrium between the resistanceof the patient and the infection which at any timemay be upset. Thirdly, there is the group in whichthe patient is doing badly and is being overwhelmedby the infection. The first group obviously needs nospecific treatment in order to ensure recovery. In thethird group a procedure bringing about further toxiceffects is not to be contemplated lightly, and addingmore poison may be actively harmful. It is probablethat in the developments of the new chemotherapythere will be found a better means of treatment forsuch cases. It is only in the second group, wherethere is already some degree of resistance, thatthe possibility of stimulating that resistance and

calling up further antibodies to the infectinggerms by injecting vaccines should be considered.(In hydrophobia immunising treatment is begunafter infection takes place, and completed beforesymptoms of the disease show themselves ; but this-is essentially prophylactic treatment, which is not nowunder discussion.) In this group of cases, wheresymptoms have already appeared but progress isdelayed and resistance is inadequate, or is liable tobreak down at any time, medical vaccine therapy is.largely used in practice, and the success of this methodof treatment has been assessed differently by variousobservers. The scientific basis for it has not beendemonstrated ; the advocates of vaccines in treatmentbase their claims upon the evidence obtained by clinical-judgment. Evidence in support from the experi-mental side is wanting, but this may well be due tothe fact that investigators of the problems of immunityhave been working on other lines. Even the

Page 2: THE FUTURE OF VACCINE THERAPY

778

.site of antibody formation is still largely a matterof conjecture, and the whole problem of immunity has- changed its aspect many times within the last 30

years and is still quite unstable. The nebulousviews of resistance to infection held by earlier patho-logists were succeeded by the coordinated idea ofphagocytosis established by METCHNIKOFF. In its

original form the phagocytic properties of the wander-ing white cells of the blood were regarded as the meansby which the body dealt with infecting bacteria. Withthe extension that the fixed cells of the lymphatics,connective tissues, and endothelium also exhibit

phagocytic and thus protective properties, METCHNI.KOFF’S idea remains the basic principle of the theoryof immunity of the present day. EHRLICH introduced,another idea, that the humours of the blood and bodyfluids carried antibodies of various kinds, which eitherwere antibacterial and antitoxic in themselves, or

stimulated the phagocytes and prepared the bacteriafor ingestion. These antibodies were represented as.actual substances in the blood. The theory was-amplified to include any new phenomena observed,and at last became a maze of incomprehensiblyinvolved patterns. A simplification followed, andM. NicoLLE saw in the immunity processes alternativephases of coagulation and lysis. Now recentadvances in physical chemistry show that colloids aresusceptible of precipitation by electrolytes, and thatone colloid may act on another sometimes in a pro-tective or stabilising way, sometimes sensitising it,.so that it becomes more easily precipitated. Accord-

ing to this physicochemical theory the changingconditions of the colloids of the blood and tissues areresponsible for the phenomena observed in theprocess of immunisation, and there are not variousantibody substances in the blood of an immu-nised animal, but phases of one immune reaction.This may be an over-simplification. Certainly inthis theory there seems little room for specificity ;whereas the immunity response consists essentiallyof a highly specific action combined with a non-

apecific general reaction. No satisfying explanationis yet forthcoming of the curious mixture of resistanceand sensitiveness that occurs in immunity. Lately,too, our ideas on the variation of bacteria, not only invirulence but even in physical characters and appear-ance in cultures, have undergone considerableextension. Much ground remains to be covered,therefore, before a satisfactory basis for the use ofvaccines in the treatment of infection can be reached.It is the time neither for complacent scepticism nor forviolent advocacy, but for open-minded discussionthat will stimulate further research.

THE MECHANISM OF COMPENSATION FOR

SILICOSIS.EACH new step in granting compensation for

-disability due to occupation seems to require newprocedure. If disability is due to an accident, theworkman carries a disputed claim into court, whereafter medical, as well as other, evidence has beenheard the issue is decided. If a scheduled disease isconcerned, medical evidence is heard and assessedby a medical referee, whose decision is final. Inrecent years compensation has been granted for adisease-silicosis-in connexion with which existingprocedure is inapplicable. Schemes have been triedout in the small refractories industry during the

past ten years ; but in the last 12 months compensa-tion has been granted widely, so as to cover practically

all industries in which a silica-dust hazard exists.These industries include the getting and use of sand-stone, whether for road metal, building, monumentalmasonry, or grinding metals ; the production anduse of powdered flint, whether in the pottery trade orfor the making of silica paints, abrasive soaps or

vitreous enamels ; and the fracture of quartz andquartzite in the granite industry or in the process oftin mining. This extension enlarges the scope of

compensation for silicosis from some 3000 workmento a large population, of which the size is uncertain ;but it numbers anything from 50,000 to 100,000.This population is scattered all over the country,but is more densely grouped in certain industrialareas, such as the gritstone district of Derbyshire,the pottery towns of Staffordshire, and the cutlerycentre at Sheffield. The problem to be faced differsfrom that tackled with such success in the gold-miningindustry on the Rand, where only about 10,000European miners are employed, both in the numbersconcerned and their wide distribution over manyvaried industries.A departmental committee, under the chairmanship

of Dr. J. C. BRIDGE, senior medical inspector offactories, was appointed in December of last year toconsider what medical arrangements should be madeto cope with the situation. Their reportl has justbeen issued. They envisage plans in which themedical services required for controlling the occurrenceof the disease, such as examination on engagementand periodically thereafter, are combined with thoseneeded for diagnosing the disease for compensationpurposes. The final recommendations of the com-mittee are modelled on the scheme which has achievedsuccess in South Africa, modified to meet our morecomplicated conditions. They include the creation atdifferent centres of medical boards, each consisting ofnot less than two whole-time experts, who will visitfactories, quarries, and mines to carry out their duties,which may be greatly facilitated in country placesby the use of efficient mobile X ray apparatus. Itis proposed that a chief medical officer should be

appointed to coordinate and standardise the workof all the boards ; he would reside at a central bureau,probably at Sheffield, where research would be

organised and pursued. The expenses involved areto be borne by the industries concerned, which willcontribute to form a joint general compensation fund,as the refractories and sandstone industries have e

already done. The wisdom of adopting this SouthAfrican precedent is seen by referring to the latestreport from the Rand,2 which tells how the production-rate of simple silicosis on the Rand is now decliningyear by year in an entirely satisfactory way. It tellsalso how this has resulted from minimising, first,the dust hazard, and then exposure to tuberculousinfection ; and how action has throughout beenbased upon and checked by exact information disclosedby the Medical Bureau. It tells, in fact, how thatpreventable associate of tuberculosis-silicosis-canbe combated. How great an influence would beexerted upon the prevalence of tuberculosis in GreatBritain by the elimination of silicosis can hardlybe guessed ; but the committee hold silicosis to befar more widespread than is generally admitted. If it’is really found to occur in industries and occupationswhere heretofore its presence has not been suspected,the effect of its control on the incidence of tuber-culosis in this country should be considerable.

1 Report of Silicosis (Medical Arrangements) Committee.London : H.M. Stationery Office. 1929. 6d.

2 Report of Miners’ Phthisis Medical Bureau for year endedJuly 31st, 1928. Pretoria : The Government Printer. 1929. 6s.