Is Mass Vaccination with B.C.G. always warranted in the Scandanavian Countries?

Reprinted from "The Medical Review"

Published by the National Anti-Vaccination League 1957

INTRODUCTION

After upholding inoculation with B.C.G. for nearly thirty years, Prof. Wallgren and other Scandinavian tuberculosis experts have come to the conclusion that mass vaccination with B.C.G. should be stopped. Prof. Wallgren would do this gradually; Dr. Heimbeck and others would do it at once. Dr. E. Carrol Palmer, a United States expert, opposes the introduction of mass B.C.G. inoculation into the States.

In Gt. Britain there was, for many years, considerable reluctance to introduce tuberculin testing and B.C.G. inoculation, but pressure from groups of doctors who based their support of B.C.G. on claims made by Prof. Wallgren and other Scandinavian doctors induced the Ministry of Health and the Department of Health for Scotland to permit a limited amount of tuberculin testing and B.C.G. inoculation. In November 1953 testing of school-leavers and inoculation of those giving a negative reaction, were sanctioned. In February 1956 a committee of the Medical Research Council issued what appeared to be a favourable report on the use of B.C.G. which was, however, severely criticised by a Northern Ireland doctor.

In view of these facts it is of the greatest importance that Scandinavian doctors who were the pioneers of B.C.G. inoculation are now advocating the cessation of mass inoculation and appear to be looking forward to the general discontinuance, eventually, of the whole system.

The debate on this subject which took place towards the end of 1955, was reported in Nordisk Medicin for January 6th, 1956. The whole of the debate has been translated into English and the following pages contain a summary of the arguments put forward by the experts who took part in this debate. It is of vital importance that medical officers of health and others should be made aware of this development in Scandinavia.

Dr. Wallgren’s conclusion that the almost universal use of B.C.G. inoculation in Sweden has not been an important factor in bringing about the decline of tuberculosis mortality, will be noted by those who read this brochure.

Dr. Wallgren also intimates that while only five cases of B.C.G. disease have been reported, four of them fatal, there may have been others which have not been reported. In France and Germany there have been reports of children dying from the effects of B.C.G. vaccination. These cases have not been admitted officially, but parents, and in some cases medical advisers, have been convinced that the fatal illness had been caused by B.C.G. inoculation. Indian doctors in letters to Indian newspapers have reported many instances of injury to health caused by B.C.G. inoculation. There is every reason to believe that the inoculation has done a great deal of harm.

There is still time for English and Scottish medical officers of health to discontinue the whole system of tuberculin testing and B.C.G. inoculation of tuberculin negatives. An unprejudiced study of this brochure should convince them that there should be no delay in revising their opinions on this matter.L.L.

Is Mass Vaccination with B.C.G. always warranted in the Scandinavian Countries? 

Professor Wallgren, introducing the discussion on Mass Vaccination with B.C.G. in the Scandinavian Countries (Nordisk Medicin 5.1.56) said that when the Calmette vaccination was introduced into Sweden about a quarter of a century ago, the tuberculosis situation in that country was quite different from what it is at present. Mortality from tuberculosis was high. The number of cases of pulmonary tuberculosis was high in relation to the beds available, the waiting period for entry to hospitals being in consequence very long, the number of sources of infection was high and cases of infection abundant for all.

Infants and young children became infected, often with fatal consequences, meningitis and miliary tuberculosis often occurred in early childhood, and primary pulmonary tuberculosis was also a cause of death in that age group. About 35% of all children infected in the first year of life died. Thereafter the mortality dropped very rapidly, being hardly 1% for children of school age, after which it rose again as from puberty.

The Calmette vaccination came as a way out of the difficulties. Professor Wallgren shows how tuberculosis mortality dropped among babies after Calmette vaccination and when measures taken in conjunction therewith were applied.

(In this connection it may be pointed out deaths from tuberculous meningitis in Denmark dropped from 420 (13 per 100,000) in 1921 to 185 in 1935 (5 per 100,000) without any claim that the drop was due to B.C.G. For England without B.C.G. deaths from tuberculosis of meninges and central nervous system dropped from 5,467 in age class 0—4 in 1931—35 to 218 in 1952.—Ed.)

Wallgren claims that B.C.G. vaccinated children showed greater resistance to virulent infection than those not vaccinated with B.C.G.

Gradually the mass vaccination of children came into being. Tuberculin testing for school children was made compulsory, babies at maternity clinics and children at the beginning and end of school age were inoculated after being tested.

They justified the B.C.G. vaccination of tuberculin negative pupils in the upper forms by the belief that there was reduced resistance to tuberculosis in adolescent years, and by the assertion that when they left the parental roof a large proportion of the children would be exposed to infection with tuberculosis. (Note: They always assumed, without proof, that B.C.G. would protect.)

Wallgren then shows how the tuberculosis situation has changed. Children, even in the youngest age group, rarely die of tuberculosis. Tuberculosis morbidity is also rare in young children and generalised forms of tuberculosis, meningitis and miliaris have become very uncommon. A few cases of clinically fresh primary tuberculosis occur in children’s hospitals, but the sanatorium departments for children which are still open are mainly social and not determined by real hospital needs.

Wallgren then took up the problem for discussion, at the request of the Editorial department of the journal, and asked the following three questions:

1. What can B.C.G. vaccination be deemed to perform in the most favourable case?

2. What part can mass B.C.G. vaccination be deemed to have played in the occurrence of the present low tuberculosis mortality and morbidity?

3. What are the prospects for the future of B.C.G. in our country?

1. What can B.C.G. vaccination be deemed to perform in the most favourable case ?

In answering this question Wallgren started by emphasizing the fact that natural resistance is a significant factor in the course of tuberculosis, a number of human races possessing high resistance, and others, particularly primitive people, possessing low resistance. Resistance also varies in different sections of the population of a country. Age affects it and also heredity. The dearth of sensitive individuals should, after many generations, bring about a general rise in general resistance.

Wallgren believes that a tuberculous primary infection produces specific immunity against further tuberculous infection, but, he says, experiments on animals have shown that the acquired immunity is only relative and cannot prevent a powerful new infection from attacking. He himself has never seen a case of clinical primary tuberculosis that occurred as a direct consequence of superinfection in a child who had previously been primarily infected. On the other hand, he has had occasion to treat "no small number of children vaccinated adequately with B.C.G., who sickened during the appearance of primary tuberculosis directly following upon a virulent infection."

However, Wallgren does not wish to minimise the significance of B.C.G. vaccination in this connection in view of the observations of Heimbeck, Hyge and Dickie, showing how small is the number of cases in those vaccinated with B.C.G. compared with the large number in whom manifest primary tuberculosis has been absent after definite virulent exposure.

He thinks it probable that B.C.G. vaccination plays a part in reducing the risk of meningitis and miliary tuberculosis, but while he has not observed a single case of T.B. meningitis in children adequately vaccinated with B.C.G., he admits that various instances of this have shown that it can occur. He refers to Difs and Dahlstrom’s investigations which show that pleurisy occurs less often in B.C.G. vaccinees than in others, and to their conclusions which show that early post-primary pulmonary tuberculosis is less prevalent in the B.C.G. vaccinated than in unvaccinated soldiers.

Coming to the ability of B.C.G. vaccination to prevent late post-primary ailments, he says that as T.B. of the legs, joints and urogenital organs is so relatively uncommon, it is hard to obtain comparative material. Moreover, all doctors with experience of these ailments have encountered these localisations of tuberculosis even in the B.C.G. vaccinated.

"Of greater significance," says Wallgren, " is late post-primary pulmonary tuberculosis which continues to be common. That this not infrequently occurs in B.C.G. vaccinees is a well-known fact in tuberculosis doctors’ circles. Of 5,000 tuberculous patients admitted in January 1935 to Swedish hospitals, 5% had previously been vaccinated with B.C.G."

Wallgren has no records of the distribution of B.C.G. vaccinated and unvaccinated within the same age groups of the population, so he cannot say whether the inoculation played any part as a prophylactic among those who did not sicken. "Nor," he says, "is it possible to draw any conclusions as to whether a reduction in mortality and morbidity, which has been taking place over a long period, is or is not caused by a universally carried out B.C.G. vaccination. W.H.O’s Tuberculosis Research Office at Copenhagen has given attention to this question which has been studied in Finland. Since 1948 a mass vaccination has been carried out in Finland of persons under the age of 25, and vaccination has since proceeded according to the same principle. The conclusion of W.H.O’s investiga

tion is that the reduction in tuberculosis mortality after the introduction of B.C.G. vaccination is not greater than in countries where little or no B.C.G. vaccination has been conducted. Dahistrom writes in his book: "The morbidity in post-primary pulmonary tuberculosis showed no statistically probable or significant difference between the two groups of the vaccinated and unvaccinated." He could not find any significant difference in the prognosis of the pulmonary tuberculosis occurring in the vaccinated and that occurring in the unvaccinated.

On theoretical grounds also Professor Wallgren doubts whether B.C.G. inoculation could have had any major significance in the decline of morbidity of post-primary pulmonary tuberculosis.

He comes to the conclusion that B.C.G. vaccination may affect the occurrence of primary tuberculosis, pleurisy, meningitis and miliary tuberculosis, as well as early post-primary tuberculosis, but with regard to the most usual form of tuberculosis, namely, late post-primary pulmonary tuberculosis, it is uncertain whether mass vaccination with B.C.G. is of any great significance in the fight against tuberculosis.

2. What part has B.C.G. vaccination played in the present fight against tuberculosis and in the reduction of mortality and morbidity?

In answering this question Professor Wallgren first discusses what other factors can be deemed to have collaborated. The most significant factor is the increased general resistance to tuberculosis and not merely the biological increase in resistance, but an increased natural resistance brought about by a raised standard of living and social-hygiene improvements. If anything happened to lower the standard of living, the acquired natural resistance might be expected to decrease and the morbidity and mortality of tuberculosis would presumably rise again.

The second factor is the earlier diagnosis and more effective early treatment of tuberculosis.

With regard to tuberculosis in children, Wallgren thinks the most important factor in its reduction is the shift of the time of primary infection from the sensitive childhood years up towards higher age groups. He accounts for this shift in various ways, and for the absence of meningitis and miliary tuberculosis, mainly diseases of the youngest children, by the elimination of the risk of exposure. "B.C.G. vaccination need not have had anything to do with the disappearance of these ailments," he writes. He pays a tribute to modern chemotherapy in saving most children if they are treated sufficiently early.

His concluding statement on this question runs as follows

"As to the part which voluntary B.C.G. mass vaccination may be deemed to play as a factor of importance for the reduction of morbidity, I can put the question in a nutshell. The value of the other factors is very obvious, and they are sufficiently effective to be able to explain the improvement that has taken place in tuberculosis mortality. The vaccination of children menaced by tuberculosis has definitely prevented a large number of the direct consequences of primary infection. It is, however, unlikely that there will now be a trend (rise) in the mortality curve if all B.C.G. mass vaccination were suddenly to stop in our country. It might perhaps lead to an increase in the number of cases of clinical primary tuberculosis, especially in the more resistant school age. It would probably also be possible to find some increase in miliary tuberculosis and pleurisy. Since, as is apparent from the above, the unknown ambulant sources of infection are now very few, and infection, especially in the delicate early childhood stage, is quite rare, the number of children saved by mass B.C.G. vaccination cannot be remarkably high. We have in the Scandinavian countries, with the mass vaccination in force here, a very low tuberculosis mortality, but equally low, or even lower, mortality occurs in certain countries without any B.C.G. vaccination at all, e.g., in certain

portions of the United States. I am, therefore, obliged to conclude that mass B.C.G. vaccination has played a very small part in the reduction of tuberculosis mortality. In any event, the other factors have dominated entirely."

3. The future of Calmette vaccination in Sweden.

Professor Wallgren thinks that in countries like Indonesia, where primary infection occurs at an early stage in childhood and meningitis and miliary tuberculosis are common, and where no other measures can be taken to check the spread of tuberculosis, there is definite indication for general B.C.G. vaccination as early as possible. But in countries like Sweden with late primary infections and good natural resistance, most of the mass B.C.G. vaccinations never have an opportunity of exerting any protective action during childhood. In a word, with only few exceptions, they are unnecessary. Only a very small fraction of all children mass vaccinated as a matter of routine really derive benefit from B.C.G. vaccination." So he asks whether mass vaccination in childhood is worth while.

He then weighs the gain and advantage of B.C.G. inoculation against the negative side — the cost and the drawbacks. There is the cost of preparing the vaccine and its distribution, medical investigation, tuberculin tests before and a certain time after vaccination, each involving at least two visits, and finally the loss of time entailed by those who accompany the child. The visit to the doctor must in many cases be repeated a number of times, that is, in those cases where the test after vaccination shows no positive result and the test and even the vaccination itself has to be repeated perhaps twice or more frequently, until there is a final "take."

Disregarding the economic side, which does not play a decisive part in the discussion of the future status of B.C.G., Dr. Wallgren comes to the argument that such easily conducted processes as B.C.G. vaccination of all newborn babies and of school children in the schools should continue, as it is then convenient to carry out the vaccination which is said to be safe in all circumstances and may do good, especially as one never knows when a child in civilised society may be exposed to infection. All doctors who sponsor B.C.G. vaccination have always stressed its absolute harmlessness, and in the past had every reason to do so, as there were no indications of serious injury or complications. No account was taken of the formation of abscesses at the point of injection or of lymphadenitis liquefaction which occurs now and again for various reasons.

In Sweden, ever since B.C.G. vaccination began to become more common, Professor Wallgren says they have kept their eyes open for complications. The Swedish National Tuberculosis Association has paid travelling and maintenance expenses for hospital observation in special wards and in Professor Wallgren’s clinic they have had a number of children with alleged or actual B.C.G. complications which, he says, in all cases consisted merely of abnormally large abscess formation at the point of the injection, or in special cases in regional glands. After a short stay in hospital the children could be sent home cured.

Although Swedish experience supported the idea that B.C.G. vaccination entails no risk, experiments on animals suggested that the B.C.G. bacilli were not as non-pathogenic as had been thought. Progressive tuberculosis in hamsters was produced by first injuring the lungs by silicosis or by weakening their general resistance by infection or other injury. In mice under certain experimental conditions (defective nutrition) B.C.G. bacilli became pathogenic.

Coming then to the fact that B.C.G. can, in exceptional cases, cause progressive disease in human beings, Professor Wallgren emphasizes the fact that proof of this has come from the Scandinavian countries. "From Denmark, Norway and Sweden," he writes, "information is now available about generalised B.C.G. processes after regularly conducted vaccination, altogether 5 cases, 4 resulting in death."

These may not be considered to weigh heavily against the 100 million vaccinations that have been carried out all over the world, but they must not be disregarded. He adds that, "The failures reported are, of course, minimum figures; many more may have occurred." While admitting that in the individual case, such a fatal effect of a prophylactic measure is under all circumstances a terrible misfortune, a catastrophe, he does not, in the cases published, blame the B.C.G. bacilli as such, nor the vaccinator. He considers "that it is the vaccinated persons who in some way were minus variants in resistance to B.C.G."

But although he blames the poor victim for not being able to resist the malignancy (for him) of the B.C.G. bacilli, Professor Wallgren has been so troubled over these tragedies that he has come to the conclusion stated by him as follows:

"The knowledge that such progressive B.C.G. diseases can occur in man must shake our faith in the harmlessness of the B.C.G. bacilli and perhaps induce us to reconsider the continuance of mass vaccination. We have hitherto encouraged by publicity as many as possible to have themselves B.C.G.-vaccinated, even if there is no obvious risk of exposure. We can no longer accept the non-dangerousness of our propaganda. Reference has been made to smallpox vaccination, which is, moreover, compulsory and is carried out on all children. It cannot be regarded as non-dangerous, as during this century a number of persons have died in our country of post-vaccinal encephalitis, more than of smallpox, yet smallpox vaccination continues. It is not possible, however, to compare the effect of smallpox vaccination with that of B.C.G. vaccination. The former definitely gives protection for ,a number of years from this often fatal disease, the latter against the immediate effect of the as a rule harmless primary infection for perhaps an equally long period."

Professor Wallgren then hastens to assure all concerned that it is only of mass vaccination of all tuberculin-negative persons that he refers to when he speaks of B.C.G. vaccination. He does not question the need, utility and value of the individual B.C.G. and vaccination performed on children in tuberculous surroundings or in certain professional groups, where the risk of exposure to infection is particularly great. He supports the B.C.G. vaccination of tuberculin negative children who have relations suffering from pulmonary tuberculosis, school children, medical students and the staff at tuberculosis hospitals or other clinics where tuberculous patients are accepted; and he goes so far as to approve of the application of the system to young conscripts and to young persons who leave the parental home to obtain professional training or employment.

Professor Wallgren says that the question of the continuance of B.C.G. vaccination has already been raised by various doctors. The published cases of generalised B.C.G. illness have been used as an effective weapon in the campaign against it as, for example, by James; but Ustvedt and Meijer think mass vaccination should continue. Wallgren, however, says : "I would nevertheless consider it conceivable that in any case the time for the cessation of vaccination is thought to be approaching gradually. When will that time come? On this point opinions are, of course, divided."

Professor Wallgren urges that he can hardly be suspected of despising B.C.G. vaccination since he was the one who introduced the system and in various ways has sponsored the universal introduction of vaccination as a link in the fight against tuberculosis. He states his opinion which, he says, was strengthened when he heard of the first fatal results of B.C.G. disease. It is "that when the natural resistance of the population has risen to a certain level, where tuberculosis morbidity has fallen so that the ailment can no longer be deemed a major problem to overcome, and mortality is reduced to minimum figures, the risk of accidental exposure to tuberculosis through unknown sources of infection is

very slight. The general specific tuberculosis immunity acquired by a mass B.C.G. vaccination has then very seldom an opportunity of being utilised. There is no real balance between the many thousands of inoculations and the very small number of inoculated persons who are accidentally exposed. With only few exceptions, B.C.G. vaccination has thus become superfluous‘."

He then comes to the point when such discrepancy between the exposed and the vaccinated is actually present and says: "For my part, I consider that the time has now come gradually to reduce mass vaccination. It is not desirable suddenly to stop all mass vaccination. There should be no abrupt change in the principles, but a relaxation should take place, gradually leading to a decline."

Considering how this could be done he pointed out that the B.C.G. vaccination appears to be least beneficial to school children, who possess the greatest natural resistance and in whom primary tuberculosis is, as a rule, very mild while miliary tuberculosis and meningitis are very infrequent. The mass vaccination of newborn babies could be continued during the transition period although exposure among infants and small children is very slight. Primary tuberculosis amongst these is often more malignant.

While he would not stop B.C.G. vaccination suddenly even for school children; and parents and guardians who, of their own accord, wish for vaccination should have their wishes met, he thought that first of all there should be an end to positive propaganda for B.C.G. vaccination for this age group and to the questionnaires aimed at an affirmative answer, addressed to children’s pa rents for their permission to have the child vaccinated. "If this method be adopted," he wrote, "and only those children are vaccinated whose parents spontaneously request vaccination, and of course all children menaced by exposure, vaccination of healthy children, who are not known to be menaced by tuberculosis, will little by little and unnoticeably decrease and finally cease altogether."

With regard to babies, when the risk of infection in infants and small children has further decreased and perhaps been practically eliminated, it would be possible to proceed in the same way: " First of all a reduction in the propaganda for vaccination at lying-in hospitals, with vaccination only of those children whose parents request it, which will gradually lead to a decline in vaccination."

He wishes to retain vaccination in the school-leaving age groups and among conscripts and for those mentioned earlier in his statement as more liable to exposure than the population in general.

Finally he mentioned another factor that might play a part in deciding on the cessation of mass vaccinations. The Swedish Anti-tuberculosis Association has financed B.C.G. vaccinations. When new ways in the fight against tuberculosis have been tested by them and proved successful, they should let the State or the Local Authority continue the work and defray the cost. Since during the past 25 years B.C.G. vaccination has become intimately incorporated in the prophylactic principles of the dispensaries, he considered that their managers should assume economic liability for this portion as well as the dispensaries’ expenditure. The National Association would thus have funds released for fresh pioneer work. What he aimed at here, above all, was the development of rehabilitation of tuberculous persons — a social-medical task of the very greatest importance at present.

 DEBATE

In the debate which followed E. Groth-Petersen of Copenhagen said it is both surprising and overwhelming that Wallgren himself, who has been one of the great advocates of the use of B.C.G. vaccination in the fight against tuberculosis, should be in favour of the gradual reduction of mass vaccination now, when in his opinion they were only just beginning to reap the benefit of mass vaccination.

In opposing Wallgren’s contentions, Groth-Petersen admitted that it is extremely difficult to obtain empirical facts establishing the power of vaccination to reduce the risk of pulmonary tuberculosis and he based his support of the system on the results of experimental inoculation of animals.

He criticised Wallgren’s suggestion that B.C.G. immunity is weaker than immunity produced through virulent infection. He declared that the danger of re-infection came from the surviving tubercle bacilli left behind in glands and elsewhere and that these bacilli survive with greater difficulty in animals with acquired immunity than in those without it.

If, as they believed, B.C.G. affords protection from the early illnesses of primary infection this must be due to the inhibition of the formation and spread of the tubercle bacilli. On the second point, the part B.C.G. vaccination has played in modern combating of tuberculosis and in the decline of morbidity and mortality, Groth-Petersen asked about the date mass vaccination was undertaken in Sweden. In Denmark it had not been undertaken at so early a period and to so large an extent that it has been able to influence mortality noticeably.

K. A. Jansen commenced work with B.C.G. vaccine in Denmark in 1927, but only in the mid-thirties did the existing T.B. stations begin to use the vaccine. In 1940 the system was extended, but even in 1946 only about 5% of the total population was vaccinated, infants 1% and only about 10% of the most important and most vaccinated age group, from 15 to 24. The mass vaccination of school children did not take place to any extent until 1948—1951 and of adults in the years 1950—52. He argued that since the great majority of all cases of tuberculosis occur among adults, and the interval between the time of infection and death must be measured in years, mass vaccination, only operative for a few years, and then chiefly affecting children, could not have left its mark on the mortality rate. Other factors, he said, have improved the

prognosis of tuberculosis so much that its reduced lethal nature might conceal a possible vaccination effect. Mortality is unsuitable as a gauge of the effect of vaccination ; this must be assessed on the basis of morbidity.

He declared that Danish experience in regard to the protection afforded by vaccination from primary tuberculosis and meningitis is just as unanimously favourable as the Swedish experience mentioned by Wallgren, "but exact investigations with valid control groups, permitting a quantitative assessment of the value of the vaccine, are not available." As regards morbidity they did not expect mass vaccination to leave noticeable traces until after 1950.

With regard to (3) — the future of Calmette vaccination in Denmark, Groth-Petersen thought that when such importance was attached to the vaccination of tuberculin-negative exposed persons, they should plump for mass vaccination since in the majority of cases of recognised tuberculosis no known source of infection had been found.

Groth-Petersen revealed how little B.C.G. vaccination is done in Denmark. He said "the vaccination of infants and small children only takes place to a modest extent in Denmark. Since exposure in general is relatively slight for small people and the drawbacks of a powerful vaccine relatively great, most specialists in tuberculosis consider it reasonable that vaccination in these age-groups should be limited to specially exposed groups, including not only known tuberculous surroundings, but also to all small children in built-up areas and social groups where there is still very much tuberculosis."

"General public vaccination only takes place at the age of 7; vaccination is popular, so that about 97% of the negative school children in the provinces and about 90% in Copenhagen are vaccinated."

He advocated the continuance of B.C.G. vaccination until it is shown that it is superfluous, or that the risks

and drawbacks are too great in relation to the utility. He admits that it is a very serious finding that B.C.G. has shown that it can be dangerous for a certain number of individuals, but he points out that only one such case is known in Denmark out of 1.3 million vaccinations. At the same time even a small number of serious cases of illness would alter vaccination policy. He declared that all cases of illness that can be attributed to B.C.G. must be investigated thoroughly and the bacteriological investigation must include the determination of virulence.

He considered that mass vaccination in the 7-year old group should be continued (1) "Because we must still reckon that several thousand children are exposed to virulent infection during school years," and (2)

"because at school it is possible to control all the vaccinated persons over a number of years and there is the possibility of re-vaccination before the children leave school."

When the time is finally ripe for relaxing mass vaccination," said Groth-Petersen, " I would prefer a sudden cessation of school vaccination, under conditions such that it is possible to keep a check on the consequences."

Tobias Gedde-Dahl of Oslo then stated his views. He had already done so in a paper read before the Norwegian Medical Society on 19.10.55.

He said "Mass vaccination is based on the assumption that protection from tuberculosis is arrived at to approximately the same extent for the population as a whole, as obtained in the groups where the effect of vaccination is known; Wallgren’s infants and small children,. Heimbeck’s nurses, Hyge’s girls during puberty, Dahlstrom and Dif’s recruits, Aronson and Palmer’s Indians. These groups had a relatively low resistance (on account of age and other conditions) and relatively brief period of observation with high risk of infection. If the whole population had lived under corresponding conditions, a corresponding effect could be expected. But this was not so."

He showed that the risk of infection is slight, this risk for children having declined very considerably in the first 25 years of this century, that the high morbidity of young folk has decreased appreciably since 1930; but during the war the decline in age groups over 20 stopped; that after 1947 when mass vaccination was introduced there was again a great decrease which had been attributed among others, by Galtung Hansen and Eyolf Dahl, to mass vaccination; that there are no statistical or epidemiological indications for this; that the detection of sources of infection are very much more intensive; that they have the mighty de-bacillating effect of modern therapy; and that a number of social conditions have altered, so that the spread of bacilli has become much more difficult.

He gave figures showing how few patients today, not hospitalized, have T.B. detectable in the sputum compared with 1930.

B.C.G. experiments suggested reduction of infection by vaccination to about one-fifth, but he contended that mass vaccination can only have given a fraction of this protection. "Of the young people admitted for the first time to Norwegian sanatoria today, about half are B.C.G. vaccinated. He suggested that without mass vaccination they would have expected a morbidity five times this half plus the other half, bringing the morbidity to the same level as during the war, but this would mean the exclusion of the other causes of the reduction of morbidity that operated after the war, which they knew had been very intense. In countries without mass vaccination they also saw a corresponding decline in morbidity.

He attributed the deficient effect of mass vaccination to defects in the actual vaccine. The farther away from the laboratory the more the inferiority of the vaccine will be of significance. The living B.C.G. constantly die off and this destruction is accelerated by light, transport, heating and infection. Until 1952, the vaccine was sent out in transparent phials and before that time a large proportion of the vaccine used must have consisted mainly of dead bacilli.

He mentioned other drawbacks of the vaccine, such as the difficulty of obtaining through vaccination an allergy which lasts, and quoted the experience of Heimbeck’s nurses. Standardisation of the vaccine is difficult and even frozen dried vaccine will not be more suitable for mass vaccination.

He maintained that "The modest protection that mass vaccination can give does not offset its drawbacks."

He dwelt on the value of the tuberculin test and concluded that an important factor is the collaboration of the public. "In the long run," he said, "it will become difficult to interest people in a vaccination of dubious durability against a disease which is steadily becoming rarer and which, when discovered early, affords such great chances of cure. The relatively large numbers of vaccinated persons in our sanatoria and the complications that arise, will discourage interest in vaccination. Partial mass vaccination of this kind is most unsuccessful. The vaccination of exposed persons is another matter which must be followed up and checked in future. In my opinion, mass vaccination cannot be retained. It will, therefore, be desirable to devote more attention in Scandinavia to epidemiological technique for the control of tuberculosis."

Seven Savonen of Helsinki showed himself to be an enthusiast for B.C.G. vaccination. He attributed all the decline of tuberculosis in Finland to this inoculation, but while he decided that they have no cause for the time being to alter the system he said:

"The time when we too will ask whether Calmette mass vaccination is altogether justified is certainly coming for Finland too, but this is not yet. We are continuing as before."

Olof Sievers of Goteborg B.C.G. Laboratory admitted that it might seem odd for a producer of B.C.G. vaccine to express his opinion on the question of whether mass vaccination with B.C.G. is still warranted in Scandinavia. He made a number of points which

showed how little is really known about the tuberculin reaction, and about the vaccines that are used, e.g., the change in the tuberculin reaction takes place more quickly and reliably if the vaccine contains live B.C.G. bacteria and so efforts are made to produce B.C.G. vaccine with as large a number of living organisms as possible; but if the vaccine contains too large a number, this may entail complications at the actual point of injection and in the regional glands. Animal experiments show that the stronger the vaccine the greater the immunity so they are compelled to make the vaccine as strong as possible and even then B.C.G. immunity is weaker than that produced by infection.

However, it is not possible for them to use a reliable immunity reaction. We are only able, he says, "by an accurate assessment of a sufficiently large number of tuberculin reactions, to obtain a frequency curve that tells us to what extent the vaccine has been serviceable."Certain investigators have found that 6—7 year old school children who had been vaccinated during the first year of life remained positive. It was not known with certainty whether they had been exposed to infection in the intervening period. However, two other investigators had found that about 29% of interned children became negative within 2.5 years and another investigator had found about 15% after 7 years.

He thought, in discussing mass vaccination that the risk of infection in childhood could not then be ruled out as children were brought together in day nurseries and kindergartens while their parents were engaged in earning their living. So long as this risk could not be ruled out with certainty and until a 100% reliable therapy is available, he thought "results such as the above" militate in favour of continued mass vaccination of small children.

With regard to the vaccine: "It has not been possible to make a standard vaccine" ; " the stability of the vaccine is, moreover, extremely limited"; "We constantly have to use new proportions, and

thus get the drawback that the batches are never quite identical."

"A freeze-dried vaccine would give us a more stable vaccine and one which it would perhaps be possible to standardise."

As for complications: "We know that complications have been observed at the point of the injection, with swelling of the regional lymph glands. . . . This risk is enhanced if the vaccine is made stronger." "Experience has shown us, however, that complications of this nature occur more often with mass vaccination."

If the vaccinations are performed by carefully trained staff, complications are less usual. Unfortunately it has been found that the stated dose is often not complied with, and has been raised from 0.1 to 0.2, sometimes to 0.25 ml. So large a dose seriously aggravates the intracutaneous injection and part of the vaccine is forced into the subcutaneous tissue. Hence there often ensues major or minor abscess formation."

Guinea-pigs are used in the different laboratories for the purpose of testing the B.C.G. strains that are used. Latterly mice and hamsters have been employed.

Sievers declared that the ability of the B.C.G. strain to produce illness, particularly in the guinea-pig, is practically non-existent, and relatively slight for the other animals; but if the experimental animals are sick, inoculation of the B.C.G. strains can lead to progressive tuberculosis.

"After the injection of B.C.G. vaccine into a human being, the increase and spread of the bacteria must be reckoned with in different parts of the individual’s organism."

He says that the protection obtained with dead bacteria is not sufficiently strong and so the present method of vaccination with live bacteria has to be used. "If necessary, immunity could be improved if repeated injections were given." For the first injection the vaccine should contain live bacteria;

for the subsequent injections, the vaccine should only contain dead B.C.G. bacteria. It would be possible to rule out the risk of complications altogether by these repeated vaccinations. "A proportion of live bacteria in the vaccine undeniably entails an element of risk. If the vaccinated individual is not perfectly healthy the B.C.G. bacteria, which are carried by the lymph and blood passages round the organism, can increase considerably in a previously diseased tissue and there make bad worse."

"Experience in recent times has shown that even a gamma globulinaemia constitutes a risk in conjunction with vaccinations and infections and this probably also applies to B.C.G. vaccination. Unhappily, in discussing these complications outside the region of the injection, it has to be noted that some deaths have occurred which have been ascribed to B.C.G. vaccination."

In trying to explain these Siever says: "The fatal result was brought about by vaccination, but the vaccine itself cannot on this account be regarded as injurious to a healthy individual."

(But were not the five injured persons, four of them fatally, perfectly healthy at the time they were inoculated with B.C.G. ? — Ed.)

While admitting more risk of complications with mass vaccination than in individual vaccination, where the vaccinating doctor is able in each individual case to assess the risk, Siever maintains that this is not a sufficiently weighty reason for stopping mass vaccination. The risks can be lessened, he says, by observing greater caution and accuracy in the preliminary investigations.

He will not admit that any reliable proof is yet available to show that mass vaccination has not affected tuberculous morbidity, nor will he admit that the complications have been of such a nature as to justify the cessation of mass vaccination. But he insists on the necessity of showing greater caution and

precision in the investigations, and he adds: By the word mass vaccination there should not be understood in connection with tuberculosis an uncritical injection of vaccine with live bacteria."

J. Heimbeck, of Oslo, a pioneer of B.C.G. inoculation, supported Wallgren’s view.

He stated that in 1926 tuberculosis was the predominant disease in Norway. Practically all were infected sooner or later and there were not enough beds in tuberculosis clinics for all the sick. In December 1926 and February 1927, reports were made to the Norwegian Medical Association that the Pirquet reaction shows considerable immunity against subsequent tuberculosis infection : (this is a curious way of stating what was claimed for the tuberculin test — L.L.) that this immunity reaction can be produced by subcutaneous B.C.G. vaccination, and that this Pirquet reaction brought about by B.C.G. has the same immunity value as the T.B. Pirquet reaction. According to the current opinion of the time B.C.G. was absolutely mild and this had, as primary infection, the same immunising effect as malignant pulmonary tuberculosis. Since all persons gradually became infected with T.B. and as by means of B.C.G. it was possible, without risk of disease, to immunise against T.B. infection, B.C.G. vaccination began to be generally used. The idea was first taken up in Sweden as far back as 1927 and little by little mass vaccination spread all over Scandinavia.

Now, after 28 years, the situation has completely altered. Only a minority is infected with tuberculosis, in large sections of the population practically none. Morbidity is reduced and tuberculosis as a national disease has dropped far back from its former position of pre-eminence.

Differing from Wallgren on this point, Heimbeck thought that B.C.G. mass vaccination had been the decisive cause of this decline. He added that mass investigations had contributed as they made the population as a whole tuberculosis-minded and changed the fight to an offensive action. By mass investigations the sick were detected as the sources of infection, who, thanks to new drugs and surgical treatment, could now obtain effective treatment. This reduced the sources of infection to a minimum. However, he maintained that new problems had arisen such as the occurrence of tuberculosis late in life which could not be mastered by B.C.G. Also he admitted that the B.C.G. diseases even if rare and transient, are nevertheless unpleasant for those who contract them, and, albeit quite exceptionally, catastrophic.

He continued : The original pre-requisites for the use of B.C.G. vaccination, general tuberculosis infection, and the absolute mildness of B.C.G. no longer therefore apply. Mass vaccination should therefore now stop, and B.C.G. vaccination be confined to uses where it is known that there is a certain likelihood of infection with tuberculosis, and where therefore B.C.G. vaccination is still necessary and worth the risk, a very small one it is true, that is involved. This will also mean that the great advantage will be derived that B.C.G. vaccination will revert to what it should be, medical art, and not as flow mass vaccination. In other respects I have nothing to add to Wallgren’s extremely comprehensive introductory paper."

Carroll E. Palmer, of the United States Public Health Service, working with the World Health Organisation and a specialist in the investigation of tuberculin reactions and the effect of B.C.G., made a very important contribution to the discussion.

He said Wallgren’s suggestion came at a singularly appropriate moment and that a re-assessment of measures that came into being under pressure from special circumstances, during the War and post-war years, is necessary now that time, man and drugs have altered so many of the decisive basic conditions of the situation as a whole.

He re-stated Wallgren’s proposals that Sweden should now prepare herself to cease B.C.G. vaccination

(1) by stopping positive publicity for B.C.G. vaccination and replace it by the passive tactics of offering vaccination to unexposed children only if the parents specially demanded it, and (2) to do away with the vaccination of babies. But that these measures are merely a start seemed to him to be apparent from the observation: "I would nevertheless consider it conceivable that one should in any case consider that the time for the cessation of vaccination is gradually approaching."

Palmer recalled to mind the three points on which Wallgren based his proposal:

(1) The colossal decline in tuberculosis morbidity and mortality during recent years: "Most medical students now never have an opportunity of seeing a fresh case of tuberculous meningitis."

(2) B.C.G. vaccination has probably only played a subordinate part in the decline of tuberculosis to its present low level. "The value of the other factors is very obvious and they are sufficiently effective to account alone for the improvement that has occurred in tuberculosis mortality."

(3) Recent reports of complications and cases of death through B.C.G. vaccination call for a revision of when B.C.G. vaccination should be performed: " We cannot well continue to include harmlessness in our propaganda."

He summarised them in these words:

"The first point indicates that the need for B.C.G. vaccination has disappeared, the second point that the value of mass vaccination is uncertain, and the third that positive measures for stopping B.C.G. vaccination are now warranted."

He stressed the enormous importance of this change in Wallgren’s attitude. He said:

"Wallgren’s survey of the period in the Scandinavian countries when B.C.G. vaccination was very popular and used to a large extent, and his conclusion that the time has come to stop mass vaccination, are aimed mainly at forming a basis for a new and more agnostic attitude to B.C.G. in Sweden. But when a man in Wallgren’s position as paediatrist and pioneer for B.C.G. vaccination, respected alike for his integrity and for his deep knowledge of the problems of tuberculosis, suggests that his country place less reliance on B.C.G. vaccination — his words cannot fail to evoke response in those who are responsible for the fight against tuberculosis in other countries."

Palmer then turns to his own country — the United States of America — and shows how tuberculosis has declined there without much B.C.G. inoculation. He says:

"In the United States B.C.G. has not been used for mass vaccination, nor has it found widespread use in the case of such ‘specially exposed’ groups as female nurses and medical students. All the same, we have witnessed an equally sharp decline in tuberculosis mortality, and no further comments are called for when medical colleges or nurses’ schools, where B.C.G. has not been performed, have not had a single case of tuberculosis in many years."

He refers to the tuberculin testing of school children. He admits that there are advocates of B.C.G. inoculation in the U.S.A. and that time after time a more widespread use of B.C.G. vaccination has been given consideration. "However," he says, "many will certainly agree with me in that, since the present situation in the United States without B.C.G. is so like the situation in Scandinavia with B.C.G. it would be as well not to start something which Sweden is now preparing to put an end to."

Reviewing the situation as it stands today, Palmer makes a very important statement about negative reactors, and the tuberculin test. British advocates of B.C.G. inoculation pretend that all negative reactors are likely to develop tuberculosis if exposed to it. Palmer says:

"Long-term studies now show that — clearly because the incidence of infection is so low —tuberculosis seldom occurs in tuberculin negative persons, i.e., in those who should be vaccinated. Most new cases of clinical tuberculosis occur obviously as an endogenous disease among the tuberculinpositive, who should not be vaccinated."

Palmer’s second point was that since they have intentionally not availed themselves of B.C.G. vaccination they can always assume that a positive tuberculin reaction signifies infection with virulent tubercular bacteria. (In a B.C.G. vaccinated person it would probably be assumed that it was the inoculation with B.C.G. that caused the positive reaction.—L.L.)

Palmer thinks that without B.C.G. inoculation they can always measure their incidence of infection, localize sources of infection, and diagnose more effectively cases that are in need of treatment. What must be still more significant in future, in his opinion, is that they can diagnose, keep under observation, and perhaps even treat prophylactically, tuberculin-positive persons who are now thought to run the greatest risk of getting clinical tuberculosis, and he concluded:

"We are coming close to the day when the aim of the fight against tuberculosis is the riddance of the last sources of infection — we should not through B.C.G. vaccination destroy the value of the tuberculin test just when we are going to need it most."

Erik Tornell (Boras), asked whether the risk of tuberculosis infection had decreased sufficiently to justify the discontinuance of mass inoculation with B.C.G. He stated that tuberculosis mortality had declined "quite independent of the commencement of B.C.G. action," but he did not think the optimism which believed that tuberculosis as a national disease will soon be eradicated, was justified.

There are still about 70,000 cases of tuberculosis in Sweden — about 1 per cent of the population. The number of cases of pulmonary tuberculosis — the most important localization of the disease — registered by the dispensaries has remained unchanged during the last ten years. The incidence of relapse is very high.

Tuberculosis continues to be a very incapacitating disease. Even if the mortality approaches zero, it is still a national disease. Moreover, tuberculous patients now often die of other ailments.

He contemplated an increased risk of incidence of acute tuberculosis epidemics if an increased risk of infection suddenly visits such a preponderantly tuberculin-negative population, in conjunction with war or displacement of persons.

He agreed that the pros and cons should be weighed against one another. "The decisive factor will finally be whether the efficiency of B.C.G. vaccination is sufficiently great to outweigh the drawbacks and expenditure which mass action always entails." He did not consider the complications (which he called "extremely scanty") weigh heavily in the assessment, "although they cannot be overlooked entirely."

Although tuberculosis in babies is certainly in process of disappearing, as long as there is any risk he thought B.C.G. vaccination of babies at lying-in hospitals should be continued. He showed how easy it is to test and B.C.G. vaccinate infants and to isolate individual children belonging to known tuberculous families. He attributed, at least in part, the decline of tuberculosis amongst young people to the B.C.G. vaccination of the school-leaving classes.

Although he was defending the practice of B.C.G. inoculation, he gave an example of how technique plays an important part in the results obtained. His tables showed how much more tuberculosis there was judging by the reaction in 20-year olds liable for military service who had been vaccinated by the "dispenser" than in those vaccinated by other doctors, although the vaccinations were carried out with the same vaccine in the same age groups. " it is hardly possible,"

he said, "to give any explanation other than that the technique was different in the two groups. (The explanation might be that there is nothing definite or exact or specific about the tuberculin reaction.—L.L.)

Tornell then discusses tuberculous manifestations occurring after a latent period of 5—10 years or more after the first infection, such cases being well-known amongst the unvaccinated.

While such late exacerbation cannot occur, in his opinion, in the vaccinated, "we may expect a reduced number of tertiary tuberculous cases after mass vaccination." But he admits that tertiary forms occur in the B.C.G. vaccinated without previous manifest primary infection and he attributes them to a super-infection, "which," he says, "is clearly very much commoner in the B.C.G. vaccinated" than in the spontaneously infected.

But he will not admit the failure of B.C.G. vaccination to protect. He writes:

"The mere fact that the occurrence is seen of an increased number of tertiary tuberculous cases after B.C.G. is no proof that the method cannot be depended upon."

Referring to Wallgren’s mention of 5,000 persons in a Swedish tuberculosis hospital, of whom 5% had previously been B.C.G. vaccinated, the lack of knowledge of the distribution of the B.C.G. vaccinated and the unvaccinated in the same age group of the population prevented any judgment as to whether vaccination played any part as a safeguard in those who sickened.

In this connection he displayed a Table showing the results of an investigation he carried out in 1950—51 within the City of Boras, which showed a much greater frequency of post primary pulmonary tuberculosis in the unvaccinated than in the vaccinated. After claiming a 14-times greater frequency in the unvaccinated, he qualifies this by admitting: "The difference in the frequency cannot, of course, merely be ascribed to the favourable effect of B.C.G. Different risks of

infection for different age groups play a certain part. A number of cases, especially in the older age-groups, were not B.C.G. vaccinated, as they were previously tuberculin-positive. For this reason, "the risk of infection is greater in the non-vaccinated groups." But he offsets this by the fact that in B.C.G. groups there is a selection of strongly exposed individuals. (But surely the fact that so many of those who had not been vaccinated were not inoculated because they were tuberculin positive, and therefore already infected with tuberculosis, according to medical theory would lead to the expectation of a far larger number of subsequent cases of T.B. amongst the unvaccinated. The B.C.G. vaccinated would not be exposed to infection except in a minority of cases, and even these would be isolated for a time and watched over.—L.L.) He claims that it may be expected that there will be five times as many cases of intrathoracic tuberculosis among the unvaccinated in the age groups 15—34 compared with the vaccinated of the same ages. He does not say, that this difference has actually been found in recent years.

He admits that in the Boras central dispensary district 117 cases of tuberculosis in B.C.G. vaccinated persons were observed during the years 1937—30.6.55, their ages varying from 1 to 55. Only 3 cases were over 34. He makes various excuses for the 42 cases that occurred in the first three years after B.C.G. vaccination and also for the cases that followed 3—10 years after B.C.G. vaccination was employed.

He admits that "The post-primary forms dominate still more than with natural infections," but he refuses to allow the conclusion to be drawn "that B.C.G. is unable to bring about relative protection from both early and late forms of tertiary tuberculosis." It will be remembered that earlier in his remarks he said that tertiary forms occur in’ the B.C.G. vaccinated.

He concluded by expressing the opinion that the risk of tuberculosis is still so great that we must not omit to use all available means for reducing it.

He favoured the continuance of mass vaccination with voluntary attendance, confined to certain age groups : babies, children leaving classes (possibly also the first classes) and 20-year-old men and women.

Arvid Wallgren in his concluding reply discussed Groth-Petersen’s views and showed that actual experience does not support them.

With reference to the influence of B.C.G. on tuberculosis in Sweden, he thought Groth-Petersen agreed with him that "B.C.G., in contrast to the usual view, has only had a trifling effect on the reduction of tuberculosis mortality." Groth-Petersen had said that "other factors have changed the prognosis of tuberculosis so much that a possible vaccination effect is not prominent." " It should be," says Wallgren, were it of major significance."

With reference to Groth-Petersen’s illustration from a Danish district between 1943 and 1951 (cases of tuberculosis with no known source of infection) he asked how many children now (1955) are contracting virulent infection in the same district. He thought mass vaccination was indicated when tuberculosis was so widespread, but what is the position now and what will it be in the near future ?

He asks for more details regarding classification by age-groups, and the prognosis for the 150 tuberculous children in the said Danish district, seeing that GrothPeterson exempts very small children from vaccination and considers that mass vaccination should start at the age of 7, when 90—97% of the tuberculin-negative children have been vaccinated.

As for the time to discontinue mass vaccination, Wallgren said:

"Groth-Petersen, in contrast to myself, would like to discontinue vaccination all at once, when the time has come to do so. Might this not attract the embarrassing attention of the public? A method that is thought to be so good that all school-children should use it — and suddenly the method becomes

redundant. B.C.G. vaccination will not become superfluous at a determined moment for all; the risk of infection and the degree of reaction to primary infection can be quite different at different ages. It should gradually, let us say in 10 years, be discontinued as a mass vaccination system."

He said little on Savonen’s observations, but on Sievers remarks he said he had not contested the view that B.C.G. had influenced tuberculosis morbidity although in his opinion exaggerated views on its intent were held. What he questions is its influence on mortality although Sievers considers that the complications were not of such a nature as to justify the cessation of mass vaccination. Nevertheless a certain amount of anxiety could be detected when he recommends great caution in the execution of the vaccination. " No lack of caution was displayed in the said complicated cases. It may be asked: ‘In what way can further care be exercised ?

As for Palmer’s. views, Waligren said

"I do not need to point out that I hold quite the opposite view to Palmer; faced by the alternatives of vaccinating and thereby losing the chances of tuberculosis diagnosis, or omitting vaccination to retain this diagnostic possibility, I am definitely on the side of vaccination. If vaccination is necessary, i.e., if there is any risk of exposure or if the age in question is a particularly sensitive one, e.g., in puberty, I consider that vaccination is called for even if thereby the diagnosis of tuberculosis infection should be aggravated. Nor do I think that the tuberculosis situation in the U.S.A. should be portrayed in too favourable a light. One should not equate the Middle West, Minnesota, etc., with, for instance, Texas and Puerto Rico, where tuberculosis is still a problem to be reckoned with."

Wallgren agreed with Tornell about mass vaccination of children in the transition classes, but not as regards babies, "because even if a method is harmless and can easily be carried out, it does not follow that it should and must be introduced. The decisive factor must be the need for vaccination."

With regard to Tornell’s Tables, Wallgren said that Tornell himself had mentioned a number of reasons why the two groups, vaccinated and unvaccinated, cannot be regarded as adequately comparable. He thought that the early form of pulmonary tuberculosis, occurring almost in direct connection with primary tuberculosis, can be prevented by B.C.G. vaccination, but as regards late post-primary tuberculosis, he doubted whether the preventive effect of B.C.G. is so manifest as certain sanatorium doctors would like to suppose. Tornell in his Table had not distinguished between early and late post-primary tuberculosis.

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