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The role of BCG vaccination
33o
TUBERCLE
munity will suffer if this is all that is done. The chest physician of an area should continue to have general cIinical responsibility for the tuberculous and their contacts, whoever m a y actually treat the 'index case', just as the medical officer of health coordinates the preventive forces: and in both tuberculosis and other chest disease, close liaison must be continued between these two. This demands much initial understanding and co-operation; but it is essential. T o place such clinical work once again under the medical officer offiealth would be a mistake. T h e chest physician must be a clinician, competent to investigate and treat chest diseases, using the resources of this field of investigation, trained in general medicine and in the social and ecDnomic aspects which first the dispensary and then the chest clinic have established as vital to this work. With this proviso the chest service can be set fairly in its place as part of the hospital service; a consultative service using its own techniques and making a large contribution to individual and public health.
The Role o f B C G Vaccination Tile efficacy of BCG vaccination h a s b e e n a subject of acute controversy for more than thirty years. M a n y believed that this controversy had at last been stilled by the publication of the first report of the Medical Research Council's trial of BCG (and vole bacillus) vaccine in 56,ooo i4-year-old children in Britain. 1 But finality is hard to achieve; and very different results have now been reported by Palmer, Shaw and Comstock 2 from two United States Public Health Service trials of BOG vaccine, in 19%ooo children aged I - I 8 in Puerto Rico, and in 64,ooo of the general population above the age of 5 in adjacent counties of Georgia and Alabama. T h e M.R.C. workers found that the incidence of tuberculosis for a period of two and a half years among Mantoux-negative participants who were vaccinated with BCG was only one-fifth of that a m o n g a similar, and randomly chosen, group who were not vaccinated. In contrast, the incidence of tuberculosis throughout a period of six to seven years among Mantoux-negative subjects who were vaccinated with BCG in each of the two U.S.P.H.S. trials was as much as two-thirds of that among the Mantoux-negative subjects, selected at random, who were not vaccinated. There were, as might be expected, differences in the vaccines used, the populations studied, and the methods of enquiry, all of which must be considered as possible explanations for these contrasting results. T w o different vaccines were used by the U.S.P.FI.S.; that for t h e P u e r t o Rican trial was prepared by D r Birkhaug at the N e w York State Department of Health and was given intracutaneously; that for the Georgia-Alabama trial was prepared by Dr Rosenthal at the Research Foundation in Chicago and Was given by a multiple puncture technique; the BCG vaccine used by the M.R.C. was prepared by the State Serum Institute in Copenhagen and was given intracutaneously. Palmer and his colleagues state that post-vaccination tuberculin sensitivity was similar in the British and Puerto Rican trims, which showed very different levels of protection; on the other hand post-vaccinal sensitivity was lower in t h e Georgia-Alabama trial, but no lower than in the trial of BCG vaccine in North American Indians, 3 in which vacciuatidn was much more e f f e c t i v e - o n a par with that in the British trial. These findings do nothing to" resolve the puzzle; indeed they add to it. Among t h e differences in execution between the British and the United S t a t e s trials three deserve particular mention. First, in Puerto Rico a very high proportion 2 9 per cent of the non-reactors - refused vaccination, a n d these refusals came both from those due to be vaccinated and those due to be left unvaccinated. T h e authors apparently assume that this large number of exclusions has not affected the comparison between the residual groups of controls and vaccinees, but it would -
THE
R O L E OF BCO V A C C I N A T I O N
331
lmve been more reassuring if they had reported fully the available evidence o n the point. Secondly, post-vaccinal sensitivity was not studied in either of the U.S.P.H.S. trials until one to two years after vaccination, and the local vaccination lesions were not examined as a routine at any time, so that there is only an imperfect check on tile potency of the vaccines. Thirdly, the follow-up both in Puerto Rico and in Georgia-Alabama was based only on the established reporting systems for identifying new cases of tuberculosis, and no attempt was made in Puerto Rico to verify the accuracy of the diagnoses. This limitation also has the considerable disadvantage that any participant migrating from the area is lost sight of, and, while this should introduce no bias, it m a y have seriously affected the completeness of the follow-up, particularly in Puerto Rico. T h e justification for this very limited follow-up in the U.S.P.H.S. trials is stated to be the need to avoid bias in the diagnosis of cases; indeed the a u t h o r s suggest, but not convincingly, that the periodic follow-up examinations, and the procedure for central independent review of cases bf possible tuberculosis, m a y have introduced such a bias in the M.R.C. trial. A further important difference is the criterion for vaccination. I n the U.S.P.H.S. trials vaccination was on the basis of a negative Mantoux test with 5 T U or xo T U , whereas in the M.R.C. trial only those :negative to Ioo T U were eligible for vaccination. Thus in the U.S.P.H.S. trials the effect of vaccination has been measured in a mixture of those negative t o ioo T U and those who would have been positive to ioo T U , though negative to the lower dose. T h e M.R.C. trial has shown that this latter group of subjects a l r e a d y has considerable natural protection against the'development of clinical tuberculosis, and any additional effect of BCG upon them m a y thus have been quite different from its effect in those negative to ioo T U , and unprotected. Although in Puerto Rico those with weak tuberculin sensitivity wei'e identified by means of ioo T U tests made at the time of giving (or withholding) the vaccine, it is singularly unfortunate that the report gives no indication of the effect of the vaccine in this group. We are thus left wondering whether this m a y provide some explanation of the differences between the American and British findings, although it seems unlikely that it could completely account for so gross a difference. Quite apart from the efficacy of BCG in non-reactors to tuberculin, who alone are eligible for vaccination, the total impact of the vaccine on tuberculosis must take account of the incidence of the disease in those already tuberculin-positive. In all three trials a high incidence of tuberculosis was found a m o n g the positive reactors. T h e U.S.P.H.S. ~[orkers estimate that if all their non-reactors had been vaccinated, tuberculosis would have been reduced only by 8 or 9 per cent; the corresponding figure in the M.R.C. trial was 55 per cent. It is thus not surprising to find that Palmer and his colleagues conclude that BCG vaccination cannot be very useful in controlling tuberculosis in the U.S.A. Whatever the causes for the divergent findings on the two sides of the A t l a n t i c and these remain o b s c u r e - t h e r e seems no good reason to doubt the high efficacy of, and considerable scope for, BGG vaccination among children about to leave school in Britain. In the present phase of tuberculosis in this country, BCG vaccination clearly has an important role to fulfil, and though the disease m a y in time diminish to a point at which large-scale vaccination in adolescence becomes unnecessary , the best immediate course is not in doubt. References
IMedlcal Research Council (x956) Brit. reed. aT., i , 413. 2Palmer, C. E., Sha~% L W., and Comstoek, G. W. (x958) Amer. Rev. Tuberc., 77, 877. SAronson, J. D., and Aronson, C. F. (I952) ,7. Amer. reed. Ass., x49, 334.
TUBERCLE
munity will suffer if this is all that is done. The chest physician of an area should continue to have general cIinical responsibility for the tuberculous and their contacts, whoever m a y actually treat the 'index case', just as the medical officer of health coordinates the preventive forces: and in both tuberculosis and other chest disease, close liaison must be continued between these two. This demands much initial understanding and co-operation; but it is essential. T o place such clinical work once again under the medical officer offiealth would be a mistake. T h e chest physician must be a clinician, competent to investigate and treat chest diseases, using the resources of this field of investigation, trained in general medicine and in the social and ecDnomic aspects which first the dispensary and then the chest clinic have established as vital to this work. With this proviso the chest service can be set fairly in its place as part of the hospital service; a consultative service using its own techniques and making a large contribution to individual and public health.
The Role o f B C G Vaccination Tile efficacy of BCG vaccination h a s b e e n a subject of acute controversy for more than thirty years. M a n y believed that this controversy had at last been stilled by the publication of the first report of the Medical Research Council's trial of BCG (and vole bacillus) vaccine in 56,ooo i4-year-old children in Britain. 1 But finality is hard to achieve; and very different results have now been reported by Palmer, Shaw and Comstock 2 from two United States Public Health Service trials of BOG vaccine, in 19%ooo children aged I - I 8 in Puerto Rico, and in 64,ooo of the general population above the age of 5 in adjacent counties of Georgia and Alabama. T h e M.R.C. workers found that the incidence of tuberculosis for a period of two and a half years among Mantoux-negative participants who were vaccinated with BCG was only one-fifth of that a m o n g a similar, and randomly chosen, group who were not vaccinated. In contrast, the incidence of tuberculosis throughout a period of six to seven years among Mantoux-negative subjects who were vaccinated with BCG in each of the two U.S.P.H.S. trials was as much as two-thirds of that among the Mantoux-negative subjects, selected at random, who were not vaccinated. There were, as might be expected, differences in the vaccines used, the populations studied, and the methods of enquiry, all of which must be considered as possible explanations for these contrasting results. T w o different vaccines were used by the U.S.P.FI.S.; that for t h e P u e r t o Rican trial was prepared by D r Birkhaug at the N e w York State Department of Health and was given intracutaneously; that for the Georgia-Alabama trial was prepared by Dr Rosenthal at the Research Foundation in Chicago and Was given by a multiple puncture technique; the BCG vaccine used by the M.R.C. was prepared by the State Serum Institute in Copenhagen and was given intracutaneously. Palmer and his colleagues state that post-vaccination tuberculin sensitivity was similar in the British and Puerto Rican trims, which showed very different levels of protection; on the other hand post-vaccinal sensitivity was lower in t h e Georgia-Alabama trial, but no lower than in the trial of BCG vaccine in North American Indians, 3 in which vacciuatidn was much more e f f e c t i v e - o n a par with that in the British trial. These findings do nothing to" resolve the puzzle; indeed they add to it. Among t h e differences in execution between the British and the United S t a t e s trials three deserve particular mention. First, in Puerto Rico a very high proportion 2 9 per cent of the non-reactors - refused vaccination, a n d these refusals came both from those due to be vaccinated and those due to be left unvaccinated. T h e authors apparently assume that this large number of exclusions has not affected the comparison between the residual groups of controls and vaccinees, but it would -
THE
R O L E OF BCO V A C C I N A T I O N
331
lmve been more reassuring if they had reported fully the available evidence o n the point. Secondly, post-vaccinal sensitivity was not studied in either of the U.S.P.H.S. trials until one to two years after vaccination, and the local vaccination lesions were not examined as a routine at any time, so that there is only an imperfect check on tile potency of the vaccines. Thirdly, the follow-up both in Puerto Rico and in Georgia-Alabama was based only on the established reporting systems for identifying new cases of tuberculosis, and no attempt was made in Puerto Rico to verify the accuracy of the diagnoses. This limitation also has the considerable disadvantage that any participant migrating from the area is lost sight of, and, while this should introduce no bias, it m a y have seriously affected the completeness of the follow-up, particularly in Puerto Rico. T h e justification for this very limited follow-up in the U.S.P.H.S. trials is stated to be the need to avoid bias in the diagnosis of cases; indeed the a u t h o r s suggest, but not convincingly, that the periodic follow-up examinations, and the procedure for central independent review of cases bf possible tuberculosis, m a y have introduced such a bias in the M.R.C. trial. A further important difference is the criterion for vaccination. I n the U.S.P.H.S. trials vaccination was on the basis of a negative Mantoux test with 5 T U or xo T U , whereas in the M.R.C. trial only those :negative to Ioo T U were eligible for vaccination. Thus in the U.S.P.H.S. trials the effect of vaccination has been measured in a mixture of those negative t o ioo T U and those who would have been positive to ioo T U , though negative to the lower dose. T h e M.R.C. trial has shown that this latter group of subjects a l r e a d y has considerable natural protection against the'development of clinical tuberculosis, and any additional effect of BCG upon them m a y thus have been quite different from its effect in those negative to ioo T U , and unprotected. Although in Puerto Rico those with weak tuberculin sensitivity wei'e identified by means of ioo T U tests made at the time of giving (or withholding) the vaccine, it is singularly unfortunate that the report gives no indication of the effect of the vaccine in this group. We are thus left wondering whether this m a y provide some explanation of the differences between the American and British findings, although it seems unlikely that it could completely account for so gross a difference. Quite apart from the efficacy of BCG in non-reactors to tuberculin, who alone are eligible for vaccination, the total impact of the vaccine on tuberculosis must take account of the incidence of the disease in those already tuberculin-positive. In all three trials a high incidence of tuberculosis was found a m o n g the positive reactors. T h e U.S.P.H.S. ~[orkers estimate that if all their non-reactors had been vaccinated, tuberculosis would have been reduced only by 8 or 9 per cent; the corresponding figure in the M.R.C. trial was 55 per cent. It is thus not surprising to find that Palmer and his colleagues conclude that BCG vaccination cannot be very useful in controlling tuberculosis in the U.S.A. Whatever the causes for the divergent findings on the two sides of the A t l a n t i c and these remain o b s c u r e - t h e r e seems no good reason to doubt the high efficacy of, and considerable scope for, BGG vaccination among children about to leave school in Britain. In the present phase of tuberculosis in this country, BCG vaccination clearly has an important role to fulfil, and though the disease m a y in time diminish to a point at which large-scale vaccination in adolescence becomes unnecessary , the best immediate course is not in doubt. References
IMedlcal Research Council (x956) Brit. reed. aT., i , 413. 2Palmer, C. E., Sha~% L W., and Comstoek, G. W. (x958) Amer. Rev. Tuberc., 77, 877. SAronson, J. D., and Aronson, C. F. (I952) ,7. Amer. reed. Ass., x49, 334.