Fifty years of BCG

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Tubercle, (1971), 52, 303 LEADING ARTICLE FIFTY YEARS OF BCG Future medical historians will find the story of BCG vaccination a strange mixture of endeavour, inertia and ineptitude. It begins with the laboratory work of Calmette and Gutrin for 13 years from 1908 attenuating a strain of M. bovis and the first vaccination of infants by the oral route in 1921 by Weill-Hall6 in Paris. Intracutaneous vaccination was used in Norway by Heimbeck in 1923 and in Sweden by Wallgren in 1927. Rosenthal in the U.S.A. introduced the percutaneous method in 1939, pricking the vaccine into the skin with a needle. In 1940 Negre and Bretey in France described the scari- fication technique, using a vaccination lancet; and in 1941 Birkhaug in Norway reported the use of an automatic stabbing instrument. The first vaccination was done 50 years ago. Half a century should have been long enough to solve major problems and exploit the results. The major problems have, in fact, been solved; but application in the field lags far behind. BCG vaccination has been widely used; but less widely than might have been expected. Before 1950 it was probably being used in less than 50 countries, by 1960 in about 75 and in the past decade in a further 20 or so. But in many countries the extent of vaccination has been so small that it could have made no important contribution. For instance, it has been estimated that in Latin America only 20 per cent of the susceptible population has been vaccinated, the proportions in individual countries varying from 6 per cent to 70 per cent (the latter in one country only). The situation is little better in the so-called developed countries of Europe. A detailed epidemiological investigation by Lotte, Perdrizet and Hatton in 15 centres in France, Poland, Switzerland and Yugoslavia revealed that in 1961 a remarkably high proportion of children had not been vaccinated. In Geneva, where vaccination was voluntary, the proportion was 84 per cent and in France, where it was compulsory, 73 per cent; in Poland the proportion was 51 per cent and in Yugoslavia 24 per cent. There are many vaccines produced. With few is there direct evidence of their protective efficiency. This cannot be inferred, as was formerly supposed, from their capacity to produce tuberculin skin sensitivity. For instance, the Glaxo freeze-dried vaccine used in Great Britain confers relatively weak tuberculin allergy; but there is evidence that it is as effective in preventing tuberculosis as was the liquid Copenhagen strain vaccine previously used3. The Latin-American Region of the International Union against Tuberculosis studied the defi- ciences of BCG vaccination campaigns in the areal. It was recommended that, because of the obvious differences in vaccines and methods of production, and the lack of systematic laboratory and field evaluation tests of quality of vaccine and efficiency in its application, there should be established an international standard for production, testing and evaluation. This is an eminently sensible recommendation. But it should not have been necessary to make it after 50 years of ex- perience. It is symptomatic of the chaotic state of BCG vaccination in the world. There has just been published a booklet on BCG in India - a failurey4. This calls for the imme- diate stopping of the ineffective, problematic and expensive mass BCG vaccination programme in India. The authors views are gloomier than the evidence warrants. Nevertheless, there is undoubtedly a case for argument. It is for this reason that a large trial of BCG vaccination is at last being carried out in that country. Previous studies have been inconclusive; and there can be little doubt that some vaccinations in India and elsewhere has been largely useless, often because the vaccine had lost its potency before it was injected. It need not necessarily be so in future. The production of freeze-dried vaccine has removed some of the difficulties that may have nullified 304 LEADING ARTICLE earlier attempts at mass immunization. Yet, with all its manifest disadvantages, liquid vaccine is still widely used. The original route of administration was by mouth. This method is still used, though it has never been proved effective by an adequately controlled field trial. Its use is justified by the protagonists on the grounds of ease of administration to infants by unskilled people such as midwives and health workers. This would be a valid argument if no other alternative to the difficult intracu- taneous technique were available. But other techniques do exist. The percutaneous method has a long history. Its efficacy, as judged by tuberculin conversion, has been adequately demonstrated by, among others, the British Tuberculosis Association 5. Yet it is little used. Even in Great Britain it has still not received official approval and supplies of the percutaneous vaccine can be obtained only for experimental purposes. This is absurd. The simple prick and scarification techniques have received little attention. Allen and Tanaka carried out a comparative trial of intradermal, multiple puncture, jet injection and needle prick techniques in Hong Kong. Their report is published on page 247. The simple prick technique used by midwives on new-born babies gave acceptably good results. The technique is old: the demon- stration of its comparative efficacy new. Surely there is no remaining justification for continuing oral vaccination. Adherence to the rigid WHO policy of intradermal vaccination in all countries and all circum- stances has not been helpful in controlling tuberculosis. Multiple puncture has been largely ignored. No doubt the resurrection of the prick technique will have the same fate, unless a more realistic policy is adopted, one that takes into account different environmental circumstances. Differences in the reported degree of protection by BCG between different controlled trials have for long been unexplained. Palmer and Long6 attempted to explain them on the basis of the different prevalence of infection by atypical mycobacteria. Such infection appears to confer some protection against infection by M. tuberculosis, to which BCG vaccination can add. Hart analysed the available evidence in 1967 and concluded that this factor was inadequate to explain all the differences, postulating different potencies of the vaccines used to explain the remaining discre- pancies. The differences have been studied again by Sutherlanda. He has related the degree of recorded protection to the incidence of tuberculosis in the unvaccinated groups. A remarkably close correlation exists. Thus, in a trial in Georgia the protection was only 14 per cent and the incidence among the unvaccinated 0.13 per 1000 per year; on the other hand, among British school children the protection was 78 per cent and the incidence among the unvaccinated l-3 per 1000. The probability of the close concordance observed in the seven controlled trials being due to chance was only 1 in 360. There were, of course, many differences between the trials other than the risk of infection. A similar analysis was done on the results of the MRC BCG vaccine trial in Great Britain, in which the same vaccine was used in all areas and in which there were no important regional differences in the prevalence of atypical mycobacterial infection. There was a similar relationship between protection and incidence of tuberculosis in the unvaccinated, the association being significant at the 1 per cent level. It seems probable, therefore, that the efficacy of vaccination depends not only on the vaccine used and the adequacy of the technique, but also on the extent of super-infection to which the vaccinated are exposed. The lower the risk of infection the lower the degree of protection. Sutherland estimated that the average annual incidence of tuberculosis in this country in unvac- cinated subjects during the next decade will be about 0.04 per 1000. Springetts estimated the rate rather higher - 0.1 per 1000. Both rates are so low that, assuming the relationship between pro- tection and infection risk to be true, BCG vaccination can make virtually no contribution at all to the reduction of tuberculosis. . . . in Britain from now on8. Clearly further investigation is required, especially into the present risk of infection in Great Britain and its trend. The current national tuberculin survey will supply accurate data from which the estimated protection from BCG can be inferred. If the observed risk is of the same order as the LETTER 305 estimates of Sutherland and Springett, mass BCG vaccination should be stopped. Selective vac- cination will, of course, still be necessary for those likely to be at special risk. The observed relationship between protection and infection risk is, of course, of even greater importance to high-prevalence countries than low-prevalence ones. It could be that the epidemiolo- gical importance of infection by other mycobacteria has been overestimated and that efficient administration of a potent freeze-dried vaccine can have a much greater effect on reducing tuber- culosis in some countries than it now has in Great Britain. But the story of BCG vaccination will remain a pathetic one unless there is a more rational, enthusiastic and administratively efficient attitude towards it. REFERENCES i XVI Congreso Latinoamericano de Tuberculosis y Enfermedades de1 Aparato Respiratorio de la Union Latino- americano de Sociedades de Tisiologia. Union International contra la Tuberculosis. Comite Regional Latino- americano VIII Reunion. (1969) La Vacunacion BCG en 10s Programas de Control de la Tuberculosis en la America Latina. Maracaibo. * Lorrz, A., PERDRIZET, S. & HATTON, F. (1971). Epidemiologic de la Tuberculose et Defaillances de la Lutte Anti- tuberculeuse chez 1Enfant. Bulletin of the World Health Organization, 44, Supplt. 3 SPRINGET~, V. H. & SUTHERLAND, I. (1970). Comparison of the efficacy of liquid and freeze-dried strains of BCG vaccine in preventing tuberculosis. British Medical Journal. 4,148. 4 SARBADHIKARI, B. C. (1971). BCG in India-a failure. Calcutta. 5 BRITISH TUBERCULOSIS ASSOCIATION (1965). BCG vaccination by multiple-puncture: third report. Tubercle, 46,111. e PALMER, C. E. & LONG, M. W. (1966). Effects of infection with atypical mycobacteria on BCG vaccination and tuberculosis. American Review of Respiratory Disease, 94,553. HART, P. ISARCY (1967). Efficacy and applicability of mass BCG vaccination in tuberculosis control. British Medical Journal, 1,587. * SUTHERLAND, I. (1971). Future policy for BCG vaccination in Britain. Postgraduate Medical Journal, 47,759. s SPRINGETT, V. H. (1971). Tuberculosiscontrol in Britain 1945-1970-1995. Tubercle, 52,136. LETTER TO THE EDITOR The recent article by Abrahams (Tubercle, (1970) 51, 316) and the case reported by Marks (Tuber&, (1970) 51, 456) revealed a pitfall which may arise in the diagnosis of mycobacterial infection both in the epidemiological and clinical fields. We wish to draw attention to a case in which a similar problem arose. A Ceylon Moor boy, 16 years of age (who had not been vaccinated with BCG) was diagnosed in 1969 as having tubercu- lous cervical adenitis. He had no other evidence of tuberculosis elsewhere; but he gave a history of abscesses leading to sinus formation which healed spontaneously in the same region where the present swelling was observed; this history was borne out by scars at the site. He was tuberculin tested when first seen by us using 5TU on the forearms with PPD-S, PPD-G (Runyons Gp. II), PPD-B (Gp. III) and PPD-F (Myco. firtuitum, Gp. IV) and yielded reactions of 6 mm., 10 mm., 4 mm., and 6 mm., respectively. A cervical lymph node biopsy was done and M. tuberculosis (of human type) was recovered. Since there appeared to be no progression of this lesion, he was followed up at the out-patient surgical clinic but no anti-tuberculosis chemotherapy was given. A year later he was again tuberculin tested, now on the outer border of the volar aspect of the forearms. The result obtained was then PPD-S - 5 mm., G - 11 mm., and B - 15 mm. (PPD-F was not at that time available). It would be interesting to find out how often differential tuberculin testing, if routinely used, would yield such erroneous results in patients with bacteriologically positive disease caused by M. tuberculosis. Department of Bacteriology, M. R. M. PINTO University of Ceylon, C. BARR KBHARAKULASINGHE Peradeniya, Ceylon. S. N. ARSECULERATNE