Operational problems in vaccine trials.
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Bacterial Vaccines↗
Biomedical subjects
J Guld
Publications and source records attributed to J Guld.
Combined vaccination with BCG and toxoid antigens.
Simultaneous vaccination with different antigens has been widely practised in recent years. A notable example is percutaneous smallpox vaccination together with the intradermal injection of BCG. In contrast, the potentially even more time-saving procedure of combined vaccination (i.e., with vaccines mixed prior to injection) has been tried on only a very limited, experimental scale. Combined vaccination with a mixture of BCG and toxoids has not been suggested before. Such a mixed vaccine, with diphtheria and tetanus toxoids, was used in experiments in vitro and in vivo.No deleterious effect of toxoids on BCG was found in terms of reduction in oxygen uptake, germination rate, or counts of viable particles. The dose-response relationships (delayed hypersensitivity and skin reactivity) for BCG with and without added toxoids were compared in guinea pigs and no differences were found. The antibody response in guinea pigs to toxoids mixed with BCG or with aluminium hydroxide was measured following both primary and booster immunization. The primary response to toxoids was lower with BCG than with aluminium hydroxide. In booster immunization, the response was identical for the two mixtures.It appears that not only is a mixture of toxoids and BCG innocuous (given intradermally) but also BCG may have an adjuvant effect on the production of antibodies to the toxoids. Further experimentation is needed, first in the guinea pig model and later in pilot trials in man, to establish suitable dose levels. Furthermore, since BCG may act as an adjuvant both in producing antibodies and in the cell-mediated response to the toxoids, it would be desirable to clarify the possible interaction of these two immune responses in protection against disease.
Animals↗
Tuberculin sensitivity in guinea-pigs after vaccination with varying doses of BCG of 12 different strains.
In several previously reported studies a number of BCG strains, including those most widely used in vaccine production, were ranked according to their in vivo activity in various experimental models in rodents and to the local and allergic response that they provoked in children. In this report, 12 strains are ranked in terms of tuberculin conversion in guinea-pigs according to the minimum sensitizing dose. For 10 of these strains, this minimum dose is very low, ranging from 5 to 50 culturable particles. Thus the traditional practice of tuberculin-testing guinea-pigs that have been vaccinated with a full human dose of BCG (of the order of one million culturable particles) has such a low discriminating power that it is useless as a routine test for currently used vaccines. The ranking obtained in this model was largely but not completely in accordance with similar rankings in other models. The Tokyo strain and, to some extent, the London strain ranked comparatively lower than they do in children. The pronounced lack of virulence of the Prague strain was confirmed.
Animals↗
Present knowledge of immunization against tuberculosis.
This is a selective review, which, after recalling some immunological aspects, analyses the present knowledge on the protective efficacy of BCG vaccination, the vaccination reactions and complications that may be observed, and current methods of vaccine production and control. As regards the application of BCG vaccination, particular attention is given to dosage and vaccination techniques, direct and simultaneous vaccination, and revaccination. Finally, the evaluation of BCG vaccination programmes is briefly discussed.
Adolescent↗
Sensitivity to tuberculin and to a nonmammalian sensitin in Mandalay District, Burma.
Delayed hypersensitivity that can be demonstrated with either a strong dose of tuberculin or a conventional dose of a sensitin prepared from certain nonmammalian mycobacteria (mycobacteria of Runyon Groups II and III, e.g., Mycobacterium avium), is known to be highly prevalent in most tropical and many subtropical areas and rare in many temperate zones. Whether such sensitivity interacts significantly with tuberculosis or with leprosy is not known.A study of reactions to tuberculin (PPD-S) and to a sensitin prepared from M. intracellulare (PPD-B) was carried out in villages close to an area in which a clinical trial of the preventive effect of BCG against leprosy was being conducted. The population had not been vaccinated with BCG. Some of the villages were in river valleys that become flooded every year for a long period during the rainy season; others were on slopes above the area subject to floods. The findings showed that sensitivity to the nonmammalian sensitin was prevalent in the area, and thus confirmed previous findings of low-grade tuberculin sensitivity in Burma and neighbouring countries. No difference in this prevalence was found between flooded and nonflooded villages.
Adolescent↗
Tuberculin sensitivity and skin lesions in children after vaccination with 11 different BCG strains.
In previously published studies, a number of BCG strains used in several production laboratories were compared in animal models. Liquid vaccines from the different strains were prepared in one laboratory with a uniform technique, the aim being to obtain uniform in vitro properties. In the studies reported here, such vaccines were compared by means of vaccinating children in India and Denmark and then measuring their post-vaccination skin lesions and tuberculin sensitivity. One strain induced delayed hypersensitivity strikingly weaker than that induced by any of the others, although the vaccine was in no way inferior in terms of exhaustive in vitro tests. Differences among the other strains were slight, although sometimes statistically significant. The implications of such differences are discussed.
Adolescent↗
The virulence of some strains of BCG for golden hamsters. Further studies.
In principle, a strain of BCG used for the preparation of live vaccine should retain a moderate residual virulence. The inoculation of golden hamsters with large doses of BCG causes progressive, fatal disease but not all strains are equally active. In a previous paper, the present authors gave data from experiments with 9 BCG strains; in this report, 4 additional strains, three of which are in routine use in vaccine-production laboratories, are compared with one of the strains used in the previous experiments. The five strains differ widely in their ability to kill hamsters and were ranked in nearly the same order in two identically designed experiments. The differences in virulence found between strains derived relatively recently from a single mother strain were particularly noticeable. These differences were sometimes accompanied by striking changes in the growth characteristics of the strains with a lower virulence. The hypothesis that the lower virulence in such cases is a sign of genetic mutation is consistent with the general biological experience that virulence is often lost in vitro but that it practically never increases.
Animals↗
The protective effect in bank voles of some strains of BCG.
The bank vole, like the guinea-pig, can be immunized against tuberculosis with very small doses of BCG, presumably because BCG is sufficiently virulent for both these species to multiply freely until the immunization of the animal has reached a maximum. Large doses of BCG induce an earlier, but not an ultimately stronger, immunity. However, the smallest immunizing dose is not the same for all BCG strains and this is a feature that may be used to differentiate strains. In the studies reported by the authors, the smallest immunizing dose for the bank vole was estimated for 11 BCG strains, some of them widely used in man. The results indicate potency ratios of 20: 1 between the strongest and the weakest strains. The ranking of strains in terms of the smallest immunizing dose was found to be correlated in most, but not in all, cases with a previously reported ranking of the lethal effects of the various strains in golden hamsters. The implications of these findings for production requirements and for reference preparations of BCG are discussed.
Animals↗
The use of jet-injectors in BCG vaccination.
In mass vaccination programmes, the jet-injection of vaccine may have considerable operational advantages over the classical techniques. The technical performance of two models of jet-injector, the Dermo-Jet and the Ped-O-Jet, in BCG vaccination was assessed in a number of studies which are reviewed by the authors. It is shown that the jet-injectors do not administer the full dose for which they are calibrated and that the size of the vaccination lesion varies more than after vaccination by syringe.By increasing the dosage considerably, the results of vaccination by jet-injection may be improved to a certain extent but the risk of unpleasant reactions is also increased.
BCG Vaccine↗
The virulence of some strains of BCG for golden hamsters.
Although the injection of a large dose of BCG causes progressive, fatal disease in the Syrian golden hamster, not all BCG strains are equally active in this respect. It has been suggested that a strain to be used for vaccinating human beings should not be too weakly virulent in the hamster.Nine BCG strains, some of them widely used for BCG production, were compared with regard to their virulence for hamsters. Five of the strains were found to be of about the same high virulence; the other 4 were less virulent.Of the strains derived from the BCG that was used with success in the BCG trial conducted in Great Britain more than 15 years ago, some are more virulent for hamsters than others. It is suggested that virulence is easily lost but not gained when strains are maintained in vitro. Thus, less virulent strains would have deviated from the original protective strain, and for this reason may be less acceptable for vaccine production.
Animals↗
The stabilizing effect of gelatin on dilutions of various tuberculins.
Adsorption of highly diluted tuberculin to the inner surface of containers is particularly pronounced for acid-precipitated PPD, and certain such preparations are routinely issued with the non-ionic detergent Tween 80 as a stabilizing agent. It has been shown, however, that Tween 80, besides its anti-adsorptive effect, also has a depressive in vivo effect, especially on tuberculin reactions that would have been weak even for a test without Tween. The authors have shown in a previous report that gelatin (0.1%) also has an anti-adsorptive effect, without apparently modifying the reaction in vivo.In the present report, the effect of gelatin on tuberculins other than acid-precipitated PPD is examined, and the loss due to surface activity in the container is found to be considerably less, though still significant, for instance, for the International Standard of PPD of Mammalian Tuberculin. The loss is particularly pronounced, and the stabilizing effect of gelatin is particularly striking, for ampoules only partly filled (i.e., with an inner surface that is large in relation to the volume of the content).It is suggested that gelatin, or some similar substance with little or no in vivo action, might be used more readily, and for more kinds of tuberculin, than Tween 80, provided that further critical studies do not reveal any so far unknown factor.
Drug Stability↗
The duration of BCG-induced tuberculin sensitivity in children, and its irrelevance for revaccination. Results of two 5-year prospective studies.
It had been shown earlier, in a retrospective study, that tuberculin sensitivity is stronger in children tested for the second time after vaccination than in those tested for the first time after vaccination. The hypothesis that the tuberculin test itself may reinforce sensitivity to a further test has now been confirmed in 2 strictly controlled prospective studies, which are reported here. The results refer to the tuberculin reactions 5 years after vaccination. These reactions were significantly larger in children who had had an intermediate test (less than 5 years after vaccination) than in those tested for the first time at 5 years. This was found equally for several BCG products, but there was a significant tendency for the PPD batch RT 19-20-21 to have a more pronounced effect than the other tuberculins.It follows from the results of these studies that a possible waning of tuberculin sensitivity cannot be revealed by regular tuberculin testing. Moreover, experiments in guinea-pigs have shown that restoration of sensitivity by means of an injection of tuberculin does not influence the acquired resistance; there are no particular reasons to believe that this should be different in man. Thus the authors consider the very common practice of giving regular tuberculin tests to vaccinated children, in order to decide on possible revaccination, to be devoid of any scientific basis.
Animals↗
[Correlation of tuberculin sensitivity before and after BCG vaccination].
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Asia, Southeastern↗
BCG-induced allergy and immunity in guinea-pigs during the first year after vaccination.
It has been traditional practice in many countries to let revaccination with BCG depend on the outcome of periodically repeated tuberculin testing. Acquired resistance to tuberculosis and tuberculin skin sensitivity are concomitant results of BCG vaccination, and it is apparently inferred that a waning resistance will be faithfully reflected in a waning tuberculin sensitivity. However, it has been demonstrated in recent years, both in man and in animals, that the waning of tuberculin sensitivity may be prevented merely by a repetition of the tuberculin test, while data presented in this and a following report indicate that tuberculin testing has no such influence on the course of BCG-induced resistance to tuberculosis.
Animals↗
Duration of allergy and immunity in BCG-vaccinated guinea pigs. A five-year study.
A five-year study has shown that the tuberculin sensitivity of guinea-pigs seemingly wanes completely after BCG-vaccination over the course of years, but it can be restored by a single injection of tuberculin to the same level as that found in newly vaccinated animals of the same age. In contrast the acquired resistance to tuberculosis in guinea-pigs vaccinated several years previously is of intermediate strength, inferior to that of the newly vaccinated, and is not restored (apparently not influenced at all) by the injection of tuberculin. It is thus not possible to follow the course and eventual waning of resistance by means of repeated tuberculin testing, and the very common practice of timing revaccination of the individual according to the outcome of such testing must therefore be considered to be without scientific basis.
Animals↗
Correlation of tuberculin sensitivity before and after BCG vaccination.
The frequent experience in the tropics of poor results of BCG vaccination is sometimes explained by a hypothetical interaction with "non-specific" tuberculin sensitivity. However, samples of data from five tropical countries, reported in this paper, demonstrate a slight, positive correlation between the individual tuberculin allergy before and after vaccination. A negative correlation might have been expected had the "non-specific" allergy been the cause of the poor vaccination results, and this particular hypothesis is therefore rejected.
BCG Vaccine↗
The effect of Tween 80 on intradermal tuberculin reactions.
Since 1958, the tuberculin dilutions used in WHO-assisted tuberculosis programmes have been stabilized with the detergent Tween 80, in order to prevent adsorption of tuberculin to the inner surface of the container. However, the reactions to tuberculin with Tween 80 tend to be somewhat softer than those to ordinary tuberculin, for a given size; and, moreover, the curves for the frequency distribution, by size, of the reactions to tuberculin with Tween 80 tend to have a somewhat different shape from those of the reactions to ordinary tuberculin, intermediate-sized reactions (5-10 mm) being less frequent in a given population when Tween tuberculin is used.Further comparisons of tuberculin with and without Tween 80, especially in high doses, are reported in this paper, and it is concluded that Tween 80 has, in addition to its stabilizing effect in vitro, an effect in vivo that may be described as depressive, reducing the size of small reactions in particular. This in vivo effect appears to have no causal connexion with the specificity of the tuberculin or with the origin of the allergy in the population tested.
Adolescent↗