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.     

The restorative influence of repeated tuberculin testing on tuberculin sensitivity in BCG-vaccinated schoolchildren

This study confirms that repeated tuberculin testing may prevent waning of, or restore, tuberculin sensitivity in BCG-vaccinated schoolchildren, and demonstrates that tuberculin testing has this effect even if it is done relatively shortly after vaccination. Therefore the results of repeated tuberculin tests cannot reveal a possible waning of BCG-induced tuberculin sensitivity. This finding shows that a revaccination policy based on the waning of tuberculin sensitivity is not rational.     

Effect of intradermal tuberculin tests on BCG-induced allergy

Trials are going forward to determine whether intradermal tuberculin testing with 10 TU at yearly intervals after BCG vaccination may prevent waning of BCG-induced allergy in schoolchildren. Meanwhile, two experiments to the same purpose, carried out in guinea-pigs, are described. They show that waning allergy in guinea-pigs can be sustantially enhanced by intradermal injection of either purified tuberculin or Old Tuberculin, the effect lasting for at least 8 weeks, even with so small a dose as 5 TU. It is pointed out that this enhancing effect has been demonstrated only in BCG-vaccinated guinea-pigs and that it is not known whether the same phenomenon would occur in guinea-pigs infected with living human tubercle bacilli.     

Determining the prevalence of tuberculosis infection in populations with non-specific tuberculin sensitivity

In tropical countries, where there is generally a high prevalence of non-specific sensitivity, the tuberculin test is inadequate for detecting tuberculosis infection. A method is proposed by which the prevalence of infection in the population can be determined under such circumstances thus making possible meaningful epidemiological surveillance of the disease. This method compares levels of tuberculin sensitivity in individuals before and after BCG vaccination. If BCG vaccination fails to produce an increase in tuberculin sensitivity, the individual must have been infected with human or bovine tubercle bacilli.     

Comparison of various tuberculosis screening strategies based on tuberculin testing in schoolchildren in Paris

BackgroundFollowing the discontinuation in 2004 of routine tuberculin testing in children in France, we have performed a study aiming at assessing the relevancy and identifying the best modalities of continuation of tuberculosis screening activities in schoolchildren in Paris.MethodThe study was conducted in children attending the last grade of primary school. A preliminary case control study was carried out in order to identify risk factors for abnormal tuberculin test results. Data on tuberculin testing activities conducted in 2004 were analyzed in order to compare the impact and the efficiency of five different target populations for screening. The impact of each of the screening strategies was assessed as the number of tuberculosis infections for which a specific treatment has been proposed and their efficiency as the average number of tuberculin tests needed to identify such an infection.ResultsBeside multiple BCG vaccinations, the main risk factor for an abnormal tuberculin test result was the fact that at least one of the child's parents was born in a country of high tuberculosis prevalence. Within the five strategies tested, two can be selected on the basis of their impact and efficiency: the testing of all children and the targeting of the testing to children with characteristics putting them at high risk of tuberculosis.DiscussionFor Paris or other large cities in France, decision-makers will have to consider the local tuberculosis epidemiology, the resources that can be devoted to tuberculosis screening of schoolchildren and the regional specificities of the new BCG vaccination policy.     

Indications for,and the significance of,the tuberculin test in the Netherlands

The almost 100-year-old tuberculin skin test still is the gold standard for diagnosing Mycobacterium tuberculosis infection. The sensitivity of this test with the usual cut-off values is high, but may be decreased with impaired cellular immunity and at older age. The specificity is primarily determined by cross-reactivity to atypical mycobacterial infections and vaccination with Bacillus Calmette-Guérin (BCG). Positivity of the skin test after BCG vaccination decreases with time after vaccination and depends on the age when vaccinated. The tuberculin reaction can be boosted by repeated tuberculin skin tests over a short time period, whereby the anamnestic immune response is stimulated. This boosting phenomenon occurs mostly with atypical mycobacterial infections, after BCG vaccination and at older age. Interpretation of the tuberculin skin test depends on the indication for the test, the expected risk of latent tuberculosis infection, higher prevalence of 'old' tuberculosis in elderly Dutch people and immigrants, BCG vaccination status and, if a baseline value is available, the boosting phenomenon. Its role in the diagnosis of tuberculosis is limited.     

EXPERIMENTAL studies of vaccination,allergy, and immunity in tuberculosis. I. Design for a research programme

With the growing popularity of BCG vaccination in tuberculosis control programmes, the tuberculin test has become a widely accepted means of determining the success of vaccination, despite persistent disagreement in scientific circles about the relation between skin sensitivity to tuberculin and acquired resistance to tuberculosis. With little hope today of solving the allergy-immunity problem by studies on human beings, and because of the urgent practical need for guide-lines for international mass BCG campaigns, a research programme in laboratory animals has been patterned on extensive studies of BCG vaccination and post-vaccination allergy in school-children.The programme, composed of a series of separate but interrelated projects, is not primarily concerned with the academic intricacies of the allergy-immunity problem. Rather, it has more directly practical objectives. First, to reproduce as nearly as possible in animals what is now being done in vaccination programmes in human beings, in order to compare, in the two species, the responses that are readily observable in man. Secondly, by challenging the vaccinated animals with virulent organisms, to study the association between those responses and resistance to virulent infection. Finally, from the results so obtained, to determine whether and to what extent some observable response to vaccination can be used (by analogy) as a practical guide to the successful vaccination of man.The experimental design takes into account variation in the animals, the vaccines, the challenge infection, and other pertinent factors. Large numbers of animals and randomization procedures have been necessary to ensure that all kinds of variation-biological, sampling, observer errors, etc.-are reduced to a minimum and distributed by chance among the various experimental groups. Observations and techniques common to the projects so far undertaken in the programme are described in the last section of the paper.     

A PRELIMINARY assessment of BCG vacination in India

A NEW ASSESSMENT ACTIVITY IN RELATION TO THE WHO/UNICEF BCG VACCINATION PROGRAMME IS DESCRIBED IN THIS REPORT: according to a detailed plan special field teams collect data on tuberculin sensitivity to determine how efficiently children are being selected for vaccination and to appraise the allergy produced by the mass vaccinations. Results of nine months' work in India have important implications for the practical BCG work.Testing of unvaccinated groups of schoolchildren shows that the pattern of tuberculin sensitivity differs in different parts of India. Specific tuberculin sensitivity is found in all areas, as evidenced by strong reactions to the 5 TU test. Many children had a low-grade non-specific sensitivity, evidenced by small reactions to 5 TU and large reactions to 100 TU. This non-specific tuberculin sensitivity was less frequent at high altitudes, and most common in low-lying humid areas: in all areas it was more prevalent than specific sensitivity.In some areas non-specific tuberculin sensitivity is so strong that it cannot be effectively distinguished from specific sensitivity: consequently, many children not infected with tuberculosis are undoubtedly being excluded from vaccination.Sample retesting of children vaccinated in the mass campaign revealed variable levels of allergy, in many instances much lower than had been expected. These results cannot be explained by a native incapacity of the Indian children to develop strong allergy-nor presumably by the vaccine used. Impairment of the vaccine by exposure to light could be no more than a contributory factor. The marked variability of the campaign results suggests that some factor connected with the handling or application of the vaccine (or possibly of the tuberculin) is involved.     

Lack of correlation between BCG-induced tuberculin skin test sensitisation and protective immunity in cattle

Vaccination of cattle with Mycobacterium bovis Bacille Calmette-Guérin (BCG) can provide significant protection against bovine tuberculosis (TB). However, BCG vaccination sensitises animals to respond to the tuberculin skin-test. This provides a potential operational impediment to the use of BCG as a cattle vaccine since the tuberculin skin-test is the primary surveillance tool used by many countries with ‘test and slaughter’ control strategies. Currently, it is also unclear what BCG-induced skin-test conversion means in respects to BCG's protective immunity. In the current study we first investigated the duration of tuberculin skin-test sensitisation in calves neonatally vaccinated with BCG. BCG vaccination induced strong skin-test responses in calves during their first 6 months. However, a rapid decay in skin-test sensitivity was observed after this time. Between 6 and 9 months this represented a reduction from 80% to 8% of calves providing a positive response in the single intradermal comparative cervical tuberculin test at standard interpretation. We next investigated the relationship between BCG induced skin-test sensitivity and retention of protective immunity. Calves were neonatally vaccinated with BCG and subsequently divided into 2 groups based on retention or loss of tuberculin skin-test responses after 6 months. In contrast to their skin-test responsiveness, these vaccinates maintained their tuberculin specific IFN-γ blood responses. Moreover, irrespective of their pre-challenge skin-test responses, following M. bovis challenge both groups of BCG vaccinated calves demonstrated comparable levels of protection, as evidenced by reduced TB-associated pathology. Therefore, we have demonstrated that following neonatal BCG vaccination of cattle, tuberculin skin-test responder frequencies waned rapidly after 6 months but importantly, loss of skin-test sensitivity did not correlate with loss of protective immunity. These findings could have implications for the practical application of BCG based cattle vaccines.     

BCG vaccination and tuberculosis in Japan

This paper summarizes Bacillus Calmette-Guerin (BCG) vaccination and revaccination policies in Japan, its cost-effectiveness, side effects, proposed selective vaccination strategy, and present tuberculosis situation in Japanese perspectives based on Medline database and other published reports. Universal BCG vaccination in infants and revaccination among children were not found economically justifiable. Overall tuberculosis incidence in Japan is higher than that of other developed countries. Trend of decline in tuberculosis incidence is similar to that of the countries where universal BCG vaccination has never been implemented. In the recent years, the number of tuberculosis group infection has been escalating. Since BCG revaccination program has already been discontinued, a consensus on universal BCG vaccination is also essential based on social, political, and economical factors. Side by side, more pragmatic strategies such as well-defined tuberculin test, selective vaccination policy based on tuberculosis incidence in each administrative zone, and early vaccination of high risk groups, should be formulated.     

Tuberculin intradermal reaction (IDR) or tuberculin test

Tuberculinic switch is defined as an increase of the intradermal reaction diameter in two tests carried out within three months of each other. The tuberculinic skin reaction proves the presence of a delayed hypersensitivity induced by mycobacterial antigens (Mycobacterium tuberculosis, BCG, some atypical mycobacteria). However, this reaction does not always prove an effective protection against the BK. The intradermal injection of a purified Purified Protein Derivative (PPD) resulting from a culture of M. tuberculosis is the only method validated for the diagnosis of tuberculosis infection (latent infection) and screening for hypersensitivity and post-vaccine BCG (Official French decree No 96-775 of September 5, 1996 and its decree relating to vaccination by BCG and tuberculin tests). The guidelines concerning tuberculin testing are: investigating on a case of tuberculosis; tracking or surveillance of people frequently exposed to tuberculosis (examination on recruitment and follow-up of exposed professionals); prevaccine testing in children over four weeks of age.     

EXPERIMENTAL studies of vaccination,allergy, and immunity in tuberculosis. II. Effect of varying the dose of BCG

Results are given for one of a series of projects designed to investigate the relation between observable post-vaccination responses and acquired resistance to tuberculosis. Controlled variations in the dose of BCG vaccine have previously been shown to cause systematic variations in the degree of skin sensitivity to tuberculin and the size of vaccinal lesions in human beings: the purpose of the present project was to see if similar variations would be produced in guinea-pigs and then, by infecting the animals with virulent tubercle bacilli, to see how survival time correlates with tuberculin allergy and vaccinal lesions.Four doses of freshly prepared BCG vaccine, ranging from 1/100 to 10 times the dose ordinarily used for intradermal vaccination of humans, and one dose of heat-killed BCG 100 times that strength, were used to vaccinate five groups of guinea-pigs, each containing 120 animals. A sixth group of 120 animals was not vaccinated. All animals were tuberculin-tested just before and five weeks after vaccination, challenged with a strong dose of H-37 Rv, and then allowed to die, so that survival time could be used as a measure of resistance.As the dose of living BCG was increased, groups of guinea-pigs showed a progressive increase in the average degree of post-vaccination tuberculin allergy, size of vaccinal lesion, and length of survival after virulent infection. The heat-killed BCG resulted in weak allergy and a short survival time, yet the vaccinal lesions averaged about as large as would be expected from a corresponding dose of living BCG. These results (excluding studies of survival time) correspond closely to those found in human studies.The implications of the results with respect to practical BCG vaccination programmes, while no more than speculative at present, point toward possible advantages in inducing high degrees of tuberculin allergy and toward the dubious significance of the vaccinal lesion as an index of a vaccine's immunizing potency.     

Tuberculin reactivity in a population of schoolchildren with high BCG vaccination coverage.

OBJECTIVE: To investigate the influence of BCG vaccination or revaccination on tuberculin skin test reactivity, in order to guide the correct interpretation of this test in a setting of high neonatal BCG vaccination coverage and an increasing BCG revaccination coverage at school age. METHODS: We conducted tuberculin skin testing and BCG scar reading in 1 148 children aged 7-14 years old in the city of Salvador, Bahia, Brazil. We measured the positive effect of the presence of one or two BCG scars on the proportion of tuberculin skin test results above different cut-off levels (induration sizes of > or = 5 mm, > or = 10 mm, and > or = 15 mm) and also using several ranges of induration size (0, 1-4, 5-9, 10-14, and > or = 15 mm). We also measured the effects that age, gender, and the school where the child was enrolled had on these proportions. RESULTS: The proportion of tuberculin results > or = 10 mm was 14.2% (95% confidence interval (CI) = 8.0%-20.3%) for children with no BCG scar, 21.3% (95% CI = 18.5%-24.1%) for children with one BCG scar, and 45.0% (95% CI = 32.0%-58.0%) for children with two BCG scars. There was evidence for an increasing positive effect of the presence of one and two BCG scars on the proportion of results > or = 5 mm and > or = 10 mm. Similarly, there was evidence for an increasing positive effect of the presence of one and two scars on the proportion of tuberculin skin test results in the ranges of 5-9 mm and of 10-14 mm. The BCG scar effect on the proportion of results > or = 5 mm and > or = 10 mm did not vary with age. There was no evidence for BCG effect on the results > or = 15 mm. CONCLUSIONS: In Brazilian schoolchildren, BCG-induced tuberculin reactivity is indistinguishable, for results under 15 mm, from reactivity induced by Mycobacterium tuberculosis infection. BCG revaccination at school age increases the degree of BCG-induced tuberculin reactivity found among schoolchildren. This information should be taken into account in tuberculin skin test surveys intended to estimate M. tuberculosis prevalence or to assess transmission patterns as well as in tuberculin skin testing of individuals used as an auxiliary tool in diagnosing tuberculosis. Taking this information into consideration is especially important when there is increasing BCG revaccination coverage.     

CERTAIN characteristics of BCG-induced tuberculin sensitivity

Post-vaccination tuberculin sensitivity is being used to evaluate the immediate effects of the extensive WHO/UNICEF mass BCG vaccination programmes currently in progress. During the past five years the Tuberculosis Research Office has been studying the tuberculin sensitivity produced by BCG vaccination, and the present paper discusses some of the most important characteristics of BCG-induced allergy. The material for the paper was drawn from the results in five countries of vaccinating more than 6,000 schoolchildren and retesting them at one or more intervals after vaccination.Tuberculin sensitivity produced by BCG is not the kind of response that may logically be described as "positive" or "negative". Rather, vaccination always produces, or increases, sensitivity to tuberculin, although, with some vaccines and in some persons, the degree of sensitivity produced may be low. BCG-induced allergy can best be described by the distribution of the sizes of the tuberculin reactions and summarized by the mean and standard deviation of the distribution. The common practice of classifying post-vaccination reactions as "positive" or "negative" is biologically meaningless and may be the cause of many fallacious notions about the allergy produced by BCG.The degree of post-vaccination allergy varies with the potency of the vaccine used: a potent vaccine has been shown to produce allergy about as strong as that produced by natural infection wherever carefully controlled studies have been made. No evidence was found that allergy wanes or is lost after intradermal vaccination: the impression that it does so may often have been the consequence of the practice of revaccination and of ignoring the influence of experimental error. Unless very weak vaccines are used, there is no indication that superinfection can be identified after vaccination. The diagnostic value of the tuberculin test is thus being destroyed in many places where mass campaigns are being done, particularly in those places where a high degree of tuberculin sensitivity is being produced.     

The BCG vaccine: information and recommendations for use in Australia

The Bacille Calmette-Guérin (BCG) vaccine since its first use in 1921 has been the subject of much controversy as to its effectiveness and applicability. BCG vaccination is still considered an important strategy in the National Tuberculosis Programs of countries with a high burden of tuberculosis (TB) because of its benefit to infants but its effect on the control of TB has been limited. By contrast, in countries with a low prevalence of TB, significant policy differences exist both within and between countries. BCG vaccination does not prevent transmission of infection to the individual. In immune-competent neonates and infants it is accepted that BCG reduces the likelihood of TB infection progressing to disease or if disease occurs, substantially lessens the chance of a severe outcome. The benefit in older agegroups is less clear. In the Australian health worker, the BCG strategy is no longer recommended as the primary means of health care worker (HCW) protection. The preferred strategy is appropriate infection control measures, staff education and a tuberculin skin testing program that identifies and treats the at-risk infected HCW. The emergence of multi-drug resistant strains has however renewed interest in BCG in the HCW. This document provides recommendations for use of the BCG vaccine in the Australian community based on the best available evidence and consensus opinion. State and Territory TB Control Units should be consulted with regard to their BCG vaccination guidelines.     

BCG vaccination among Canadian Indians and Inuit: the epidemiological bases for policy decision

It is necessary to reassess tuberculosis (TB) control among Canadian Indians and Inuit, particularly the policy of BCG vaccination, because of the perceived decreased risk of TB among Indians and Inuit as well as the uncertainty surrounding BCG effectiveness due to conflicting results from several large-scale trials in different regions of the world. An attempt is made here to assess the epidemiological situation of TB among the Indian and Inuit population in Canada, to review publications on BCG and TB control, focusing on their relevance to the Canadian situation; and to consider policy options for TB control among Canada's Native population. On the basis of special studies conducted in Frobisher Bay, Northwest Territory, Brzybowski et al. estimated the annual risk of infection among the Inuit to be 3%-4% in 1971 and 1.5%-2% in 1974, ignoring tuberculin sensitivity attributed to BCG. 5 surveys over 20 years in Alaska, where mass BCG had not been applied universally, showed a marked decline in the prevalence of tuberculin sensitivity. A 1957 survey of the total population of Manitoulin Island, Ontario, which included 1475 unvaccinated Indians, revealed a prevalence of tuberculin positivity much higher than in whites in all age groups. Among Indians, 18% of the under 15, 63% of the 15-39, and 82% of the over 40 age groups were tuberculin positives. Springett concluded that vaccination was indicated in a population where not more than 20% were tuberculin positive, but the risk of new infection should exceed 10% over the next 10 years. An urgent need exists to conduct a series of tuberculin surveys of representative samples of Natives at different age groups to determine the current situation. If one wants to eliminate "false-positives" due to the effects of BCG on tuberculin sensitivity, then the suggestion that BCG be withheld from selected cohorts which are then put under intensive surveillance and tested at periodic intervals should be adopted. 2 randomized controlled trials of BCG vaccination -- the American Indian Trial and Ferguson and Sime's Saskatchewan Indian trial, initiated during the 1930s--showed high protective efficacy in the 80% range. Both were conducted at a time when the risk of infection, the case rate, and the mortality rate were all very high. A 5-year retrospective study among 2500 Inuit who were free of active disease in 1964 found that those who were vaccinated had a 1.2% mean annual incidence rate of active TB, lower than the incidence among the nonvaccinated. The complications arising from BCG vaccination usually are mild and infrequent. Research needs and policy options are outlined.     

Relation between pre-vaccination and post-vaccination tuberculin sensitivity. A contribution to the ecology of BCG vaccination

BCG vaccination is commonly assessed in terms of post-vaccination sensitivity to tuberculin. If vaccination is followed by the development of a high degree of tuberculin sensitivity, it is assumed that the vaccination was successful. If, on the other hand, tuberculin sensitivity does not develop, it is assumed that the vaccination was unsuccessful. Both these assumptions equate post-vaccination tuberculin sensitivity with BCG-induced tuberculin sensitivity and disregard the possibility that environmental factors, such as the prevalence of low-grade naturally acquired tuberculin sensitivity, may affect the outcome of vaccination. Thus, while it seems reasonable to equate post-vaccination and BCG-induced tuberculin sensitivity in areas where low-grade sensitivity is uncommon, it might be unjustifiable to do so in areas where such sensitivity is prevalent.     

Trial of BCG vaccines in south India for tuberculosis prevention: first report: Tuberculosis Prevention Trial*1

The protective effect of BCG vaccination is being evaluated in a controlled community trial near Madras in south India. After tuberculin and sensitin testing and radiographic and bacteriological examinations, BCG vaccines and placebo were allocated randomly to about 260 000 individuals, of whom 115 000 were definitely tuberculin negative at the time of vaccination. Intensive efforts are being made, by means of regular follow-up surveys, to identify all new cases of tuberculosis occurring in the community. This report presents the findings of the first 7½ years of follow-up. Incidence of infection was high in the study population. However, incidence of bacillary disease was more frequent among initial tuberculin reactors, especially among the older persons, than among non-reactors of whom the majority were in the younger age groups. The distribution of new cases of bacillary tuberculosis among those not infected at intake did not show any evidence of a protective effect of the BCG vaccines.     

Diagnosis of tuberculosis infection

The prevalence of tuberculosis infection varies between countries, with an estimate in adults in Spain of 25%. The technique for its diagnosis, in spite of its antiquity, is tuberculin. Even today, this test continues to be in use in the majority of countries. In recent years two methods of immunodiagnosis based on detection of IFN-g released by T cells in response to M. tuberculosis-specific antigens, enables us to diagnose the infection in a laboratory without all of the problems deriving from the administration of tuberculin. From the contact studies made it has been shown that these techniques correlate better with the degree and duration of exposure to Mycobacterium tuberculosis and that prior vaccination with BCG does not interfere with their results, which without doubt will result in a reduction in the number of unnecessary chemoprofilaxis.     

Case-control evaluation of a school-age BCG vaccination programme in subtropical Australia

In 1956 a programme was initiated to vaccinate all children aged 12-14 years who were attending schools in Queensland, Australia. In view of the declining incidence of tuberculosis in Australia as a whole, there was a need to evaluate the effectiveness of the programme and its procedures. We therefore carried out a case-control study of Queensland's population, excluding certain known high-risk groups. Cases were Queensland residents with notified tuberculosis and of the appropriate age; two controls per case were chosen from the electoral roll. Information on vaccination status was obtained mainly from questionnaires and school records, where available. The results show that at best BCG vaccination had a modest protective effect, approximately 30% when the patients were diagnosed, which was on average 15 years after they had been vaccinated in the school programme. In the north the climate of Queensland is tropical, while in the more heavily populated south it is subtropical. A substantial proportion of the school records reported weak positive reactions to preliminary tuberculin testing, believed to be due largely to atypical mycobacteria. A similar phenomenon has been observed in other tropical regions, and may help to explain the apparent absence of a strongly protective effect for BCG vaccination.