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.     

Lysed BCG vaccines. 2. The effect of lysis on the immunogenicity and allergenicity of BCG vaccines

The authors have attempted to prepare lysed BCG vaccines retaining the protective antigens of the BCG cell wall and yet eliciting in experimental animals limited sensitivity to the tuberculin substances, the advantage sought being to retain the usefulness of the tuberculin following vaccination as an indicator of superinfection.     

Tuberculosis prevention: where do we go from here?

The Karonga (Malawi) Prevention Trial revealed that repeat BCG vaccinations did not protect against pulmonary tuberculosis (TB) but appeared to provide some protection against glandular TB. They increased protection against leprosy. In fact, a single BCG vaccination conferred 50% protection against leprosy and a repeat BCG vaccination increased protection by another 50%. This trial's findings confirm the need for maintaining BCG vaccination programs in countries where leprosy is a public health problem, for individuals at high risk of leprosy (i.e., contacts of leprosy cases), and because BCG provides some protection against severe forms of TB (i.e., miliary disease and TB meningitis). An alternative TB vaccine needs to be developed, however. The protective efficacy of BCG against pulmonary TB is higher at latitudes far from the equator (80% in northern Europe vs. 0% in India and Malawi). It appears that the immunologic effects of environmental mycobacteria compromise BCG's protective effect against pulmonary TB. There is heterologous immunity between various mycobacterial infections. Low-level delayed-type hypersensitivity (DTH) to tuberculin in non-BCG vaccinated people reflects exposure to environmental mycobacteria. These people are at lower risk of TB than are people with either no DTH or strong DTH to tuberculin. Intradermal exposure to different mycobacteria provides varying degrees of protection against TB in guinea pigs. The warmer and the wetter the environment, the more widespread is colonization by mycobacteria. An area of future research is mapping the distribution of environmental mycobacteria, correlating it with the pattern of DTH responses to tuberculin, and then laboratory work to isolate relevant antigens of the mycobacteria. Another approach is identifying mycobacterial antigens that elicit protective immune responses in vitro so researchers can then identify which antigens and responses are associated with patterns of DTH known to reflect low risk of TB and which response patterns are elicited by BCG against leprosy but not TB antigens. New vaccines are not on the imminent horizon, however.     

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.     

Tuberculosis studies in Muscogee County,Georgia. Twenty-year evaluation of a community trial of BCG vaccination.

A controlled trial of BCG vaccination was conducted in 1950 in Muscogee County, Ga., and Russell County, Ala. The study population consisted of 64,136 volunteers over the age of 5 years who had satisfactory skin tests with 5 tuberculin units of purified protein derivative and whose chest photofluorograms were considered by two readers to show no significant pulmonary abnormalities. Approximately half of the nonreactors to tuberculin were vaccinated with the Tice strain of BCG by a multiple-puncture method. During a 20-year period of follow-up, 207 cases of tuberculosis were identified among the persons who had been tuberculin reactors in 1950, 36 cases were identified among the controls, and 32 cases were identified among the vaccinees. The average annual case rates per 100,000 were 47.0 for reactors, 13.4 for controls, and 12.6 for vaccinees.     

BCG scar and positive tuberculin reaction associated with reduced child mortality in West Africa. A non-specific beneficial effect of BCG?

Previous studies have suggested that the bacille Calmette-Guérin (BCG) vaccine may have a non-specific beneficial effect on childhood survival in areas with high mortality. We examined whether BCG-vaccinated children with a BCG scar or a positive tuberculin reaction had better survival than children without such reactions. As part of an ongoing two-dose measles vaccine trial for which children were recruited at 6 months of age, we examined 1813 children for BCG scar at 6 months of age and 813 BCG-vaccinated children were skin-tested for delayed hypersensitivity to tuberculin, tetanus and diphtheria. We found that BCG-vaccinated children with a BCG scar had significantly lower mortality compared with BCG scar-negative children, the mortality ratio in the first 12 months of follow-up being 0.41 (0.25-0.67). BCG-vaccinated children with a positive tuberculin test had a mortality ratio of 0.45 (0.24-0.85) compared with tuberculin negative children. These results were unchanged by control for potential confounders or using different cut-off points for a tuberculin-positive response. Exclusion of dead children who had HIV antibodies did not modify the estimate (mortality rate (MR)=0.46 (0.23-0.94)). After censoring for tuberculosis (TB) exposure at home, the mortality ratios for having a scar and being tuberculin-positive were 0.46 (0.27-0.79) or 0.42 (0.21-0.84), respectively. Children positive to tetanus or diphtheria in the skin test had the same mortality as children not responding to these vaccine-related antigens. Thus, BCG scar and a positive tuberculin reaction were associated with better survival in early childhood in an area with high mortality. Since nothing similar was found for responders to diphtheria-tetanus-pertussis (DTP) vaccine, and the effect could not be explained by protection against tuberculosis, the effect of BCG vaccination could be due to non-specific immune-stimulation protecting against other infections.     

Loss of anti-mycobacterial efficacy in mice over time following vaccination with Mycobacterium bovis bacillus Calmette-Guérin

Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the most often used vaccine worldwide and sole vaccine against tuberculosis. BCG is protective against severe form of childhood tuberculosis but less or not protective to adult pulmonary tuberculosis. Therefore, improved vaccination strategies and development of new tuberculosis vaccines are urgent demands. For those purposes, appropriate animal models that reflect human are critically useful. However, in animal models, BCG vaccination protects well against subsequent challenge of Mycobacterium tuberculosis. In this study we evaluated the duration of protective efficacy of the BCG vaccination in mice over time and found that efficacy was diminished 40 weeks after vaccination. The aged mice older than 45 weeks are protected sufficiently after the vaccination with BCG, suggesting that loss of its efficacy is not dependent on the age of mice but rather depends on the period from vaccination. The loss of protection occurred in TH1 polarized STAT6 deficient mice despite the maintenance of interferon (IFN)-gamma production activity of lymph node cells and splenic CD4⁺ T cells against M. tuberculosis antigens. Our data suggest that the duration from vaccination may explain the variation in BCG efficacy against adult pulmonary tuberculosis.     

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.     

The BCG controversy: a reappraisal of the protective effect against tuberculosis and leprosy

BCG (Bacillus Calmette Guerin) vaccine remains a highly controversial method of preventing tuberculosis and leprosy despite more than eighty years of use. The protective effect against tuberculosis observed in various studies ranged from -56% to 98%. Case-control studies carried out at Nagpur reported moderate effectiveness of BCG vaccination in prevention of tuberculosis. Its effectiveness was higher against extra-pulmonary tuberculosis. The summary protective effects obtained from meta-analysis of trials, cohort studies and case-control studies of BCG vaccination and tuberculosis were 51 (33-64), 76 (63-85), and 65 (57-72) percent respectively. The case-control studies carried out at Nagpur also demonstrated a significant protective association between BCG vaccination and leprosy. The summary protective effects obtained from meta-analysis of trials, cohort studies and case-control studies of BCG vaccination and leprosy were 43 (27-55), 62 (53-69), and 59 (46-68) percent respectively. The results of the current study and systematic review thus supported arguments favoring use of BCG vaccine for prevention of tuberculosis and leprosy.     

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.     

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.     

A case-control study to evaluate the effectiveness of mass neonatal BCG vaccination among Canadian Indians

This paper reports a case-control study to assess the protective effect of BCG (bacille Calmette-Guérin) vaccination among Indian infants in Manitoba, Canada. A record of past BCG vaccination was found in 49 per cent of the tuberculosis cases, compared to 77 per cent of the controls, yielding a relative risk of 0.30. Stratified analysis, controlling for age, increased the relative risk to 0.39 (95% confidence interval 0.22 - 0.69). The preventive fraction was 44 per cent. Non-differential misclassification of exposure status could have occurred; if this was adjusted for, the relative risk would be reduced. If only bacteriologically confirmed cases were analyzed, the age-adjusted relative risk was 0.27. The protective effect of BCG vaccination in the newborn among Manitoba Indians is therefore at least 60 per cent. The implications for health policy in this population are further discussed.     

Vaccination of animals against Mycobacterium bovis

Vaccination could potentially be used as a practical means of controlling bovine tuberculosis in countries in which a wildlife reservoir of the disease is present, and also in those countries which cannot afford conventional control strategies. An understanding of the processes involved in the protective immune response to tuberculosis is desirable for the rational development and testing of new vaccines for tuberculosis. The authors review current knowledge regarding the processes involved in protective immune responses to tuberculosis, much of which has been derived from studies in mice. This knowledge is discussed in relation to the problem of using vaccination to induce protective immunity in cattle, deer and wildlife. Challenge models have now been developed to test candidate vaccines in many domestic animals and wildlife species and these models are being used to evaluate tuberculosis vaccines. Most studies of the efficacy of tuberculosis vaccines in target animals have focused on the use of bacillus Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis. Recent advances in immunology and the molecular biology of mycobacteria have greatly increased the options for candidate vaccines and future studies will test new types of vaccines including new attenuated strains of M. bovis, sub-unit protein vaccines and recombinant deoxyribonucleic acid vaccines. Several of these vaccines have shown promising results when tested in small animal models. Although progress has been made in the development of vaccine delivery systems for animals, the technical problems associated with vaccination of wildlife remain a challenge.     

Immunogenicity of Danish-SSI 1331 BCG vaccine in the UK: comparison with Glaxo-Evans 1077 BCG vaccine

The immunogenicity and reactogenicity, in British schoolchildren, of the newly introduced Danish-SSI 1331 BCG vaccine was compared with that of the previously used Glaxo-Evans 1077 BCG vaccine. Interferon-gamma (IFN-gamma) response to M. tuberculosis purified protein derivative (M.tb PPD) in a 6-day whole blood assay and delayed type hypersensitivity (DTH) to tuberculin PPD were determined before and 1 year after receiving BCG or no vaccination. Scar size was measured 1 year after vaccination. There was no evidence of a difference in immunogenicity (IFN-gamma and DTH conversion rates) but evidence of lower reactogenicity (scar size) with Danish-SSI 1331 compared to Glaxo-Evans 1077 vaccines.     

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.     

The tuberculin skin test in the Netherlands: new policies for an old test; guideline from the Netherlands Tuberculosis Control Policy Committee

The primary function of tuberculin skintesting is to demonstrate latent tuberculosis infection. The Netherlands Tuberculosis Control Policy Committee revised the guideline for the use and interpretation of the test because of new insights and changes of the epidemiological situation. Tuberculin testing should target persons who are likely to benefit from treatment of latent tuberculosis infection, such as contacts of tuberculosis-source cases, persons with increased occupational risk of tuberculosis exposure and persons with an increased risk of breaking down from infection to active disease as a result of depressed cellular immunity. The contribution of the tuberculin skintest to the diagnosis of active tuberculosis is limited. Different cut-off values for a positive test result are recommended in order to obtain optimum positive and negative predictive values in different target groups. In screening programmes, if the initial test result is 3-9 mm, follow-up tests are only indicated after exclusion of boosting by the initial two-step method. In contact investigations and persons with immune disorders, a history of Bacillus Calmette Guérin (BCG) vaccination should not longer be regarded a contraindication for tuberculin testing.     

Effect of storage at 37��C on allergenic potency of dried BCG vaccine

Experiments were carried out to determine the effect of storage at 37°C on the allergenic potency for humans of dried BCG vaccine. From four lots of liquid vaccine, eight kinds of dried vaccine were prepared, four with 1% sodium glutamate and four with 1% sucrose as adjuvant. The eight vaccines were stored at 5°C and at 37°C for periods ranging from 1 month to 9 months, and were then used for the inoculation of primary-school children in Tokyo. These children were tuberculin-tested 1, 3 or 4 and, in a few cases, 12 months after vaccination, and the reactions were read approximately 48 hours after the tuberculin injection had been given.     

卡介苗预防儿童结核性脑膜炎和粟粒性结核效果的系统评价

目的通过卡介苗对儿童结核性脑膜炎（结脑）和粟粒性结核保护效果的系统评价,为完善卡介苗免疫策略提供依据,为开展效果研究提供线索。方法采用系统评价方法,以卡介苗、结脑、粟粒性结核为检索词,全面检索中国医院知识数据库（China Hospital Knowledge Database,CHKD）期刊全文库（1979～2007年）、CHKD会议论文全文数据库（1999～2008年）和万方学术期刊数据库（1982～2007年）,对纳入文献相关信息进行分析。结果符合纳入标准的文献28篇,1篇涉及粟粒性结核,25篇涉及结脑,2篇既涉及结脑又涉及粟粒性结核。卡介苗对结脑发病的保护效果系统评价显示：生态学研究均认为卡介苗对结脑的发病有保护作用;结脑病例中接种卡介苗所占的比例差别较大（0～69.08%）,粟粒性结核卡介苗未接种的比例为17.24%。Mete分析卡介苗对结脑的保护效果为81%,95%可信区间为57%～91%。结论接种组与未接种组的对照研究显示,卡介苗对预防结脑有保护效果。粟粒性结核保护作用研究的文献少,无法得出确切结论。     

BCG vaccination of children against leprosy: fourteen-year findings of the trial in Burma

The value of BCG vaccination in preventing leprosy among children was studied in an area of high leprosy endemicity in Burma through a controlled trial; one group of 13 066 children received BCG and another group of 13 176 served as controls. The overall protective effect of BCG, which was only about 20% over the 14-year period, was found to vary with the batch of vaccine, as well as age, sex, and contact status of the children. BCG protection was found to be independent of the initial tuberculin status of the children. The protective effect of BCG against the lepromatous type of leprosy could not be measured because of the low incidence. Protection was observed throughout the fourteen years of the study except for the first year. The results are compared with those of three other major BCG trials in leprosy. The trial has shown that BCG provides only a very modest level of protection and that BCG vaccination is not likely to be an important solution for leprosy control.