Protective effect of Bacillus Calmette Guerin (BCG) vaccination in prevention of pulmonary tuberculosis

A hospital-based, pair-matched, case control study was carried out at Government Medical College Hospital, Nagpur to estimate the effectiveness of BCG vaccination in the prevention of pulmonary tuberculosis. The study included 412 incident cases of pulmonary tuberculosis, which were born onwards 1962. Each case was pair-matched with one control for age, sex and socio-economic status. Controls were selected from subjects attending study hospital for conditions other than tuberculosis and leprosy. The significant protective association between BCG vaccination and pulmonary tuberculosis was observed (OR = 0.47, 95% CI = 0.35-0.63). The overall vaccine effectiveness was 53% (36.5-65.3%). BCG vaccine was non-significantly more effective in age less than or equal to 20 years, among males and in upper and middle socio-economic stratum. The overall prevented fraction was estimated to be 38.6% (24.2-43.6%). Results of this study, thus, demonstrated a moderate effectiveness of BCG vaccination in prevention of pulmonary tuberculosis in study population.     

A case-control study of protection against tuberculosis by BCG revaccination in Recife, Brazil.

SETTING: Metropolitan region of Recife, Brazil. OBJECTIVE: To estimate the additional protection against tuberculosis (TB) provided by a second dose of bacille Calmette-Guérin (BCG) vaccine. DESIGN: Case-control study. Cases were cases of TB newly diagnosed by the TB control programme, independent of clinical form. Three matched neighbourhood controls were selected using a systematic routine, starting from the case's address. The matching was within the age groups 7-9, 10-14 and 15-19 years. RESULTS: Analysis was conducted among 169 cases and 477 controls. For the efficacy of BCG revaccination against TB overall, matched (crude) vaccine effectiveness (VE) was -3 (95% CI -50-29) and matched (adjusted) VE was 8 (95% CI -77-52). CONCLUSIONS: This study suggests that a second dose of BCG does not offer additional protection. Revaccination should not be offered. As large numbers of subjects are already vaccinated and vaccine appears to offer some protection in older subjects, further studies with larger sample sizes could investigate the potential efficacy of revaccination with BCG in the age group > or = 15 years.     

BCG vaccine effectiveness against Buruli ulcer: a case-control study in Benin

BCG remains the only possible prophylactic intervention against Buruli ulcer (BU). Estimating its public health impact on BU control is an important issue. We conducted a case-control study to investigate the vaccine effectiveness of routine BCG vaccine against BU in southern Benin. From August 2002 to August 2003, BCG vaccination status was obtained for 279 clinically diagnosed BU cases and 988 age- and sex-matched neighborhood controls. BCG coverage, which was estimated by the presence of a scar or a vaccination record, was 64.5% in cases and 67.2% in controls. There was no evidence of a protective effect of routine BCG vaccination against BU in southern Benin (vaccine effectiveness adjusted for socioeconomic status = 12%, 95% confidence interval = -24% to 37%).     

Tuberculin survey in the Eastern Province of Saudi Arabia

We present the results of the Mantoux test (5 units tuberculin) survey in the Eastern Province of Saudi Arabia, which was conducted as part of a nationwide epidemiological survey of tuberculosis. A total of 1105 subjects were screened out of whom 630 gave a history of BCG vaccination in the past and 363 were BCG-negative. Among BCG-negative children aged 5-14 years, only 5% had a positive Mantoux, a rate lower than most Third World countries but higher than developed countries were under 2% of children are tuberculin reactors. This calls for continuation of free treatment of active cases and increased efforts towards screening of contacts. The results also vindicate the current policy of giving BCG vaccine at birth and probably indicates the need to revaccinate at school leaving age, in accordance with WHO recommendations. Tuberculin reactivity rose steeply with age (32% at age 15-24 and 72% at age 45-64 years) indicating the presence of a large pool of subjects at risk of breaking into active disease. Finally, 71% (201/283) of children aged 5-14 years who had received BCG vaccine at birth, reacted negatively to the Mantoux test. This supports the findings of previous studies that in the majority of subjects, BCG-induced tuberculin sensitivity fades a few years after vaccination.     

Coincident filarial, intestinal helminth, and mycobacterial infection: helminths fail to influence tuberculin reactivity, but BCG influences hookworm prevalence

The prevalence of helminth and tuberculosis infections is high in South India, whereas Bacille-Calmette-Guerin (BCG) vaccine efficacy is low. Our aim was to determine whether concurrent helminth infection alters the ability to mount a delayed-type hypersensitivity response to tuberculin. In a cross-sectional study in southern India, individuals 6-65 years of age were screened for intestinal helminths, circulating filarial antigenemia, tuberculin reactivity, active tuberculosis, and history of BCG vaccination; 54% were purified protein derivative (PPD) positive, 32% had intestinal helminth infection, 9% were circulating filarial antigen positive, and 0.5% had culture-confirmed active tuberculosis. Only age and BCG vaccination were significantly associated with PPD reactivity; however, BCG vaccination was associated with a lower prevalence of hookworm infection relative to those without prior BCG vaccination. Neither intestinal helminth infection nor filarial infection was associated with diminished frequencies of PPD positivity. Our findings suggest that preceding helminth infection does not influence significantly the delayed-type hypersensitivity response to tuberculin.     

BCG vaccination: where are we now?

The bacillus Calmette-Guerin (BCG) vaccine is administered and recommended for the prevention and control of tuberculosis in developing countries with high-risk settings. A new general BCG vaccination programme against tuberculosis has been introduced since 1997 in Turkey. The aim of this study was to evaluate the BCG vaccination status in Düzce and to analyze contributing factors for the vaccination programme. BCG screening were performed in 1100 8th class students from nine primary schools of Düzce city centre and seven counties. BCG scar presence was taken as authoritative for vaccination status. BCG vaccination ratio was 0.94. Of 1100 students, 1030 had BCG scars; 478 had single scar, 536 had two scars and 16 had three scars. The significant negative correlation was observed between the BCG administration ratio and the number of children under age of 15 per health personnel (r= -0.771, p= 0.025). Furthermore, based on some published studies marked regional variation of BCG vaccination status in Turkey was also discussed in this article.     

Protective value of BCG vaccination in children in Bangkok, Thailand

The protective effect of bacille Calmette-Guérin (BCG) vaccination against tuberculosis is controversial. In a study, 330 patients less than 12 years of age with tuberculosis, 52.1% of whom had had BCG vaccination, were compared with a control group of 1106 patients free of tuberculosis, 81% of whom had BCG vaccination. The occurrence of disseminated forms of tuberculosis, tuberculous meningitis, tuberculous peritonitis, and tuberculosis of bone and joints in BCG-vaccinated patients was quite low. With BCG vaccination, the incidence of the disseminated form of tuberculosis was significantly lower than that of pulmonary tuberculosis with pulmonary parenchymal lesions, primary pulmonary complexes, and pleural effusion. Tuberculous peritonitis was significantly less frequent than pulmonary tuberculosis with pulmonary parenchymal lesions, enlarged hilar glands, pulmonary primary complex, and pleural effusions. The study demonstrated that BCG gave an overall protective effect of 74% and that a major effect of this immunity was to produce a localized form of tuberculosis.     

Theoretical and methodological aspects of BCG vaccine from the discovery of Calmette and Guérin to molecular biology. A review.

The BCG vaccine has been used to prevent tuberculosis since 1921 and applied for immunostimulation in neoplasia since the 1960s. Both the preventive and immunostimulation effects have been evaluated and communicated with contradictory, positive and negative conclusions. For an objective evaluation and interpretation of the protective efficacy, effectiveness and efficiency of the BCG vaccination it must be considered that: (1) several BCG substrains have been developed in manufacturing laboratories that differ in the residual virulence which determines immunogenicity and reactogenicity; (2) various liquid and freeze-dried BCG vaccine production methods are used, resulting in different BCG viable units per dose; (3) quantitative bioassay methods are not yet being used for statistical quality control of the vaccine; (4) BCG products are applied in various demographical, epidemiological and socioeconomic conditions with different vaccination policies; (5) inadequate biostatistical models are often used to analyse efficacy, effectiveness and adverse reactions. The same conditions influence the precise evaluation of BCG immunostimulation in neoplasia. Recombinant DNA technology will modify production methods, and explain at the molecular level the mechanism of the protective effects BCG confers in tuberculosis and immunostimulation in neoplasia. High level laboratory techniques and biostatistical methods, based on probability logic and inductive inference, ensure appropriate experimental designs and the exact analysis of laboratory data and the results of vaccination policies. They will lead to the evaluation of the protective effect of BCG in order to reduce the BCG contradictions.     

Impact of BCG vaccination programmes in children and young adults on the tuberculosis problem.

There is general agreement that BCG vaccination with a potent strain, when given to previously uninfected subjects, is highly effective in preventing the development to tuberculosis among them. This "direct" effect may be measured in practice in terms of the proportion of cases prevented in the age-groups in which the vaccination has been made. It is also clamined that mass BCG vaccination-especially at school-leaving age-can be expected to yield benefits not only directly, but also indirectly, by breaking the chain of transmission and so preventing the development of tuberculosis in unvaccinated subjects. This "indirect" effect may be measured, by analogy, in terms of the reduction in the numbers of cases in the age groups in which no vaccinations have been performed (the older age groups, and also young children, if BCG vaccination is given, for instance, to school-leavers). The indirect effect will be observed in terms of changes in both smear-positive and smear-negative cases. However, because smear-positive cases are the principal sources of infection, it is more meaningful to measure the indirect effect in terms of the reduction in the numbers of smear-positive (infectious) cases. The present paper falls into three parts: I. A comparison of the trends in the incidence of infectious tuberculosis in Norway, Denmark and The Netherlands. The study confirms that the substantial direct effect of BCG vaccination on the total tuberculosis incidence, which was shown by Bjartveit and Waaler, also applies to the incidence of infectious tuberculosis. II. A comparison of the trends in the incidence of infectious tuberculosis in the three countries and in different age groups over 30, and in the incidence of all forms of tuberculosis in children, in whom BCG vaccination has not been used. These comparisons suggest that the indirect effect of BCG on infectious cases of tuberculosis in persons aged 30 years and over, and on all forms of tuberculosis in children, in whom BCG vaccination has not been used, is not readily detectable, and so may not be large. However, the trends in tuberculosis incidence measure the total effects of all the policies for control used in the three countries under study. The comparisons between the three countries can therefore not isolate the "pure" direct and indirect effects of BCG from the effects of other differences between the control policies. For this reason a theoretical study of the problem has been made. III. A theoretical examination of the maximum likely indirect effect of a mass BCG vaccination policy in diminishing the prevalence of sources of infection in the population. This shows that the effect of BCG in preventing smear-positive cases in developing countries (if a constant risk of infection of about 3 per cent is presumed), is between 0.3 per cent and 2.0 per cent per year. This effect depends mainly upon the efficacy of BCG vaccine, the population covered and the duration of protection from BCG vaccination...     

The value of counting BCG scars for interpretation of tuberculin skin tests in a tuberculosis hyperendemic shantytown, Peru.

SETTING: The tuberculin skin test (TST) is widely used as a diagnostic or screening test for Mycobacterium tuberculosis infection and disease. A peri-urban shantytown in the desert hills of south Lima, Peru, highly endemic for tuberculosis, and where bacille Calmette-Guérin (BCG) vaccine had been given in multiple doses until 1995. OBJECTIVE: To analyze the effect of multiple BCG vaccines on TST in a community-based setting. DESIGN: Point-prevalence survey of TST reactions of 572 people aged 6-26 years from 255 households. TST reactions were compared to the observed number of BCG scars and other potential risk factors (age, living with a TST-positive person, and contact with active tuberculosis). RESULT: People with two or more scars had significantly larger reactions, even after adjusting for potential risk factors. The adjusted population attributable fraction of being TST-positive and having two or more BCG scars was 26%. CONCLUSION: There is no demonstrated benefit of repeat BCG vaccination. We therefore recommend that physicians take into consideration the number of BCG scars when interpreting the TST and that programs give no more than one BCG vaccination.     

A new vaccine against tuberculosis shows greater protection in a mouse model with progressive pulmonary tuberculosis

SETTING: The effectiveness of Bacillus Calmette-Guerin (BCG) vaccination in reducing tuberculosis (TB) prevalence rates is poor, resulting in urgent need for improved immunization programs, with new and more effective vaccines against TB. OBJECTIVE: To develop a recombinant Tice BCG vaccine against TB that overexpresses the 38-kDa antigen of Mycobacterium tuberculosis in order to protect against infection by M. tuberculosis H37Rv and hyper-virulent M. tuberculosis Beijing genotype. DESIGN: M. tuberculosis 38-kDa protein was cloned into a mycobacterial shuttle plasmid, which was used to overexpress the 38 kDa protein in BCG Tice to produce the recombinant vaccine, rBCG38 Tice (rBCG38). RESULTS: Compared with BCG Tice, which conferred little protection against the Beijing strain of M. tuberculosis, vaccination with the rBCG38 increased survival of mice infected with either M. tuberculosis H37Rv or a Beijing strain of M. tuberculosis, isolate 9501000. Vaccination with either BCG Tice or rBCG38 resulted in enhanced protection against mycobacterial growth in lung tissue by reducing the number of colony-forming units (CFU). The vaccine induced a strong and highly significant Th1 response, shown by the high level of IL-2 and IFN-gamma cytokine producer cells found in the lungs of challenged mice, and an increase in the IgG2a:IgG1 ratio found in the pooled sera of the vaccinated mice. CONCLUSIONS: This study showed that rBCG38 vaccine induced a strong Th1 response, demonstrated by the high levels of IL-2 and IFN-gamma producer cells and IgG2a. Protection was mediated for as long as 6 and 4 months after challenge with M. tuberculosis H37Rv and Beijing genotypes, respectively.     

Effectiveness of BCG vaccination in England and Wales in 1983

The effectiveness of BCG vaccination, at about age 13 years, in the prevention of tuberculosis at ages 15-24 years in England and Wales in 1983, has been determined by the same method as in two previous surveys in 1973 and 1978. In 1983, the tuberculosis notification rate among those vaccinated in the schools' scheme was 3.30 per 100,000, compared with an estimated rate of 13.20 per 100,000 among those who were tuberculin negative and not vaccinated in the scheme. The protective effectiveness of BCG vaccination at ages 15-24 years in England and Wales in 1983 is thus estimated as 75%; the estimated efficacy in the white ethnic group is closely similar, namely 76%. The estimated efficacy of BCG at ages 15-19 and 20-24 years in the three surveys, both in the white ethnic group and in the entire cohort, has been compared with that found in the Medical Research Council's controlled trial of tuberculosis vaccines which began in 1950. There is no evidence of any decrease in the protective efficacy of BCG vaccination between the four cohorts of young adults, which span a total period of 29 years. However, there were steep decreases between the cohorts in the annual notification rates for the white ethnic group; these decreases occurred in the BCG vaccinated and in the tuberculin negative unvaccinated groups, as well as among those found tuberculin positive (and not vaccinated) in the schools' scheme. It is concluded that the level of protective efficacy of BCG vaccination at ages 15-24 years is high, and has remained unchanged since the start of the BCG in schools' scheme. However, as the tuberculosis notification rate in young adults has decreased steeply throughout this period, and is continuing to decrease, the benefits to be expected from the BCG in schools' scheme will decrease equally rapidly.     

Novel vaccines against M. tuberculosis

CDC and ACET in U.S.A. reported that novel vaccines instead of BCG are required for the protection against infection of Mycobacterium tuberculosis worldwide. However, no novel vaccine for clinical use has not yet been developed in the world including U.S.A. and Europe. We have developed two novel tuberculosis (TB) vaccines; a DNA vaccine combination expressing mycobacterial heat shock protein 65 (HSP 65) and interleukin-12 (IL-12) by using the hemagglutinating virus of Japan (HVJ)-liposome (HSP 65 + IL-12/HVJ). A mouse IL-12 expression vector (mIL-12 DNA) encoding single-chain IL-12 proteins comorised of p40 and p35 subunits were constructed. In a mouse model, a single gene gun vaccination with the combination of HSP 65 DNA and mIL-12 DNA provided a remarkably high degree of protection against challenge with virulent Mycobacterium tuberculosis; bacterial numbers were 100 fold lower in the lungs compared to BCG-vaccinated mice. To explore the clinical use of the DNA vaccines, we evaluated HVJ-liposome encapsulated HAP 65 DNA and mIL-12 DNA (HSP 65 + mIL-12/ HVJ). The HVJ-liposome method improved the protective efficacy of the HSP 65 DNA vaccine compared to gene gun vaccination. This vaccine provide remarkable protective efficacy in mouse and guinea pig models, as compared to the current by available BCG vaccine. HSP 65 + IL-12/HVJ vaccine induced CD8+cytoxic T lymphocyte activity against HSP 65 antigen. Protective efficacy of this vaccine was associated with the emergence of IFN-gamma-secreting T cells and activation of proliferative T cells as well as CTL induction upon stimulation with the HSP 65 and antigens from M. tuberculosis. Furthermore, we extended our studies to a cynomolgus monkey model, which is currently the best animal model of human tuberculosis, to evaluate the HSP 65 + IL-12/HVJ vaccine. Vaccination with HSP 65 + IL-12/HVJ provided better protective efficacy as assessed by the Erythrocyte Sedimentation Rate, chest X-ray findings, and immune responses than BCG. Most importantly, HSP 65 + IL-12/HVJ resulted in an increased survival for over a year. This is the first report of successful DNA vaccination against M. tuberculosis in the monkey model. Novel TB vaccines using the monkey model will be discussed in this issue. The development of novel vaccines against tuberculosis was also studied in murine and cynomolgus monkey systems. Four distinct methods; DNA vaccination (1. plasmid, 2. adenovirus vector, 3. adenoassouated virus), 4. recombinant BCG, and 5. subunit (recombinant protein) were used for the development of novel vaccines. Genes (HSP 65 gene, IL-12 gene as well as Ag 85A-, 85B-, MPB51-gene) and IL-6 related genes (IL-6 gene + IL-6R gene +gp130 gene) were administered into the Balb/c mice infected (i.v. or intra-tracheal injection) with Mycobacterium tuberculosis (M. tuberculosis). Elimination of M. tuberculosis in lungs, liver, and spleen of these mice and survival were studied in these models. HSP 65 gene + IL-12 gene vaccination, or recombinant BCG (BA51 : Antigen 85B(-) + Antigen 85A(-) + MPB51-gene recombinant BCG) were more prophylactically efficient than parental BCG Tokyo vaccination. In contrast, IL-6 related genes vaccination using adenovirus vector showed therapeutic effect on M. tuberculosis infected mice. Cytotoxic T cells (CTL) activity against M. tuberculosis in the spleen cells from mice treated with IL-6 related genes vaccination were significantly augmented. Furthermore, NOD-SCID-PBL/hu mice treated with anti-IL-2 receptor beta-chain antibody provide an useful tool for analyzing in vivo human T cell immunity against tuberculosis. In conclusion, we demonstrate the development of a novel HVJ-liposome DNA vaccine encapsulating HSP 65 DNA plus IL-12 DNA. These results suggest that HSP 65 + IL-12/HVJ could be a promising candidate for a new tuberculosis DNA vaccine, which is superior to the currently available BCG vaccine. The goal of our study is to develop a new tuberculosis vaccine superior to BCG. To this aim, we believe that the protective efficacy and protective immune responses for vaccine candidates should be addressed in larger animals, such as nonhuman primates, before proceeding to human clinical trials. Although other DNA vaccine candidates that appear to protect against virulent M. tuberculosis in mice better than BCG have failed to provide better protection than BCG in guinea pigs against aerosol challenge of a low dose of virulent M. tuberculosis, some of them are being prepared to enter early human clinical trials. More recently, we evaluated the HSP 65 + hIL-12/HVJ vaccine in the cynomolgus monkey model, which is currently the best non-human primate animal model of human tuberculosis. Monkeys were subsequently challenged with virulent M. tuberculosis by the intra-tracheal route after the third vaccination. This challenge dose normally causes death from acute respiratory infection within 4-6 months. In this particular experiment, monkeys vaccinated with HSP 65 + hIL-12/HVJ induced HSP 65-specific T-cell proliferation and improvement of chest X-P findings, resulting in an increased survival for over a year, superior to BCG group. Thus, we are taking advantage of the availability of multiple animal models (mouse, guinea pig, and monkey) to accumulate essential data of the HVJ-liposome DNA vaccine, including the vaccine efficacy and safety, for up-coming Phase I clinical trials.     

Increased protection against bovine tuberculosis in the brushtail possum (Trichosurus vulpecula) when BCG is administered with killed Mycobacterium vaccae

SETTING: The Australian brushtail possum is the major wildlife reservoir for Mycobacterium bovis infection in New Zealand. Development of an effective tuberculosis vaccine for possums will reduce the spread of infection to cattle and farmed deer. OBJECTIVES: To determine whether killed M. vaccae can improve the efficacy of vaccination with M. bovis bacillus Calmette Guerin (BCG) against bovine tuberculosis in the possum. DESIGN: Groups of possums (n=6-8) were vaccinated via intranasal and intraconjunctival routes with BCG alone or BCG in combination with heat-killed M. vaccae. Controls were non-vaccinated or vaccinated with heat-killed M. vaccae alone. After challenge with virulent M. bovis, protection was assessed by a reduction in loss of body weight and bacterial counts in lungs and spleens. Blood lymphocyte proliferative responses to M. bovis purified protein derivative were monitored throughout. RESULTS: The earliest lymphocyte responses following vaccination were from animals inoculated with BCG plus 100 microg heat-killed M. vaccae. Loss of body weight was significantly reduced in all BCG-vaccinated groups compared control groups. Spleen bacterial counts were significantly lower in animals vaccinated with M. vaccae plus BCG compared to the non-vaccinated group. Furthermore, vaccination with 100 microg M. vaccae plus BCG significantly reduced spleen bacterial counts compared to vaccination with BCG alone. CONCLUSION: The possum infection model is one of the first to show that novel vaccine strategies may offer better protection against tuberculosis than BCG alone.     

BCG: the challenge continues

It is widely recognized that BCG provides inconsistent and often inadequate protection against tuberculosis; however, simple estimates of efficacy fail to reflect the complexity of protection within, let alone between, populations. A decline in protection with an increase in age at vaccination has been seen in many studies. This may reflect 2 things: (i) that as people age they are exposed to a variety of mycobacterial challenges which may interfere with, or mask, the protection of BCG; and/or (ii) that the vaccine is better at protecting against primary disease than against either reactivation- or reinfection-type disease. These factors need to be taken into consideration when interpreting the results obtained with screening vaccines in animal models, as most of these models mimic acute primary-type disease. In addition, we have no evidence that the protection induced by BCG lasts for > 15 y, in any population. Recent data from South India indicate a complex interaction of age and time effects: BCG imparted consistent protection in children, but no protection for subjects > 15 y old, and may even have imparted negative protection among these older individuals. If true, these findings have important implications for efforts to develop a vaccine against adult pulmonary tuberculosis.     

Tuberculosis vaccines: past, present and future

PURPOSE OF REVIEW: The current vaccine against tuberculosis protects against severe forms of the disease in children but confers variable effectiveness against pulmonary disease. With tuberculosis eradication on the horizon new vaccines with better protection than Mycobacterium bovis bacillus Calmette-Guérin (BCG) are needed. This review will outline the most promising tuberculosis vaccine candidates from selected publications. RECENT FINDINGS: The enormous effort of the scientific community in the last 10 years has generated hundreds of tuberculosis vaccine candidates. These include sub-unit vaccines and live vaccines such as recombinant BCG and other attenuated live vaccines. Some of these are being included for the first time in phase I clinical trials. SUMMARY: For more than 80 years now no new tuberculosis vaccine has successfully been developed. There is now renewed optimism that vaccines superior to BCG can be developed in the coming years. The goal is to obtain a new generation of vaccines effective against more transmissible forms of tuberculosis. As a first step, good candidate vaccines able to boost BCG and improve BCG protection could be a reality in the near future. Tuberculosis vaccine candidates, able to replace the currently used BCG and make the eradication of tuberculosis feasible, can be expected in the mid-term, and live vaccines are reliable and promising candidates.     

Retrospective evaluation of the efficacy of the BCG vaccination campaign of newborns in Barcelona,Spain

The efficacy of the BCG vaccination campaign of neonates in Barcelona, carried out in the period 1966–1974, was evaluated with a study of cases and controls made during the period 1978–1988 in patients between the ages of 4 and 21 years. It shows that the efficacy of this vaccination campaign was 32%, that it was greater in men than women and that it decreased with the passage of time. The number of cases of tuberculosis prevented by this campaign is calculated at 13.4%.Given that the vaccine used offered maximum guarantees, the authors consider that this poor efficacy must be attributed to operational deficiencies in the vaccination campaign itself.     

Immune response to postprimary tuberculosis in mice: Mycobacterium tuberculosis and Miycobacterium bovis bacille Calmette-Guérin induce equal protection

We addressed the question of whether protective immunity induced by natural infection with Mycobacterium tuberculosis and that induced by vaccination with Mycobacterium bovis bacille Calmette-Guerin (BCG) differ in the murine model. We infected mice with M. tuberculosis Erdman, cured them by chemotherapy, and subsequently reinfected them with a low dose of M. tuberculosis H37Rv. The course of tuberculosis was compared with that in mice previously vaccinated with BCG Danish 1331. Protection against postprimary M. tuberculosis infection did not differ significantly between the 2 groups. After challenge infection, numbers of interferon- gamma -positive splenocytes did not differ between mice with primary infection and vaccinated mice. Splenocytes from primary M. tuberculosis-infected mice conferred marginally higher protection than did those from BCG-vaccinated mice. Serum transfer did not protect against reinfection in either group. Our data emphasize that natural infection with M. tuberculosis and vaccination with BCG do not differ in their capacity to induce protective immunity against tuberculosis and support the notions that reinfection contributes to the development of active disease and that any novel vaccine against tuberculosis has to perform better than both vaccination with BCG and immunity evoked by natural infection.     

The effect of BCG vaccination on tuberculin reactivity and the booster effect among hospital employees

BACKGROUND: We estimated the effect of remote BCG vaccination on tuberculin reactivity and the booster effect among hospital employees. METHODS: Cross-sectional survey at a university hospital. All personnel employed during a 24-month period were included in the study. Employees were administered 2-step tuberculin testing, and BCG vaccination scars were verified. RESULTS: Of 665 hospital employees studied, 239 (36%) had been vaccinated with BCG in childhood. Significant tuberculin reactions (> or =5 mm) were more frequent among BCG-vaccinated (60%) than among nonvaccinated (29%) employees (odds ratio [OR], 3.6; 95% confidence interval [CI], 2.6-5.2). The predictive value of tuberculosis infection increased with increasing reaction size and greater age (from 37% in subjects 30 years or younger with indurations > or =5 mm to 100% in subjects 50 years or older with indurations > or =15 mm). Among 374 employees with a negative tuberculin test reaction who underwent a second test, 39 (43%) of 91 vaccinated subjects had a positive booster reaction in contrast to 51 (22%) of 232 nonvaccinated subjects (OR, 3.4; 95% CI, 2-5.7). Neither different size criteria nor different definitions of the booster effect had an impact on the predictive value of tuberculosis infection. CONCLUSIONS: Remote BCG vaccination largely influences the tuberculin reaction and the boosting phenomenon among hospital employees. The interpretation of the results of 2-step tuberculin testing in a BCG-vaccinated subject must take into account age, size of the reaction, and local prevalence of tuberculosis infection. No single criterion, however, can accurately separate reactions caused by true infection from those caused by BCG vaccination.     

Tuberculin reactivity in a chest clinic: the effects of age and prior BCG vaccination

Heaf tests were performed in 834 adults and children seen during one year in a tuberculosis contact clinic in Edinburgh. All subjects with a past history of tuberculosis, or who subsequently developed evidence of tuberculous infection and 63 subjects of Asian origin were excluded to leave 749 'healthy' adults and children broadly representative of the local caucasian population. All Heaf tests in 178 children without BCG vaccination were negative or grade I whereas 16 (73%) of the 22 children with a history of previous BCG vaccination were positive grade I or II. A strongly positive Heaf test (grade III-IV) in any child with or without previous BCG vaccination seen as a tuberculosis contact implies recent infection and merits consideration for chemoprophylaxis or prolonged follow-up. Two hundred and seventy adults without previous BCG vaccination showed an increasing incidence of strongly positive Heaf tests (grade III or IV) with age reaching a peak of 55% in the 45-65 age group; beyond the age of 65 this fell to 37%. Two hundred and eighty-one adults with previous BCG vaccination showed significantly more Heaf grades I and II, fewer negatives and fewer strong positives than the unvaccinated group. A strongly positive Heaf test (III-IV) is a frequent finding in a healthy adult and has little discriminatory value in the diagnosis of active tuberculosis infection in Edinburgh, and by implication elsewhere in the United Kingdom. Positive tuberculin tests should be viewed in the context of the tuberculin profile of the local population.