Clinical Efficacy and Laboratory Improvement of Bacillus Calmette-Guerin Vaccination on Adult Atopic Asthma A Cohort Study
© World Allergy Organization; licensee BioMed Central Ltd. 2008
Received: 20 October 2007
Accepted: 31 January 2008
Published: 15 April 2008
Recent studies have shown that Bacillus Calmette-Guerin (BCG) vaccination is inversely related to asthma, a Th2 cell-associated with allergic disease, which BCG in humans induces Th1-cell immune responses and prevents airway remodeling.
To investigate whether thrice BCG vaccinations are clinically effective and could induce laboratory improvement compared with placebo on phase 1 (12 weeks) and single BCG vaccination on phase 2 of the study, then finding out whether the effect might last until 9 months after thrice vaccination and 9 months after single vaccination on adult atopic extrinsic asthma.
According to the Global Initiative for Asthma criteria, 40 mild to moderate persistent atopic asthma patients were randomly assigned in a double-blind fashion into groups that received intra-dermal injection of 0.1 mL of BCG (n = 20) or 0.1 mL of placebo (n = 20) on the first day. On the first phase, subjects on BCG vaccinations were given intradermal injections 3 times on the deltoid region every 4 weeks. On the second phase, at the 12th week, the placebo group was given BCG vaccination once, and this group became the single BCG group. The symptom score (SS) and drug score (DS), lung function, eosinophil blood count (EBC), total serum immunoglobulin E, interferon-γ (IFN-γ), interleukin 4, and transforming growth factor-β1 (TGF-β1) were examined on the first phase (before the treatment and at the 12th week) and on the second phase (on the sixth and ninth months after the third vaccination for thrice BCG group or after single BCG for control group) to monitor the efficacy.
There were some improvements of asthma SS (P < 0.05) and DS (P < 0.05), forced expiratory volume in 1 second (P < 0.05), peak expiratory flow rate (P < 0.05), EBC (P > 0.05), IFN-γ (P < 0.05), and TGF-β1 (P < 0.05) on thrice BCG group compared with prevaccination and with placebo on the first phase and second phase of the study compared with single BCG (formerly placebo).
Based on the previous findings, we could confirm that thrice BCG vaccinations proved to be better than the placebo group and single vaccination. The efficacy of thrice BCG vaccinations on asthma was detected by the improvement of SS, DS, forced expiratory volume in 1 second, peak expiratory flow rate, EBC, IFN-γ, and TGF-β1 until 9 months from the last vaccination without any side effects.
KeywordsBCG symptom/drug score IFN-γ IL-4 TGF-β1 adult atopy asthma
In Indonesia, the prevalence of asthma ranges from 3.8% to 6.9% . In the past decades, treatment of asthma had emphasized long-term suppression of airway inflammation plus relief of symptoms. Inhaled corticosteroids proved to be the most effective agents available on asthma symptomatic control in improving pulmonary function, but potential side effects might occur when increasing the dosage, whereas corticosteroids do not consistently abrogate airway inflammation . Conventional allergen immunotherapy can be effective in many, but not all, patients. Furthermore, an allergist is needed for possible anaphylaxis reaction . Therefore, because of limited treatment of asthma, which is relatively high cost, we need a new modality that is more effective, safer, and cheaper .
Bacillus Calmette-Guerin (BCG) is a vaccine used against tuberculosis and as an immunomodulator that primes Th1 lymphocytes to produce cytokines that antagonize atopy in animal models and in human clinical trials [5–9]. Considering atopy as the main risk factor for asthma, we hypothesized that vaccination inducing Th1 responses can be protective against asthma because the Th1 and Th2 cells were reciprocally regulated [10, 11]. These hypotheses are based on observations that there was a negative significant correlation between tuberculosis rates and asthma prevalence in children, reduced rating of current asthma symptoms of Japanese school children,  and that in murine models of allergen-induced airway eosinophilia, intranasal BCG infection 4 weeks before allergen airway challenges resulted in a 90% to 95% reduction in eosinophilia within the lungs compared with uninfected control mice . There were also a number of reports in Chinese medical literature from the past 30 years that repeated administration of BCG is effective in the management of asthma [13, 14]. Also from the regions where tuberculosis is prevalent, [4, 15–19] they reported on an association between BCG vaccination and lower rates of atopic disorders. A recent study of Choi and Koh  suggested that repeated BCG vaccinations might be more effective in atopic asthma than once. There is no conclusive evidence of the efficacy of BCG against allergy, although the association between BCG and asthma remains a matter of debate [4, 20–23].
This article describes an original, randomized, controlled, double-blind, pretest and posttest clinical trial to investigate the efficacy of BCG vaccinations on adult atopic asthma patients during a 12-month cohort study.
Adult atopic asthma patients were recruited from the Allergy-Immunology outpatient clinic, Prof. RD Kandou Hospital, Sam Ratulangi University, Manado, Indonesia. All patients had asthma for more than 1 year and fulfilled the criteria for mild and moderate asthma set down by the Global Initiative for Asthma 2002 . All patients were reluctant to take fenoterol and budesonide inhaler from the first until the second vaccination, and discontinued budesonide inhaler since the first day of the third vaccination. The subjects were clinically stable for at least 4 weeks before entering this study. Candidates were excluded from the study based on these criteria: chronic obstructive pulmonary disease, acute infectious diseases, smoking at least for 1 year before, malignancies, cell-mediated immune deficiency, human immunodeficiency virus, severe dermatitis on deltoid, severe nutritional deficiency, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, multiple sclerosis, previous specific immunotherapy, pregnancy, or lactation. This study was approved by the ethical research committee of the School of Medicine, Sam Ratulangi University. All patients were informed about the experimental procedures and provided written informed consent.
The primary end points showed weekly changes in signs and symptoms and spirometry (PEFR, FEV1, and MMEV) above the baseline values, measured at the end of the run-in period. Secondary end points included changes in EBC, IgE, and serum IFN-γ, IL-4, and TGF-β1 levels. The baseline values for each of the variables recorded in the diaries were determined as the averages or sums of weekly values for 4 weeks of the run-in period for the first phase and then every week until 9 months. Categorical variables were compared by using the Fisher exact test for intergroup differences. The differences in continuous variables between the 2 groups were analyzed using the unpaired Student t test for parametric data and Mann-Whitney U test for nonparametric data. The differences within the same group were analyzed by using the paired Student t test for parametric data and the Wilcoxon signed rank test for nonparametric data. A P < 0.05 value was considered statistically significant.
Baseline Characteristics of Prevaccinated Asthma Patients on Both Groups
BCG Group (n = 20)
Placebo Group (n = 20)
10 (50%)/10 (50%)
8 (40%)/12 (60%)
Age, yrs (mean ± SD)
34.95 ± 11.55
34.90 ± 12.32
Body mass index, kg/m2 (mean ± SD)
23.35 ± 3.16
22.97 ± 2.70
Old healed TBC lesions
History of anti-TBC drugs
Previous BCG vaccination scar
Asthma triggers, no. (%)
Duration of asthma, yrs (no. [%])
Asthma grading (GINA 2002)
14.76 ± 1.53
14.42 ± 1.68
Eosinophil in differentialcount, %
9.85 ± 6.70
9.80 ± 6.52
Student t test for continuous variables; Fisher exact test for categorical variables.
Median/Mean Values of Spirometry, Blood Eosinophil Count, TSIgE and Serum Cytokines, Prevaccination and Postvaccination on Both Groups on First and Second Phases
Thrice BCG Group
360.5 ± 61.1
403.5 ± 71.9*,†
409.5 ± 63.9*,†
428.0 ± 77.6*,†
398.3 ± 101.0*,‡
380 ± 86.1§,‡
2.02 ± 7.6
2.33 ± 0.7*,†
2.52 ± 1.3
3.12 ± 1.3*,†
Eosinophil count (/μL)
608 ± 493.1
516 ± 522.1§,‡
453.9 ± 313.1§,‡
410 ± 299.0*,‡
1366 ± 1934.6
1395 ± 1563.7§,‡
1502.82 ± 2184.0§,‡
1440 ± 2084.4§,‡
3.55 ± 2.2
4.22 ± 3.8§,‡
4.58 ± 2.8*,†
4.67 ± 0.5*,‡
0.04 ± 0.039
0.08 ± 0.05*,‡
0.09 ± 0.03*,†
0.1 ± 0.04*,†
54,396 ± 6908
50,720 ± 7111.4*,‡
38,066 ± 9279||,‡
48,271 ± 9634||,‡
Single BCG Group
360 ± 53.3
343 ± 67.4§,†
325 ± 63.8*,†
315.50 ± 72.9*,†
371 ± 73.98§,‡
346 ± 95.8§,‡
2.04 ± 0.65
1.64 ± 0.5*,†
2.51 ± 1.2
2.01 ± 1.95*,†
Eosinophil count (/μL)
649 ± 580.7
393 ± 358.4*,‡
569 ± 553.7§,‡
593 ± 582§,‡
Total IgE (IU/mL)
887 ± 794.4
1053 ± 863.2§,‡
927 ± 1076.3§,‡
791 ± 1094.3§,‡
3.65 ± 1.8
3.85 ± 1.95§,‡
5.25 ± 0.90*,†
4.81 ± 1.30*,‡
0.08 ± 0.13
0.08 ± 0.11§,‡
0.16 ± 0.09*,†
0.16 ± 0.13*,†
53,910 ± 7525
51,480 ± 6084.9§,‡
40,853 ± 12,772||,‡
45,942 ± 9453||,‡
Mean serum IL-4 after thrice BCG was significantly increased from the 12th week until the ninth month (P < 0.05), except that in the single BCG group on the 12th week, it remained stable and then increased on the sixth and ninth months. Between the groups on the 12th week, there were no significant differences, but on sixth and ninth months, they became statistically significant (Figure 5).
Mean serum TGF-β1 after thrice BCG was significantly decreased beginning on the 12th week; on the sixth and ninth months, they were further very significantly decreased (P < 0.001), with its peak on the sixth month. Those patterns were the same as single BCG, but on the 12th week, it was only slightly decreased; between the groups, there were no significant differences until the ninth month (Figure 3).
Besides the scars on the deltoid in the thrice and single BCG groups, which were 7 to 10 mm in diameter, there were no other side effects including autoimmune responses or visiting the emergency department in both groups and in both phases on 9 months' follow-up.
Mean serum TGF-β1 in mild and moderate persistent asthma was not significantly different. The serum IFN-γ correlated negatively with serum TGF-β1 on single BCG vaccination on the sixth month (r = -0.63, P = 0.001).
Sex ratio between male and female in the BCG group was 1:1, and in placebo, 2:3. Mean age was 34.8 years for both groups; body mass index was normal in both groups. These were similar to reports by Shirtcliffe et al  in 2001, where their mean age was 33 years. But Choi and Koh  reported a male-female ratio of 4:5 in the BCG group and 1:1 in the placebo group, with a mean age of 47.8 years, subjects were older than those of this study. Body mass index was normal between groups, so there was no negative influence on immune responses, which was similar to the study by Choi and Koh, [4, 20] Aaby et al,  Shirtcliffe et al,  and Marks et al.  The allergens on both groups were the same, of which house dust mites were the most prevalent in this study. The duration of asthma in this study was mostly 5 to 10 years, and the clinical diagnosis was mostly moderate persistent asthma (70%) on both groups. In other studies, it was more than 10 years with severe persistent asthma (65%-75%), whereas mild persistent asthma was not included in their studies [19–22].
Choi and Koh  reported that weekly SS was significantly decreased only on week 7 in the single BCG group, and there was no difference compared with placebo overall. On the other hand, DS was significantly decreased in the BCG group and in the placebo group. In this study, where the budesonide inhaler was discontinued on both groups, the DS on the placebo group was increased, higher than baseline but not significantly (P > 0.05). So SS and DS were significantly decreased in the thrice BCG group starting on week 10 until week 12 (P < 0.05) (Figure 2). The influence of discontinuing corticosteroid inhalation in both groups on the eighth week, when the third vaccination was already done, could not be excluded in the placebo group. Spirometry was significantly increased in the thrice BCG group (P < 0.05) in this study, this showed a better result than that of Choi and Koh  with single BCG.
In the thrice BCG group, the IgE between prevaccination and postvaccination slightly increased (P < 0.05); and between postvaccination in both groups was not significantly different, it means that BCG vaccinations could not suppress the IgE synthesis directly. This was similar to the study of Lichtenstein et al (cited in Rale and Patterson ) on IgE in pollen immunotherapy, which increased for several months and remained high until 1 to 2 years.
Choi and Koh  gave revaccination to the BCG group and for the first time in the placebo group; examination of serum IFN-γ and IL-4 was done before and after 12 weeks from vaccination. In our study, after thrice BCG vaccination, there was slightly increased serum IFN-γ after 12 weeks (P > 0.05) and then was significantly increased on the sixth and ninth months (P < 0.05) (Figure 5); the increase in serum IFN-γ at 12 weeks in the thrice BCG group was not significantly different from prevaccination in the first phase. Perhaps the 4 weeks' time after the last vaccination was not yet enough to find a significant result compared with the evaluation of Choi and Koh  after 16 weeks and may be because their dosage was higher. The significant increase in serum IFN-γ after thrice and single BCG vaccination on the sixth and ninth months reflected the immune responses mediated by Th1 cells. Serum TGF-β1 was significantly decreased (P < 0.001) via immune response stimulation of Th1 cells after thrice and single BCG vaccination, which increased the IFN-γ. The decrease of EBC in the thrice BCG group on the 12th week until the sixth month of this study had not occurred significantly, perhaps because of overstimulation by the antigen of thrice BCG. This was similar to the mean IgE, which was still increasing until the ninth month, although in the single BCG group on the ninth month, it began to decrease. On the contrary, during the first phase in placebo group, the EBC was significantly decreased, perhaps influenced by corticosteroid inhalation without any antigen stimulation; and on the sixth and ninth months after single BCG vaccination, the EBC was increased again. These features were similar to the mean IgE under pollen immunotherapy reported by Lichtenstein et al (cited by Rale and Patterson ). The mean levels of serum TGF-β1 were also not significantly different between mild and moderate persistent asthma, it means that the increase in TGF-β1 expression has already occurred and began in mild persistent asthma. Serum TGF-β1 has a tendency to stimulate the expression and accumulation of fibro-blast cells, deposition of extracellular matrix and collagen on peribronchial tissues, and the proliferation and hypertrophy of bronchial smooth muscle, and all of these will stimulate hyperreactivity and bronchial obstruction . From the results of the mean PEFR and serum TGF-β1 on the sixth month, we concluded that the peak of improvement of asthma had occurred on the sixth month postvaccination, and after that, the efficacy of BCG vaccination started to decrease in both groups. Choi and Koh  reported that the efficacy on PEFR of BCG revaccination after 1 year was better than single vaccination. From our study, we found that BCG has the ability to modulate the asthma immune responses, especially on increasing IFN-γ and inhibiting the expression of EBC, and serum TGF-β1. The studies of Choi and Koh, [4, 20] Erb et al,  Strannegard et al,  and Hoft et al  showed the modulating ability of BCG vaccination to influence the immune responses and change the balance of Th1 and Th2. In another study, Hopfenspirger and Agrawal  reported on the effect of BCG vaccination on asthma, they did not reveal differences in mean IgE between treated and control groups. Hoft et al,  in their study on the effect of single BCG on a normal person, reported the significant increase in serum IFN-γ and the significant decrease in serum IL-4, but they did not find any differences in IgE between the BCG and placebo groups. They proposed that BCG vaccination influences only the immune response that is mediated by Th1 cells, and not by Th2 cells. Cohn et al  and Smart et al  reported the same thing. This is similar to our finding that BCG vaccinations can improve clinical symptoms and lung function, and significantly increase serum IFN-γ levels, although the mean IgE and serum IL-4 also increased until 6 months. In our study, BCG vaccinations were able to increase serum IFN-γ and suppress serum TGF-β1 and EBC. This was similar to the reports of Choi and Koh [4, 20] in Korea, Strannegard et al  in Puerto Rico, Aaby et al  in Guinea-Bissau, Shirtcliffe et al  in New Zealand, Marks et al  in Australia, and Zuany-Amorin et al  in Brazil. They were all successful in showing immune response modulation to balance the Th1/Th2 in asthmatic patients with BCG vaccine or Mycobacterium vaccae. Most of their study subjects (65%-85%) have never had BCG vaccination in childhood. Moehrenschlager et al  from the MIRIAM study in Germany also found no hint that BCG vaccination or whole-cell pertussis vaccination may lead to higher prevalences of asthma, allergic rhinitis, eczema, or allergic sensitization at preschool age. Recently, Martignon et al  reported a significantly reduced risk of having atopic diseases in adolescents being vaccinated (BCG, diphtheria-tetanus-poliomyelitis, pertussis) in contrast to nonvaccinated controls, and this effect was strongest for atopic eczema and stronger in boys than in girls. On the contrary, the study conducted in regions where BCG vaccination was not given routinely in childhood, as the study of Alm et al  in Sweden and Anderson et al  in Belgium, could not show the effectivity of BCG on suppressing Th2 cytokines. The increase in serum IFN-γ correlated negatively to serum TGF-β1. The TGF-β1 is a major cytokine of T regulator cells, in particular, it is a potent regulator of fibroblast and myofibroblast function and controls the production of several extracellular matrix protein, including collagens, proteoglycans, and tenascin. Other cell types involved in allergic inflammation as potential sources of TGF-β1 include eosinophils, macrophages, mast cells, neutrophils, endothelial cells, and smooth muscle cells and fibroblasts themselves. The thickening of subepithelial lamina reticularis in bronchial asthma has been related to an increase of fibroblasts in correlation with TGF-β1 expression. Therapeutic treatment of mice with anti-TGF-β1 antibody significantly reduced peribronchial extracellular matrix deposition, airway smooth muscle cell proliferation, and mucus production in the lung (Duvemelle et al, Hashino et al, and Mc Milan et al, as cited by Akdis et al ). So the decrease of serum TGF-β1 in this study might contribute to the improvement of clinical signs and symptoms, and lung function, and the decrease in eosinophils. The improvement of clinical signs and symptoms including PEFR could be taken as the best parameter to monitor the efficacy of BCG vaccination. As a conclusion, we could see that thrice BCG vaccination is better than a single one based on lung function from the fourth week until the 12th week, although on the sixth and ninth months, the differences were not significant. Furthermore, on thrice BCG, serum IFN-γ was significantly higher on the sixth month than on single BCG. Then, on the ninth month, the PEFR and serum TGF-β1 began to worsen again, although it was still better than at prevaccination. Maybe after the ninth month for thrice BCG, one could suggest a first booster vaccination.
The efficacy of thrice BCG vaccination on asthma was demonstrated by the improvements of SS, DS, FEV1, PEFR, EBC, IFN-γ, and TGF-β1 until 9 months after the last vaccination, without any side effects.
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