|Year : 2014 | Volume
| Issue : 1 | Page : 1-4
How to avoid the impact of environmental mycobacteria towards the efficacy of BCG vaccination against tuberculosis?
Department of Immunology, National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra 282004, India
|Date of Web Publication||24-Feb-2017|
Department of Immunology, National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra 282004
Source of Support: None, Conflict of Interest: None
Bacillus Calmette–Guérin (BCG) remains the only widely used vaccine against tuberculosis (TB). Consistent efficacy has been proved in infants but not in adults from developing countries. Epidemiological and experimental studies have pointed out that, prior exposure to prevailing environmental mycobacteria could be responsible for the poor efficacy of BCG as an anti-TB vaccine in adults living in developing countries. Sensitization by environmental mycobacteria may down-modulate the immunologic behavior of BCG on the one hand and may mask its efficacy on the other hand. Some of the important deciding factors for poor efficacy of BCG, due to exposure of the subjects to prevailing environmental mycobacteria, are thought to be (i) Life stage: neonatus versus adolescence; (ii) shared antigens between prevailing environmental mycobacteria and BCG; and (iii) generation of cross-reactive T-regulatory cells against environmental mycobacteria and BCG. In this communication, some novel strategies have been discussed for countering the down modulating impact of environmental mycobacteria towards performance of BCG as an anti-TB vaccine.
Keywords: Tuberculosis, BCG, Vaccine, Environmental mycobacteria, Immunoprophylaxis
|How to cite this article:|
Parkash O. How to avoid the impact of environmental mycobacteria towards the efficacy of BCG vaccination against tuberculosis?. Int J Mycobacteriol 2014;3:1-4
|How to cite this URL:|
Parkash O. How to avoid the impact of environmental mycobacteria towards the efficacy of BCG vaccination against tuberculosis?. Int J Mycobacteriol [serial online] 2014 [cited 2022 Jan 18];3:1-4. Available from: https://www.ijmyco.org/text.asp?2014/3/1/1/200920
| Introduction|| |
Tuberculosis (TB) caused by Mycobacterium tuberculosis is a major global health problem, causing more than 1.3 million deaths every year . The most effective and economic way of controlling this problem would be the availability of an effective vaccine. Bacillus Calmette–Guérin, known as BCG in the abbreviated form, is an attenuated form of Mycobacterium bovis which was isolated by Albert Calmette and Camille Guérin nearly a century ago and highly resembles M. tuberculosis . The use of BCG for human vaccination against TB was initiated in 1921 and to date there is no alternate of this vaccine. Immunologically, BCG is known to generate T-cell helper type-1 (Th1) immunity for protection of the host from M. tuberculosis infection . As documented, BCG has been found to be significantly protective against severe forms (disseminating and meningeal) of TB in children; however, its efficacy in adults is inconsistent and varies from 0–80% in different geographical regions ,. Moreover, there are evidences of exacerbated disease in certain vaccinated individuals. Nevertheless, BCG is still being used worldwide for vaccination against TB despite foregoing drawbacks. The poor performance of BCG in developing countries, where rates of TB are much higher, is very discouraging. The reasons why BCG is not very effective in immunocompetent individuals are considered to be: strain differences in BCG, prevalence of environmental mycobacteria, genetics of host, nutritional factors and presence of helminthes co-infections, etc. . Among the various reasons for poor efficacy of BCG in immunocompetent individuals, prior exposure to environmental mycobacteria is thought to be an important and widely accepted cause of poor efficacy of BCG vaccine in adults from developing countries ,,,,,. This study discusses how the environmental mycobacteria may contribute towards yielding weak efficacy of BCG as an anti-TB vaccine. Also, this study describes possible strategies to overcome such down-modulating impacts towards performance of BCG as a vaccine.
| BCG and its efficacy in neonates versus adults|| |
BCG has been reported to be significantly effective in children when it is delivered in the neonatal stage at birth and the magnitude of specific CD4+ T cells peaks 6–10 weeks after vaccination . It is well-documented that in addition to immunizing the Th1 cells, BCG is known to act as an immunomodulator ,, as well. Though BCG primarily induces Th1-type of immune response , depending upon antigen and cytokine milieu, BCG may also induce Th2-like immune response ,. At the neonatal stage, the immune system is considered to be immature, and along with aging, progressive maturation of the immune system occurs due to persistent exposure to antigens present in the surroundings ,,. In neonates, the naïve Th0 cells are abundant  and along with maturation of the immune system, these cells switch towards Th1 or Th2. Since exposure of the immune system to environmental mycobacteria is expected to be less in neonates when compared with adults, down-modulation of the BCG efficacy by environmental mycobacteria would be lower at the neonatal stage. Hence, during the developmental stage of the immune system in the neonates, exposure to vaccinated BCG may play a pivotal role in switching the naïve Th cell towards Th1. On the other hand, adults have a mature immune system and almost an established Th1/Th2 profile. When compared with adults, the better efficacy  of BCG in infants/children might be due to more intense switching of the immune system towards Th1 during the neonatal stage. This all could be due to immunomodulating as well as immunizing behavior of BCG at the level of Th1.
Regarding adults, the efficacy of BCG has been reported to be lower in the developing countries  where most of the people from the neonatal stage onwards live in an environment where mycobacteria are highly prevalent. Hence, along with aging as well as persistent exposure to mycobacteria, a consistent evocation of the Th1-mediated immunity occurs. Of course, the total period of exposure of the adults to environmental mycobacteria remains more than the time span needed for growth of a neonate to a child. During such a time span of about 15 years for reaching the neonate to adolescence stage, the immune response involving shift (due to environmental mycobacteria) of Th0/Th2 to Th1 might reach a threshold where subsequent vaccination with BCG may not show a significant difference in protection between the non-vaccinated and vaccinated groups. As a result thereof, it is reflected as if efficacy of BCG vaccine is weak or the vaccine is non-effective. The same has been explained by two hypotheses : (i) blocking hypothesis: due to cell-mediated immunity generated by exposure of the host to the prevailing environmental mycobacteria, BCG delivered to the host might be killed. This may result in limiting the available BCG-derived antigens from further evoking the immune system. Thereby, a diminished immunity, against M. tuberculosis, in the host is generated. It is called blocking effect of environmental mycobacteria towards BCG efficacy; and (ii) masking hypothesis: it is a phenomenon where the background immunity generated due to prior exposure of individuals to environmental mycobacteria masks the efficacy of subsequent BCG vaccination. As a result thereof, it is reflected as if efficacy of the BCG vaccine is weak or the vaccine is non-effective.
| Possible role of T-regulatory cells on efficacy of BCG|| |
T-regulatory (Treg) cells  are subtypes of CD4+ T-helper cells that are known to regulate the immune system by suppressing the proliferation of lymphocytes, the production of cytokines and the production of antibodies. Primarily, there are two subsets of regulatory cells: (i) adaptive – such Treg cells are induced in the periphery due to stimulation by prevailing sub-optimal levels of antigens; and (ii) natural – these are derived from thymus and already have immune-suppressing capability. Induced Treg cells are again of two types: (i) iTr cells which have suppressive action by releasing IL-10; and (ii) Th3 cells which act by releasing TGF-β, an immunosuppressive cytokine. Treg cells also act through cell–cell contact where CTLA-4 (cytotoxic lymphocyte associated antigen-4) present on Treg cells modulates functions of antigen-presenting dendritic cells, through binding to CD80 and/or CD86 molecules on antigen presenting cells. This results in inhibition of maturation, down-regulation of CD80/CD86, and induction of immunoregulatory enzyme indoleamine-2,3-desoxygenase which transmits an inhibitory signal to T-cells. Also, Treg cells compete with effector CD4+ T-cells for interaction with antigen-captured antigen-presenting cells .
Currently, the vaccine immunogenicities are analyzed keeping possible involvement of Treg cells towards dampening of their efficacies. In the context of the anti-TB vaccine, the environmental mycobacteria are considered to weaken the efficacy of BCG. There is information describing the induction of Treg cells by environmental mycobacteria ,,. The sensitised Treg cells generated by such antigens are thought to be stimulated by vaccinated BCG which in turn may dampen the immune response generated by BCG through inhibiting the T-cell effector functions . Additionally, BCG itself has also been reported to be involved in the generation of Treg cells ,,. Priming the host with BCG vaccine followed by boosting with Treg down-regulating mycobacterial proteins has been reported to be promising ,. This further supports implication of Treg cells in down-modulating the efficacy of BCG as a vaccine. However, attenuation of Treg concomitant to immunization with BCG and before immunization with BCG did not improve the vaccine outcome ,. These findings also point out that Treg cells generated after BCG vaccination may play a role in suppressing the anti-TB efficacy of BCG vaccine. Treg cells are known to be produced during M. tuberculosis infection as well ,, which may play an important role in TB pathogenesis ,,,,, and also in further dampening the BCG immunizing capacity , against TB. Thus, the Treg cells have suppression effect on the efficacy of BCG at three different levels described in the foregoing. It is speculated that pre-exposure to mycobacterial antigens (present in environmental mycobacteria) may induce and sensitize the Treg cells in the host. These sensitized cells may further be stimulated by vaccination with BCG and subsequently by M. tuberculosis infection. Eventually, all this may result in the generation of a larger pool of Treg cells which in turn could influence the BCG vaccine efficacy . Keeping all of this information in view, it is worth mentioning that the generation of Treg cells by environmental mycobacteria may initiate the process leading towards down-modulation of the efficacy of the BCG vaccine.
| Perspectives|| |
The foregoing discussion points out that, probably, shared antigens between environmental mycobacteria and BCG may be responsible for blocking as well as masking the effect towards immunizing the efficiency of the anti-TB vaccine. Such effects due to environmental mycobacteria may not occur only with conventional BCG; rather, they may be noticed even with genetically engineered BCG as well. This study suggests two remedies ([Figure 1]) that may help in unravelling the factual efficacy of BCG vaccines and in improving the performance of anti-TB vaccines respectively: (i) the testing of candidate BCG vaccines must be conducted with the people living in the regions where prevalence of environmental mycobacteria may be negligible. Doing so would eliminate the blocking and masking effects of environmental mycobacteria; and (ii) genes encoding only those proteins that may be present in BCG as well as M. tuberculosis but absent in environmental mycobacteria may be selected through genomic comparisons of the concerned mycobacterial species. Employing the selected desirable genes, the corresponding antigens may be produced by genetic engineering. In case such proteins are found to be immunologically potential, then they may prove to be promising antigens for anti-TB vaccines as they would be devoid of the undesirable down-modulating and masking effects of environmental mycobacteria.
|Figure 1: Strategies for avoiding the impact of environmental mycobacteria (EM) on efficacy of BCG as a vaccine against tuberculosis.|
Click here to view
Keeping in view the possible role of Treg cells towards weakening the efficacy of the BCG vaccine, this write-up suggests that ([Figure 1]): (i) Strategies to modulate the Treg cell-mediated down-modulating effect on Th1 cells to weaken the efficacy BCG need to be developed, perhaps on the lines described elsewhere ; (ii) Identifying Treg cell-inducing BCG antigens is worth attempting. By identifying immunosuppressive antigens, better BCG vaccines might be created by dissecting out Treg cell-inducing proteins from BCG. Development of such deficient versions of BCG for Treg cell-inducing proteins may be carried out by genetic manipulation of BCG genes through disruption or deletion of concerned genes; And (iii) Developing recombinant BCG (rBCG) strains expressing Treg down-regulating antigens might stimulate more potent immune responses against M. tuberculosis infection.
Most likely, these suggested strategies may lead towards the bettering of BCG as an anti-TB vaccine. Nonetheless, whatever may be the strategy to improve the performance of BCG through reducing the Treg population, the ratio of Th1-type of CD4 cells (through which BCG acts) and Treg cells should be maintained at such a level so that tissue damage might be low with high efficacy of the BCG vaccine.
| Conflict of interest|| |
There is no conflict of interest regarding this manuscript.
| Acknowledgements|| |
Thanks to Infolep, Amsterdam, The Netherlands, for helping in providing the scientific literature. Thanks to Juraj Ivanyi, Department of Oral Medicine & Pathology, Guy's Campus, Medical and Dental Schools of Kings College, London, United Kingdom. Thanks to Ms Sonali Agrawal for helping in preparing the sketch diagram. Thanks to Indian Council of Medical Research for routine support.
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