Tuberculosis (TB) continues to be one of the major public health threats, accounting for approximately 1.5 million deaths per year across the globe. BCG (Bacillus Calmette-Guerin), which was developed nearly 100 years ago, is the only available vaccine against TB. Despite conferring significant protection against childhood manifestations of TB, protective efficacy of BCG against adult pulmonary TB is highly variable (1, 2). Lowest efficacy of BCG against adult pulmonary TB has been observed in the tropics, which account for the major burden of the disease. Why BCG confers significant protection against childhood TB but fails against the adult pulmonary disease remains an open question.

Mycobacterium tuberculosis (Mtb), the causative agent of TB, shares an intricate relationship with the host immune system and leads to different clinical outcomes. Therefore, TB is considered a heterogeneous disease, occurring in different patterns and presentations and having distinct mechanisms of pathogenesis (3). In young children, Mtb infection leads to the primary disease commonly affecting extra-pulmonary sites. On the other hand, TB develops after reactivation of latent infection and preferentially affects lung tissue in most immunocompetent adults. Among various factors involved in defining the efficacy of BCG and the outcome of Mtb infection, exposure to environmental mycobacteria (EMb) has been shown to play a particularly important role (1).

In the present manuscript, I shed light on the variable efficacy of BCG and explained it by taking into account the heterogeneity of TB, mechanisms of TB pathogenesis, and the effect of EMb on anti-Mtb immunity. It is believed that a refined understanding of the success and failure of BCG will help in the development of effective anti-TB vaccines.

BCG was derived by French researchers Albert Calmette and Camille Guerin by in vitro passaging M. bovis for nearly 13 years. Clinical studies with BCG took place in France and Belgium in the 1920s and demonstrated its efficacy against childhood TB (4). As the effectiveness of BCG against childhood TB was observed in these and other European countries, World Health Organization (WHO) recommended expansion of the BCG vaccination program to the TB-endemic countries (1).

Despite more than 3 billion people receiving BCG, TB continues to be a devastating disease worldwide. A major drawback of BCG is its variable efficacy (ranging from nil to 80%) against adult TB. Palmer and colleagues were first to recognize that BCG is more effective against pulmonary TB at higher latitudes (1). Various factors including strain variations and poor cold-chain maintenance were suggested to be responsible for the variable efficacy of BCG against the adult disease. However, as the same BCG strains exhibited higher anti-TB efficacy in other countries, and were effective against leprosy in areas of their poor anti-TB efficacy, role of these factors in variable efficacy of BCG against adult TB was proved to be unfounded (5).

Currently, two hypotheses (masking hypothesis and blocking hypothesis) are considered most pertinent for explaining the failure of BCG against pulmonary TB. Masking hypothesis was based on the work by Palmer and colleagues, who observed in large-scale experiments in guinea pigs that immunization with EMb induces an appreciable level of protective immunity against Mtb and that the effects of subsequent BCG vaccination in these animals are markedly reduced (6). It was deduced that EMb, while imparting certain degree of protective immunity against Mtb, mask the efficacy of BCG to confer protection against the TB bacilli (6). Blocking hypothesis was based on the work by Anderson and colleagues, who demonstrated with a mouse model that prior exposure to EMb induces potent antimycobacterial immune responses, which block the duplication of BCG and thereby abrogate its efficacy to induce protective immunity against subsequent Mtb infection (7). As BCG is a live attenuated vaccine, its duplication in immunized people was considered as a precondition for induction of effective immunity against Mtb.

In either case, augmenting antimycobacterial immune response with booster doses of BCG could have been a potent strategy to enhance the anti-TB efficacy of BCG. However, repeated BCG administration has been found to not confer additional protection against pulmonary TB (although protection against leprosy is improved) (8, 9). Also, it is unlikely for the infants to receive significant EMb exposure before BCG vaccination, for they are immunized soon after birth. Moreover, the above hypotheses are based on animal studies, which have yielded contrasting result, with their applicability in humans difficult to verify (10–12). Therefore, why BCG fails to confer significant protection against adult pulmonary TB needs to be revisited.

TB is a heterogeneous disease occurring in different patterns and presentations (13). Two distinct presentations of TB can be seen in infants and immunocompetent adults (14, 15). In infants and young children, Mtb infection leads to primary disease with a high mortality rate. This form of disease commonly affects extra-pulmonary sites and in severe cases, can occur in disseminated form (miliary TB) (15). On the contrary, initial Mtb infection in immunocompetent adults is mostly contained as latent TB (LTB). This state of asymptomatic infection may persist lifelong in most but 5-10% of people, who would develop active disease during their lifetime (3). Active TB in immunocompetent adults preferentially affects lung tissue.

The primary and extra-pulmonary nature of TB in infants/young children is suggestive of their incompetence to contain Mtb. In keeping with this, immunological milieu in young children has been shown to be skewed towards the T_H2 side, with dampened T_H1-type of immunity and inflammatory pathways (16). Moreover, CD4⁺ T cells in young children are recent thymic emigrants with defective functionality and differentiation bias towards T_H2 effector cells (17). That is why most children would respond poorly to mycobacterial antigens during tuberculin skin testing (TST) and IFN-γ release assay (IGRA) (15). On the other hand, immune system is effective against Mtb in most adults. These people mount a robust T_H1 type of immune response to Mtb, resulting in sequestration of infected macrophages into lung granulomas and containment of infection as LTB (18). Paradoxically, host immune system has also been implicated in the reactivation of latent infection into active TB in immunocompetent adults (19).

Host response to Mtb begins with its recognition by resident lung macrophages which, along with dendritic cells, induce adaptive immune responses to bacilli. T_H1-polarized CD4⁺ T cells are the key orchestrators of protective immunity against Mtb (18). Critical role of these cells in protection against Mtb is demonstrated by increased risk of TB in CD4⁺ T cell-lymphopenic HIV/AIDS patients. Similarly, CD4⁺ T cell depletion from animal models has been shown to increase the susceptibility to mycobacterial disease. Antimycobacterial functions of CD4⁺ T cells are partly mediated by TNF-α and IFN-γ, which induce bactericidal mechanisms in infected macrophages and facilitate their sequestration in the granulomas (3). Other cell types including CD8⁺ T cells, NK, and NKT cells have also been shown to contribute towards host resistance to Mtb (3).

LTB, which follows initial Mtb infection in most adults, is considered a state of protection against Mtb (20). It is characterized by a moderate anti-Mtb immune response in comparison to active pulmonary TB, wherein an aggravated antimycobacterial immunity is commonly observed (19). Heightened IFN-γ⁺CD4⁺ T-cell response to mycobacterial antigens, as evidenced by tuberculin reaction, IGRA, and in vitro assays, occurs frequently in active TB patients and is an important parameter distinguishing active TB from latent infection (21–24). Indeed, increased IFN-γ levels in different tissues is one of the most common and consistent observations during active TB (3). Importantly, IFN-γ levels directly correlate with TB severity and subside with its successful treatment, suggesting that mycobacterial burden could also contribute towards the aggravation of anti-Mtb immune responses (3). It is worth mentioning that host genetics also plays an important role in tuberculin sensitivity and some people may not exhibit tuberculin reactivity despite active disease (25, 26). Interestingly, these people have been shown to exhibit fewer symptoms but a more advanced disease (25).

TB-associated immune reconstitution inflammatory syndrome (TB-IRIS), which develops with the reactivation of asymptomatic Mtb infection in a subset of antiretroviral therapy (ART)-treated HIV-infected people, provides direct evidence for the pathological role of aggravated immunity during Mtb infection. ART-mediated decline in viral load results in the over-expansion of Mtb-specific CD4⁺ T cells in HIV and Mtb-coinfected patients (27). Lower baseline CD4⁺ T-cell count and rapid increase in these cells number with ART are the major risk factors for the development of TB-IRIS (28). Importantly, ART-treated people who are destined to develop TB-IRIS exhibit a more strong T_H1-type of CD4⁺ T-cell response to Mtb antigens (27). Similar results have been obtained from animal studies, wherein the human condition was mimicked by adoptively transferring CD4⁺ T cells in M. avium-infected, TCRα^−/− mice (29). After receiving CD4⁺ T cells, these animals developed an aggravated immune response to the bacilli, exhibited wasting, lost weight, and eventually died of exacerbated immunity (29). Interestingly, development of immune reconstitution disease in these animals was mediated by hyperactive IFN-γ⁺CD4⁺ T cells.

The course of Mtb infection in PD-1^−/− mice also implicates aggravated CD4⁺ T-cell response in TB pathogenesis. PD-1 is a cell-surface receptor involved in the negative regulation of T-cell responses, and its deficiency results in significantly increased susceptibility to mycobacterial diseases, compared with wild-type mice (30, 31). Mechanistic studies have shown that PD-1^−/− mice mount a hyperactive CD4⁺ T-cell responses to mycobacteria, which drive mycobacterial pathogenesis in these animals (32). In agreement with animal studies, PD-1 blockade in cancer patients (a type of immunotherapy) has resulted in multiple cases of TB (33). It is noteworthy that PD-1 blockade-mediated TB development is associated with increased frequency of Mtb-specific IFN-γ⁺CD4⁺ T cells (33).

Significantly higher risk of TB in the immunocompetent adults cured of its previous episode also implicates aggravated CD4⁺ T-cell responses in TB development (34). Mtb-specific CD4⁺ T-cell responses are elevated during active TB, and a proportion of these cells can persist as memory cells after successful treatment (35, 36). It has been estimated that ~70% of people cured of pulmonary TB exhibit positive tuberculin reaction and IGRA up to 30 years after treatment (37). With Mtb reinfection, these hosts are more likely to mount hyperactive CD4⁺ T-cell responses, leading to active TB.

The success of BCG against childhood TB and its variable efficacy against adult pulmonary disease are explained below by taking into account the heterogeneity of TB, protective versus pathological immunity during Mtb infection, and effect of EMb on anti-Mtb immune responses.

TB is a heterogeneous disease occurring in different patterns/presentations with distinct mechanisms of pathogenesis (3). In infants and young children, the immune system is poorly developed with dampened T_H1 responses and inflammatory pathways, rendering them susceptible to Mtb (16, 17). BCG vaccination promotes a T_H1-type of anti-Mtb immunity in these people and therefore, confers significant protection against childhood TB (38). In immunocompetent adults, development of pulmonary TB has been attributed to an aggravated anti-Mtb immune responses (18, 19). Since a more intense antimycobacterial immune response is observed in the tropics, it is plausible that higher incidence of adult pulmonary TB would be reported from these areas. Also, BCG, which acts by inducing anti-Mtb immunity, would not be effective against pulmonary TB in these places. On the contrary, BCG-vaccinated people demonstrate a moderately intense antimycobacterial immune response at higher latitudes. For a moderate antimycobacterial response is protective against Mtb, BCG exhibits higher protective efficacy against adult TB in these areas. Firm support for the above explanation of the variable efficacy of BCG is provided by its effectiveness in rural versus urban settings (58). A more intense antimycobacterial immune response is observed in rural areas, wherein the efficacy of BCG has been found to be lower, compared with that in urban places (56, 57).

It can be proposed that a different vaccination approach against adult TB is required in the tropics. Most likely, an effective vaccine against adult TB in these areas would focus on moderating Mtb-specific IFN-γ⁺CD4⁺ T-cell responses and balancing pro- and anti-inflammatory pathways. That’s probably how we can prevent adult pulmonary TB and save millions of lives.

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