Wait, do BCG vaccines even work?
Although there is some nuance with regards to vaccination schedule and outcome, overall, yes. A relatively recent systematic review by
Roy and colleagues (2014. PMCID 4122754) found:
The primary analysis included 14 studies and 3855 participants. The estimated overall risk ratio was 0.81 (95% confidence interval 0.71 to 0.92), indicating a protective efficacy of 19% against infection among vaccinated children after exposure compared with unvaccinated children.
Yes, you read that right, 19%.
Thankfully, other studies have found more substantial effects, such as this one by Nguipdop-Djomo and colleagues (2016. PMID 26603173):
Vaccine effectiveness against pulmonary tuberculosis up to 9 years (excluding tuberculosis episodes in the first 2 years) was 67%, 10-19 years was 63%, 20-29 years was 50%, and 30-40 years was 40%.
What are the immune mechanisms underlying BCG efficacy?
You are not alone in being confused about how BCG prevents Mycobacterium tuberculosis infection. This appears to be a hot area of research.
As Foster and colleagues note in a recent review (2021. PMCID 8252066):
The immunological mechanisms of BCG‐induced protection against Mycobacterium tuberculosis (Mtb) infection are incompletely understood. BCG‐mediated protection against TB has historically been attributed to vaccine‐induced memory CD4+ T cells which rapidly secrete Th1 cytokines and control secondary infection with Mtb. However, there is little evidence that vaccine‐induced memory CD4+ T cells confer protection against TB in immune‐competent hosts.
Foster and colleagues mention a number of other potential mechanisms, including the innate immune system:
Innate immune mechanisms likely play a role in protection against Mtb infection. In the initial stage of infection, inhaled aerosolized Mtb encounters the lung‐resident alveolar macrophages as the first line of defence against pathogens in the lung alveoli. ... Macrophages are endowed with the ability to kill internalized Mtb and produce pro‐inflammatory cytokines and chemokines to recruit other immune cells... Innate immune cells recognize Mtb through germline‐encoded pattern recognition receptors (PRRs), both on the cell surface and in the cytosol, which leads to phagocytosis of Mtb and immune activation. Engagement of various toll‐like receptors (TLRs), a subgroup of PRRs, by mycobacterial cell wall components triggers the production of pro‐inflammatory cytokines
But if the innate immune system is... well... innate, how does a vaccine help?
The authors suggest trained immunity the answer. Under this mechanism, the innate immune system is primed to respond more effectively to subsequent challenges. They go on to say:
Based on our work and that of others, we think that the answer may lie in BCG‐induced trained immunity. Vaccination is traditionally based on the induction of specific adaptive immune memory against a particular pathogen, which leads to enhanced responsiveness of lymphocytes upon subsequent infection with the same pathogen. However, an increasing body of evidence suggests that a number of live‐attenuated vaccines, including BCG and measles vaccine, also provide protection against unrelated infectious diseases.
In fact, some authors have found evidence to suggest BCG vaccination may be associated with protection against severe COVID disease (Escobar et al 2020. PMC 7395502).
This figure from the Foster paper explains how such trained immunity works:
Figure 1 from Foster et al 2021 available here.
Under this model, innate immune cells that are exposed to BCG antigens are permanently altered through epigenetic and metabolic changes. Thus, once they are exposed to a different pathogen (in this case Mycobacterium tuberculosis rather than Mycobacterium bovis found in BCG) the immune cells produce higher levels of cytokines and have stronger antimicrobial functions.
Why aren't we vaccinating everyone?
In the United States, the Centers for Disease Control notes:
BCG is not generally recommended for use in the United States because of the low risk of infection with Mycobacterium tuberculosis, the variable effectiveness of the vaccine against adult pulmonary TB, and the vaccine’s potential interference with tuberculin skin test reactivity.
At least of historical concern was the risk of disseminated M. bovis infection among HIV infected individuals (Ninane et al 1988. PMCID 1779046). There have also been concerns that BCG vaccination may slightly increase the risk of malignancy (Kendrick and Comstock 1981. PMID 7009946).
Thus, the combination of low prevalence in the United States, low total efficacy rates, rendering skin tests ineffective, and concerns about disseminated infection and malignancy prevent widespread adoption.
How about in endemic areas?
In contrast to the United States, the World Health Organization recommends:
In settings where tuberculosis is highly endemic or where there is high risk of exposure to TB, a single dose of BCG vaccine should be given to all infants.
They go on to provide tables of countries organized by decreasing TB incidence.
There is some evidence to suggest that in these endemic areas that BCG vaccination is associated with decreases in all-cause mortality (Storgaard et al 2015. PMID 26060293). This could be potentially mediated by the "trained immunity" protecting against non-TB infections.
