Oral Tolerance to Environmental Mycobacteria Interferes with Intradermal, but Not Pulmonary, Immunization against Tuberculosis

Abstract

Bacille Calmette–Guérin (BCG) is currently the only approved vaccine against tuberculosis (TB) and is administered in over 150 countries worldwide. Despite its widespread use, the vaccine has a variable protective efficacy of 0–80%, with the lowest efficacy rates in tropical regions where TB is most prevalent. This variability is partially due to ubiquitous environmental mycobacteria (EM) found in soil and water sources, with high EM prevalence coinciding with areas of poor vaccine efficacy. In an effort to elucidate the mechanisms underlying EM interference with BCG vaccine efficacy, we exposed mice chronically to Mycobacterium avium (M. avium), a specific EM, by two different routes, the oral and intradermal route, to mimic human exposure. After intradermal BCG immunization in mice exposed to oral M. avium, we saw a significant decrease in the pro-inflammatory cytokine IFN-γ, and an increase in T regulatory cells and the immunosuppressive cytokine IL-10 compared to naïve BCG-vaccinated animals. To circumvent the immunosuppressive effect of oral M. avium exposure, we vaccinated mice by the pulmonary route with BCG. Inhaled BCG immunization rescued IFN-γ levels and increased CD4 and CD8 T cell recruitment into airways in M. avium-presensitized mice. In contrast, intradermal BCG vaccination was ineffective at T cell recruitment into the airway. Pulmonary BCG vaccination proved protective against Mtb infection regardless of previous oral M. avium exposure, compared to intradermal BCG immunization. In conclusion, our data indicate that vaccination against TB by the pulmonary route increases BCG vaccine efficacy by avoiding the immunosuppressive interference generated by chronic oral exposure to EM. This has implications in TB-burdened countries where drug resistance is on the rise and health care options are limited due to economic considerations. A successful vaccine against TB is necessary in these areas as it is both effective and economical.

Immune Responses to Bacillus Calmette–Guérin Vaccination: Why Do They Fail to Protect against Mycobacterium tuberculosis?

“…An explanation for this could be the environment surrounding the BCG-vaccinated infants [e.g., parasitic coinfections that dampen protective immune responses (117), or EM (118)]. Indeed, oral tolerance to EM is a detrimental factor following intradermal BCG vaccination, an effect that could be overcome by vaccinating via the pulmonary route due to lack of tolerance to EM in the lung (119). However, virulent lipids on the mycobacterial cell wall (including M.tb and M. bovis BCG), particularly TDM, have prevented the use of pulmonary vaccination.…”

“…Low BCG protective efficacy is reported in regions of the world closer to the equator, where EM are common. Thus, BCG protective efficacy could be affected by prior host T reg cell development due to pre-exposure to EM (119). The importance of CD4 + T reg cells mainly relies on studies showing that their depletion decreases M.tb burden in BCG-vaccinated mice (132).…”

Tuberculosis susceptibility and vaccine protection are independently controlled by host genotype

“…This variable efficacy could be due to differences in the vaccine strain or preparation, the environment, or the genetic background of the host. The roles of genetic variation in the vaccine strain (21-24) and previous exposure to environmental mycobacteria (25-27) have been investigated extensively. In contrast, the role of host genetic variation in BCG efficacy has been more difficult to quantify.…”

Neonatal vaccine effectiveness and the role of adjuvants

“…This indicates that the right immune signals can induce favorable adaptive immune responses in early life. Nevertheless, poor BCG efficacy in regions closer to the equator has been associated with prior Treg induction by environmental mycobacteria [71], highlighting the challenges even for a successful neonatal vaccine-like BCG.…”