Do successful tuberculosis vaccines need to be immunoregulatory rather than merely Th1-boosting?

Abstract

Tuberculosis vaccine candidates are entering clinical studies in areas where BCG fails. This is a high risk strategy. We suggest that geographical variation in the efficacy of BCG is related to the presence in developing countries of a cross-reactive background Th2-like response, probably attributable to exposure of mother and infant to helminths and environmental mycobacteria. Such Th2-like activity can stop M. tuberculosis from being pushed into a latent state by the Th1 response, impair bactericidal functions and cause toxicity of TNF-α and pulmonary fibrosis. A successful vaccine, rather than driving a Th1 response, might need to suppress this pre-existing subversive Th2-like component.

The History of Tuberculosis and Bacillus Calmette–Guérin Vaccine in Iran

“…This vaccine also appears to generate CD4+ central memory T cells rather poorly, potentially compromising control of subsequent TB infection (19,20). Another factor that may underlie BCG failure is the unusually high concentrations of IL-4 that have been found in patients from developing countries (21,22). IL-4-producing Th2 cell responses may predominate in these patients due to exposure to non-tuberculous mycobacteria (NTM) and/or helminth infections.…”

“…IL-4-producing Th2 cell responses may predominate in these patients due to exposure to non-tuberculous mycobacteria (NTM) and/or helminth infections. Resultant IL-4 production and regulatory T-cell development may negatively regulate generation of Th1 type cells that could potentially contain TB infection, thereby leading to active disease and vaccine failure (12,18,(21)(22)(23). In recent mouse studies, CD4+ regulatory T-cells induced by BCG appeared to down-regulate effector T cell activity in mice infected with a virulent W-Beijing TB genotype; a finding with implications for BCG vaccination against highly virulent circulating TB strains (24).…”

Immunogenicity and Protection Induced by a Mycobacterium tuberculosis sigE Mutant in a BALB/c Mouse Model of Progressive Pulmonary Tuberculosis

“…These observations justify the hypothesis that the sigE mutant could have strong potential as a novel attenuated vaccine, since the response to its infection fits well into the proposition that the aim of a "classical" vaccine is to mimic natural infection as closely as possible, inducing a strong immune protective response without causing extensive disease (39). In addition, the lack of a Th2 response in the presence of a strong Th1 response is considered one of the essential characteristics for a new antitubercular vaccine (34)(35)(36). Moreover, the sigE mutant can be considered a good vaccine candidate since it is highly attenuated in SCID mice (27) and at the latest time points produces a significantly lower mortality than BCG in nude mice.…”

“…This could be explained by the fact that the mice used in this study received Mexico City autoclaved, but not filtered, tap water, known to contain high loads of environmental mycobacteria. Preexposure to these environmental mycobacteria probably resulted in a basal level of immunization against mycobacterial antigens, which has been hypothesized to cause poor responsiveness to BCG vaccination (34,36). Further experiments in other animal models in which the protective potential of BCG is higher than that obtainable in our model are needed to confirm the superiority of the protective potential of the sigE mutant with respect to that of BCG.…”

Orally Administered Mycobacterium vaccae Modulates Expression of Immunoregulatory Molecules in BALB/c Mice with Pulmonary Tuberculosis

“…We have pointed out previously that high IL-4 levels occur in TB most often in developing countries close to the equator, particularly in low-lying areas (22). We have suggested that this is due to the combined influence of high exposure to environmental mycobacteria and to helminths, followed by high-dose challenge with M. tuberculosis (23,25).…”