New TB Vaccine Candidate with Enhanced Post-Translational Modifications in Mycobacterium Tuberculosis

Tuberculosis remains one of the most lethal infectious diseases globally, claiming over one million lives yearly. Despite the widespread administration of the BCG vaccine, which is highly effective in children, its efficacy significantly reduces in adults. This limitation has prompted the pursuit of booster vaccines to enhance adult immunity.

Mycobacterium tuberculosis (M. tuberculosis) infects about a quarter of the global population, though most carriers remain asymptomatic and do not develop the disease. The pursuit of more effective vaccines has led researchers to explore specific proteins from M. tuberculosis that can trigger strong immune responses. One such protein, Mycobacterial DNA-binding protein 1 (MDP1), has shown promise due to its ability to elicit higher IFN-gamma responses in individuals who manage to suppress the disease’s progression.

The BCG vaccine's limited effectiveness in preventing new tuberculosis cases—over 10 million annually—emphasizes the need for advanced vaccines. Scientists are focusing on the immune response marker IFN-gamma, produced by T cells, which is critical for protection against tuberculosis. However, there is a paradox where proteins that prompt higher IFN-gamma production in tuberculosis patients, who have already developed the disease, are considered potential vaccine candidates over those who prevent the disease onset. Additionally, vaccine studies often overlook the native structure and post-translational modifications of these proteins, which could be crucial for an effective immune defense.

MDP1 is a significant protein in both BCG and M. tuberculosis, undergoing extensive post-translational modifications. Recent research suggests that MDP1 induces stronger IFN-gamma responses in individuals who control tuberculosis progression, highlighting its potential as a vaccine candidate. To evaluate MDP1's efficacy as a booster vaccine, researchers produced recombinant MDP1 and tested it on blood samples from BCG-vaccinated adults.

In their study, Ozeki et al. expressed MDP1 in two different hosts: the non-pathogenic, fast-growing mycobacterium M. smegmatis and Escherichia coli (E. coli). Notably, MDP1 expressed in M. smegmatis (mMDP1) exhibited significant post-translational modifications, closely resembling the native MDP1 in M. tuberculosis. In contrast, MDP1 expressed in E. coli (eMDP1) lacked these modifications.

When peripheral blood from BCG-vaccinated adults was cultured with the two MDP1 variants, mMDP1 induced significantly higher IFN-gamma levels than eMDP1. This indicates that the immune system of BCG-vaccinated adults can recognize MDP1 with post-translational modifications, suggesting its potential as an effective booster vaccine.

Moreover, mMDP1 showed a superior capacity for IFN-gamma production compared to other vaccine candidate antigens like the Antigen 85 complex. Typically, protein antigens in vaccines need adjuvants to enhance their immunogenicity or prevent degradation. Previous studies reported that MDP1, due to its affinity for bacterial DNA, could protect mice from M. tuberculosis infection when co-administered.

In this study, the combination of mMDP1 and G9.1, a novel CpG-DNA type, elicited significant IFN-gamma production from BCG-vaccinated adults' peripheral blood. This indicates that mMDP1, displaying post-translational modifications, combined with G9.1, could potentially reinvigorate the diminishing effect of BCG, making it a promising candidate for a booster vaccine.

The findings suggest that mMDP1, with its post-translational modifications, when used alongside G9.1, could enhance the immune response in adults, offering a viable booster to the BCG vaccine. This approach holds promise for better controlling tuberculosis and reducing its global mortality rate.