BCG - old workhorse, new skills.

Area of Science:

• Microbiology
• Immunology
• Vaccinology

Background:

• The current tuberculosis (TB) vaccine, Bacille Calmette-Guérin (BCG), exhibits limitations in efficacy, immunogenicity, and safety.
• Significant research is dedicated to developing novel TB vaccines to overcome BCG's shortcomings.

Purpose of the Study:

• To review current strategies in TB vaccine development, focusing on engineered live mycobacteria.
• To highlight key preclinical findings, including correlates of protection and optimal vaccination routes.
• To consider the non-specific effects of BCG in the context of new vaccine development.

Main Methods:

• Engineering live mycobacteria (e.g., BCG, M. tuberculosis, M. smegmatis) to modulate host intracellular pathways.
• Evaluating vaccine candidates targeting phagosome biology, apoptosis, and autophagy.
• Assessing correlates of protection in preclinical models, including T cell responses and immune cell recruitment.
• Comparing mucosal versus parenteral vaccination routes.

Main Results:

• Several engineered mycobacterial vaccine candidates are in development (e.g., BCG Δzmp1, BCG ΔureC::hly, Mtb ΔphoP ΔfadD26).
• Preclinical studies indicate that increased central memory CD4+ T cells and lung-recruited antigen-specific T cells are correlates of protection.
• Mucosal vaccination demonstrates superiority over parenteral administration in preclinical models.

Conclusions:

• Engineered live mycobacteria represent a promising avenue for next-generation TB vaccines.
• Optimizing T cell responses and targeting mucosal immunity are critical for effective TB vaccine design.
• The beneficial non-specific effects of BCG warrant consideration when evaluating potential BCG replacements.