Mining the CD4 antigen repertoire for next-generation tuberculosis vaccines

Area of Science:

• Immunology
• Vaccinology
• Infectious Diseases

Background:

• Tuberculosis (TB) is a leading global infectious disease killer.
• Bacillus Calmette-Guérin (BCG) is the only current TB vaccine.
• Selecting effective TB vaccine antigens is challenging.

Purpose of the Study:

• To identify novel TB vaccine antigens through systematic screening.
• To evaluate the efficacy of a new multi-antigen mRNA vaccine.
• To assess cellular immune responses to candidate antigens in humans.

Main Methods:

• Screened CD4 T cell target antigens for TB vaccine efficacy in mouse models.
• Developed a trivalent mRNA vaccine with PPE20, EsxG, and PE18.
• Assessed vaccine efficacy in multiple mouse models and cellular immunity in humans.

Main Results:

• Identified significant heterogeneity in antigen efficacy; many top antigens are not in clinical trials.
• Demonstrated immunologic cross-reactivity among clustered antigens due to shared epitopes.
• The trivalent mRNA vaccine surpassed BCG protection in mouse models.
• Detected cellular immune responses to vaccine antigens in 84% of TB-exposed humans.

Conclusions:

• Novel TB vaccine antigens have been identified, advancing vaccine immunology.
• A trivalent mRNA vaccine concept combining PPE20, EsxG, and PE18 shows promise for clinical development.
• These findings provide a new strategy for developing more effective TB vaccines.