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Mining the CD4 antigen repertoire for next-generation tuberculosis vaccines

Samuel J Vidal1, Ninaad Lasrado2, Lisa H Tostanoski2

  • 1Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Cell
|September 16, 2025
PubMed

Insights

Developing a new tuberculosis (TB) vaccine, researchers identified novel CD4 T cell antigens. A trivalent mRNA vaccine using PPE20, EsxG, and PE18 showed superior protection against TB in mice.

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.
Keywords:
Bacillus Calmette-GuérinCD4antigenmRNAscreentuberculosisvaccine

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