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. 2025 Sep 15:S0092-8674(25)00982-1.
doi: 10.1016/j.cell.2025.08.027. Online ahead of print.

Mining the CD4 antigen repertoire for next-generation tuberculosis vaccines

Samuel J Vidal  1 , Ninaad Lasrado  2 , Lisa H Tostanoski  2 , Jayeshbhai Chaudhari  2 , Esther R Mbiwan  2 , Ganad D Neka  2 , Ellis A Strutton  2 , Alejandro A Espinosa Perez  2 , Daniel Sellers  2 , Julia Barrett  2 , Michelle Lifton  2 , Shoko Wakabayashi  3 , Behnaz Eshaghi  4 , Erica N Borducchi  2 , Malika Aid  2 , Wenjun Li  5 , Thomas J Scriba  6 , Ana Jaklenec  4 , Robert Langer  4 , Dan H Barouch  7
Affiliations

Mining the CD4 antigen repertoire for next-generation tuberculosis vaccines

Samuel J Vidal et al. Cell. .

Abstract

Tuberculosis (TB) is the leading cause of death from infectious disease worldwide, and Bacillus Calmette-Guérin (BCG) remains the only clinically approved vaccine. An enduring challenge in TB vaccine development is systematic antigen selection from a large repertoire of potential candidates. We performed an efficacy screen in mice of antigens that are targets of CD4 T cells in humans. We found striking heterogeneity in protective efficacy, and most of the top protective antigens are not currently in clinical development. We observed immunologic cross-reactivity among phylogenetically clustered antigens, reflecting common CD4 epitopes. We developed a trivalent mRNA vaccine consisting of PPE20 (Rv1387), EsxG (Rv0287), and PE18 (Rv1788), which augmented and exceeded BCG protection in multiple mouse models. Finally, we observed cellular immune responses to these antigens in 84% of humans exposed to M. tuberculosis. These data advance our understanding of TB vaccine immunology and define a vaccine concept for clinical development.

Keywords: Bacillus Calmette-Guérin; CD4; antigen; mRNA; screen; tuberculosis; vaccine.

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Conflict of interest statement

Declaration of interests S.J.V. and D.H.B. are co-inventors on US Patent application no. 63/610,211 describing the novel TB vaccine antigens. A.J. receives licensing fees (for patents on which she was an inventor) from, invested in, consults (or was on Scientific Advisory Boards or Boards of Directors) for, lectured (and received a fee) at, or conducts sponsored research at MIT (for which she was not paid) for the following entities: The Estée Lauder Companies, Moderna Therapeutics, OmniPulse Biosciences, Particles for Humanity, SiO(2) Materials Science, and VitaKey. For a list of entities with which R.L. is or has been recently involved, compensated or uncompensated, see https://www.dropbox.com/scl/fi/xjq5dbrj8pufx53035zdf/RL-COI-2024.pdf?rlkey=fwv336uoepiaiyg4e7jz5t4zo&dl=0.

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