Mining the CD4 antigen repertoire for next-generation tuberculosis vaccines
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.
Authors
- Michelle A. Lifton (ORCID: https://orcid.org/0000-0003-0279-2198)
- Lisa H. Tostanoski (ORCID: https://orcid.org/0000-0001-9255-5684)
- Ninaad Lasrado (ORCID: https://orcid.org/0000-0001-6762-2654)
- Ellis A. Strutton (ORCID: https://orcid.org/0009-0002-1463-1455)
- Erica N. Borducchi
- Malika Aïd (ORCID: https://orcid.org/0000-0002-4498-7893)
- Daniel Sellers (ORCID: https://orcid.org/0000-0002-8815-9459)
- Ganad D. Neka
- Behnaz Eshaghi (ORCID: https://orcid.org/0000-0003-4543-4067)
- Dan H. Barouch (ORCID: https://orcid.org/0000-0001-5127-4659)
- Thomas J. Scriba (ORCID: https://orcid.org/0000-0002-0641-1359)
- Ángel Pérez (ORCID: https://orcid.org/0000-0002-6273-2405)
- Ana Jaklenec (ORCID: https://orcid.org/0000-0001-6096-0538)
- Shoko Wakabayashi
- Julia Barrett (ORCID: https://orcid.org/0000-0002-5857-3632)
- Jayeshbhai Chaudhari (ORCID: https://orcid.org/0000-0002-1864-562X)
- Samuel J. Vidal (ORCID: https://orcid.org/0000-0002-3419-0469)
- Wenjun Li (ORCID: https://orcid.org/0000-0001-5335-7386)
- Robert Langer (ORCID: https://orcid.org/0000-0003-1703-6707)
- Esther R. Mbiwan (ORCID: https://orcid.org/0009-0001-2292-3741)
Institutions
- Beth Israel Deaconess Medical Center (US)
- University of Massachusetts Lowell (US)
- Harvard University (US)
- University of Cape Town (ZA)
- South African Tuberculosis Vaccine Initiative (ZA)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Cell
- Published
- 2025-09-16
- DOI
- https://doi.org/10.1016/j.cell.2025.08.027
- Citations
- 8
- Primary Topic
- Tuberculosis Research and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 11.17
Funders
- Bill and Melinda Gates Foundation
- National Institute of Allergy and Infectious Diseases
- National Center for Advancing Translational Sciences