Vidal Samuel J, Lasrado Ninaad, Tostanoski Lisa H, Chaudhari Jayeshbhai, Mbiwan Esther R, Neka Ganad D, Strutton Ellis A, Espinosa Perez Alejandro A, Sellers Daniel, Barrett Julia, Lifton Michelle, Wakabayashi Shoko, Eshaghi Behnaz, Borducchi Erica N, Aid Malika, Li Wenjun, Scriba Thomas J, Jaklenec Ana, Langer Robert, Barouch Dan H
Center 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.
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Cell. 2025 Sep 15. doi: 10.1016/j.cell.2025.08.027.
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.
结核病（TB）是全球传染病致死的主要原因，而卡介苗（BCG）仍然是唯一获得临床批准的疫苗。结核病疫苗开发中一个长期存在的挑战是从大量潜在候选抗原中进行系统性抗原选择。我们在小鼠中对人类CD4 T细胞靶点抗原进行了疗效筛选。我们发现保护效力存在显著异质性，并且大多数顶级保护抗原目前尚未进入临床开发阶段。我们观察到系统发育聚类抗原之间存在免疫交叉反应，这反映了共同的CD4表位。我们开发了一种由PPE20（Rv1387）、EsxG（Rv0287）和PE18（Rv1788）组成的三价mRNA疫苗，该疫苗在多个小鼠模型中增强并超过了卡介苗的保护作用。最后，我们在84%接触结核分枝杆菌的人类中观察到了对这些抗原的细胞免疫反应。这些数据推进了我们对结核病疫苗免疫学的理解，并为临床开发定义了一种疫苗概念。
