Investigation of granuloma-targeted host-pathogen interactions identify vaccine correlates of immune protection associated with control of M. tuberculosis replication

• Published in: International journal of infectious diseases Vol. 152; p. 107642
• Main Authors: Ackart, David Forrest, Lanni, Dr. Faye, Mitcham, Victoria, Anderson, Dr. G. Brooke, Lyons, Dr. Michael, Henao-Tamayo, Dr. Marcela, Podell, Dr Brendan
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.03.2025; Elsevier
• ISSN: 1201-9712
• DOI: 10.1016/j.ijid.2024.107642

Immune correlates of protection to guide vaccine development for tuberculosis (TB) have remained elusive. While a number of blood transcriptomic signatures have been shown to predict clinical states of TB in human subjects, no correlates exist to indicate immune signatures that control bacterial growth, which would inform improved vaccine design. To identify correlates of protection, RS ratio in situ hybridization, a measure of M. tuberculosis (Mtb) replication rates within individual granulomas of infected tissue, was combined with high-dimensional multiplex immunohistochemistry to quantify granuloma-centric vaccine induced immune responses associated with the control of Mtb replication. Granulomas were isolated as independent regions of interest on histopathology sections using AI-driven image analysis algorithms. Each granuloma was evaluated for Mtb replicative state and immune composition across multiple stages of TB disease in mice vaccinated with BCG, boosted with the ID93/GLA-SE candidate vaccine after BCG vaccination, or left unvaccinated. Mice left unvaccinated have a bimodal distribution of granulomas containing Mtb populations with either low or high replication, indicating variable response across granulomas within a single group of mice. Early in the course of infection, granulomas permitting a high Mtb replication rate have an early accumulation of CD138 plasma cells and low recruitment as well as low proliferation rate of Tbet- and Ki67-expressing Th1 CD4 T cells. Among granulomas exhibiting low Mtb replication rates, vaccine-mediated immunity allows for rapid recruitment and heavy proliferation of activated T cell populations, while limiting B cell involvement. These data suggest that early T cell recruitment and specific polarization states are important correlates of protection that mediate control of Mtb replication at the granuloma level. This study indicates that granuloma-level investigation of host-pathogen interaction may identify immune correlates of protection to target with new or alternative approaches for TB vaccines.