A prime-pull TB vaccine regimen optimized to induce lung-resident T cells

About This Grant

PROJECT SUMMARY Mycobacterium tuberculosis (Mtb) remains the world’s deadliest infectious killer, and an effective vaccination regimen is urgently needed. However, the standard vaccine approaches that have saved millions of lives from other infectious pathogens have not been successful against tuberculosis (TB). While most vaccine-preventable infections rely on antibody-mediated immunity, protection against TB is multifaceted and incompletely understood, reflecting the complex Mtb life cycle. Recent insights from TB vaccine studies in animals have shown that lung T resident memory cells (TRM), including CD4 and CD8 TRM, are potent and critical mediators of immune protection. Unfortunately, very few TB vaccine candidates currently in pre-clinical or clinical development were developed with the goal of lung TRM induction. Here we propose a TB vaccine development plan that seeks to optimize protection by targeting the induction of this protective T cell population. The project arises from a three- year collaboration between investigators at Akagera Medicines, Inc. and Seattle Children’s Research Institute and has resulted in the identification of two lead mRNA-lipid nanoparticle (mRNA-LNP) vaccine candidates that are currently undergoing head-to-head testing. These lead candidates have multiple innovations that are designed to improve immunogenicity, efficacy, and importantly, safety. The project also features several innovations in vaccine testing in mice that enable the measurement of new metrics of protection, including prevention of detectable infection, and provide a greater opportunity to discern protective differences between vaccine candidates and regimens. As a result, we seek to identify promising vaccines and to make potential improvements that can be re-tested in an iterative manner. We will use a “prime-pull” strategy in which a robust peripheral CD4 and CD8 T cell response will be induced by intramuscular delivery of our lead mRNA-LNP vaccine candidate followed by intrapulmonary administration of the vaccine antigens to boost and “pull” the antigen-specific T cells into the lung. Three different methods for the intrapulmonary “pull” will be tested and dose optimized (Aim 1). Next, we will test the optimized dose for each of the three methods for their performance in our improved mouse models, including in an Mtb post-exposure model (Aim 2). Our primary metric for advancing our lead “prime-pull” strategy will be the capacity to prevent detectable infection, with secondary metrics being reduction of bacterial burdens and prevention of disseminated Mtb infection. The selected vaccine will then be developed for production as a final GMP-produced product and assessed for toxicology (Aim 3). The overall outcome of this product development will be a vaccination regimen that promises to be safe, cost-effective, efficacious in pre-clinical models, and ready to progress to human clinical trials.