Deciphering the Influence of the Immune Environment on Trained Immunity Induction

Trained immunity is a novel vaccination concept that enhances innate immune responses through epigenetic reprogramming. Targeting trained immunity provides tremendous opportunities for vaccine generation against infections and conditions in which classical, adaptive immunity failed to provide protection (e.g., Tuberculosis, sepsis). For clinical application, the robustness of vaccination strategies in heterogenous populations is crucial. Diverse baseline immune statuses originate from genetics as well as persistent conditions, e.g., chronic infections and allergies. To date, the extent to which the host’s baseline immune status impacts trained immunity generation is unknown. To evaluate vaccine robustness across different immune environments, we have tested trained immunity-inducing vaccination in mouse models of both pro-inflammatory and pro-allergic skewed immune systems. To that end, we administered β-glucan, a potent inducer of trained immunity, to mice of different genetic backgrounds with or without established allergic sensitization and challenged these mice in sepsis experiments. Immune responses were measured by flow cytometry. While trained immunity vaccination conferred host protection independent of the immunological background of the mice, protection was mediated through different pathways. Characterizing the impact of immune environments on trained immunity induction will strengthen clinical translation and enable host-directed adaptation of these next generation vaccines.