Challenge Specific Modulation of Responses to Adjuvant-Induced Innate Immune Memory

Understanding the innate immune memory induced by adjuvants provides an opportunity to improve vaccine efficacy by inducing nonspecific secondary responses alongside the intended adaptive defence against the target antigen. To understand the consequences of adjuvant-induced immune training, we treated mice with commercially available Sigma Adjuvant System (SAS) and performed functional assays of bone marrow-derived innate immune cells, assessed its functional consequences in vivo, determined the resulting haematopoietic stem and progenitor cell (HSPC) phenotypes, and extensively analyzed the HSPC transcriptome. SAS induced temporal shifts in HSPC frequencies, alterations in the circulating blood profile, and lowered proinflammatory output by macrophages. SAS-induced training caused disparate outcomes in models of inflammation and acute infection. Further, SAS enhanced antibody responses after primary immunisation, that were profoundly altered upon a secondary dose. Integrated transcriptional analysis revealed shifts in HSPCs defined by altered transcription factor activity and lineage-specific shifts in metabolic, epigenetic, myeloid, and kinase genes, resulting in enhanced antimicrobial neutrophil responsiveness and revealing regulators of central training. Together, these results contribute to the understanding of the plasticity and limitations of innate immune training.