Trained immunity induced by repeated vaccination

Each year, tens of millions of vaccine doses are administered to humans, including 30-60 million doses of influenza and COVID-19 vaccines, most as boosters. Yet, it remains unknown whether the innate immune system responds similarly to each dose or undergoes cumulative reprogramming, even when the effects of individual doses are transient. This represents a critical gap, especially in light of trained immunity (TI), a phenomenon in which innate immune cells such as monocytes and NK cells exhibit memory-like responses. Supporting the idea that repeated vaccination cumulatively reprograms innate immunity, we and others have observed that individuals receiving a SARS-CoV-2 mRNA booster 6-8 months after the primary series exhibit marked elevation in circulating inflammatory cytokines such as IL-6 and TNF, hallmarks of TI. We hypothesize that repeated mRNA vaccination induces an epigenetically poised innate immune state, resulting in enhanced inflammatory responses to booster doses, and heterologous immune stimuli. To test this, we established a mouse system that recapitulates TI-like innate immune responses observed in humans following mRNA vaccination. In contrast to mRNA, seasonal influenza vaccine - also administered repeatedly in humans - does not elicit a similar response, highlighting distinct effects of vaccine platforms. In Aim 1, we will define mechanisms underlying the enhanced inflammatory response to mRNA boosters, using IL-6 as a biomarker and single-cell multiomic profiling to identify cellular sources and epigenomic states. In Aim 2, we will evaluate how prior mRNA or seasonal influenza vaccination shapes de novo immune responses to unrelated adjuvanted protein vaccines, building on our preliminary finding that pre-immunization with mRNA enhances CD8 T cell responses to heterologous antigens. Collectively, these studies will define how repeated vaccination reprograms innate immunity and begin to dissect how such innate immune reprogramming alters immunity to future immune challenges, offering insights to improve vaccine design and immune health.