Influence of vaccine delivery route on immune imprinting in influenza vaccination

Influenza vaccines are predominantly administered intramuscularly. Yet, their effectiveness remains variable across seasons, age groups, and exposure histories, due to immune imprinting or original antigenic sin. Immune imprinting arises when early-life exposures to influenza durably bias subsequent immune responses toward epitopes from the priming strains. This limits the recruitment of naïve B cells and the breadth of responses to drifted or shifted viruses. As next-generation universal vaccines increasingly focus on conserved antigens and novel platforms, understanding how the vaccination route interacts with imprinting has become a critical but underexplored question. This review summarizes the mechanistic basis of influenza immune imprinting and how the vaccine delivery route might modulate imprinted responses. Importantly, direct evidence that the vaccination route can reprogram established imprinting by changing epitope hierarchy or recruiting naïve B cell clones in primed hosts is essentially lacking; most available data instead demonstrate route-dependent shifts in antibody compartment, isotype, and anatomical localization. We describe the cellular and molecular features of imprinting, and compare intramuscular vaccination with alternative strategies. We emphasize that each route engages distinct antigen-presenting cell networks, lymphoid structures, and systemic versus mucosal compartments, which are likely to influence clonal selection and epitope hierarchy. Further, we discuss the interplay between delivery route, antigen design, and adjuvants as an integrated design space for potentially modulating influenza immunity and the expression of imprinting. We highlight experimental models to analyze route-dependent imprinting and identify key translational gaps, including limited incorporation of immune history, inadequate use of epitope-resolved and mucosal readouts, and lack of clinical trials focused on investigating imprinting-related endpoints. Finally, we outline future directions, arguing that rational combinations of conserved antigens, adjuvants, and routes offer a tractable path to broaden and rebalance imprinted responses. This has direct implications for universal vaccine development and for age- or history-tailored vaccination strategies.