Impact of influenza immune imprinting on immune responses to subsequent vaccinations in mice

The immune memory imprinted during an individual's initial influenza exposure (influenza imprinting) has long-lasting effects on the host's response to subsequent influenza infections and vaccinations. Here, we investigate how different influenza virus imprinting impacts the immune responses to subunit, inactivated virus, and protein-based nanoparticle vaccines in Balb/c mice. Our results indicated a phylogenetic distance-dependent effect of influenza imprinting on subunit hemagglutinin (HA) or formalin-inactivated (FI) virus vaccine immunizations. Aichi (H3N2, group 2) HA (HA3) or FI-Aichi vaccination in mice imprinted with closely related Phili (H3N2) triggered significant Aichi-specific HAI antibody and balanced HA3-specific Th1/Th2 antibody immune responses, resulting in robust protection against Aichi. In contrast, HA3 vaccination in PR8 (H1N1, group 1) imprinted mice (PR8-2HA3) induced Th2-leaning responses comparable to those observed in mice without prior influenza immune imprinting (PBS-2HA3). However, subsequent heterosubtypic infections and vaccinations eliminated such effects on antibody subtype profiles. Nonetheless, initial virus exposure established a long-lasting capacity to produce HAI antibody responses against the imprinting strains. Moreover, Phili imprinting followed by HA3/NP nanocluster vaccination protected mice from Aichi infections and induced enhanced cross-reactive immunity. Our study highlights the significance of considering an individual's influenza exposure history when designing and evaluating the effectiveness of influenza vaccines.