Differential antigenic imprinting effects between influenza H1N1 hemagglutinin and neuraminidase in a mouse model

Understanding how immune history influences influenza immunity is essential for developing effective vaccines and therapeutic strategies. This study investigates the antigenic imprinting of influenza hemagglutinin (HA) and neuraminidase (NA) using a mouse model with sequential infection by four seasonal H1N1 strains. Our findings reveal that, among pre-2009 H1N1 strains, the extent of infection history correlates with the restriction of antibody responses to antigenically drifted HA, but not NA. This suggests the mouse model failed to recapitulate NA imprinting in humans, likely due to the difference in NA immunodominance hierarchy between humans and mice. Nevertheless, pre-existing antibodies induced by infection with pre-2009 influenza virus impeded both functional HA and NA antibody responses against a 2009 pandemic H1N1 strain. Overall, this study provides insights into antigenic imprinting for influenza virus, as well as the limitations of using mouse models for studying antigenic imprinting. ImportanceInfluenza viruses continue to pose a significant threat to human health, with vaccine effectiveness being a persistent concern. One important factor is the individual immune history can influence subsequent antibody responses. While many studies have focused on how pre-existing antibodies influence the induction of anti-HA antibodies after influenza virus infections or vaccinations, the impact on anti-NA antibodies has been less extensively investigated. In this study, using a mouse model, we highlighted within the pre-2009 H1N1 strains, a greater extent of immune history negatively affected anti-HA antibodies but positively influenced anti-NA antibody responses. However, for the 2009 pandemic H1N1 strain, which underwent with antigenic shift, both anti-HA and anti-NA antibody responses have been impeded by the antibodies induced by pre-2009 H1N1 virus infection. These findings have important implications for enhancing our understanding of antigenic imprinting on anti-HA and anti-NA antibody response and for developing more effective vaccination strategies.