Abstract

Significance Vaccination is the most effective means of attaining protection against influenza viruses. However, the constantly evolving nature of influenza viruses enables them to escape preexisting immune surveillance, and thus thwarts public health efforts to control influenza annual epidemics and occasional pandemics. One solution is to elicit antibodies directed against highly conserved epitopes, such as those within the stem region of influenza HA, the principal target of virus-neutralizing antibody responses. This study shows that annual influenza vaccines induce antibody responses that are largely directed against the highly variable HA head region. In contrast, heterologous immunization with HA derived from influenza strains that are currently not circulating in humans (e.g. H5N1) can substantially increase HA stem-specific responses.