Outflanking Immunodominance to Target Subdominant Broadly Neutralizing Epitopes

ABSTRACT A major obstacle to vaccination to antigenically variable viruses is skewing of antibody responses to immunodominant epitopes. For influenza virus hemagglutinin (HA), the immunodominance of the variable head impairs responses to the highly conserved stem. Here, we show that head immunodominance depends on the physical attachment of head to stem. Stem immunogenicity is enhanced by immunizing with stem only-constructs or by increasing local HA concentration in the draining lymph node. Surprisingly, co-immunization of HA and stem alters stem-antibody class switching. Our findings delineate strategies for overcoming immunodominance with important implications for human vaccination.