Identification of Antibodies Targeting the H3N2 Hemagglutinin Receptor Binding Site following Vaccination of Humans

Antibodies targeting the receptor binding site (RBS) of the influenza virus hemagglutinin (HA) protein are usually not broadly reactive because their footprints are typically large and extend to nearby variable HA residues. Here, we identify several human H3N2 HA RBS-targeting monoclonal antibodies (mAbs) that are sensitive to substitutions in conventional antigenic sites and are therefore not broadly reactive. However, we also identify an H3N2 HA RBS-targeting mAb that is exceptionally broadly reactive despite being sensitive to substitutions in residues outside of the RBS. We show that similar antibodies are present at measurable levels in the sera of some individuals but that they are inefficiently elicited by conventional vaccines. Our data indicate that HA RBS-targeting antibodies can be effective against variable viral strains even when they are somewhat sensitive to substitutions in HA residues adjacent to the RBS. [Display omitted] •Many mAbs target the RBS of H3 HA, but most are not broadly reactive•Rare H3 HA RBS mAbs are tolerant of substitutions in adjacent sites•Broadly reactive H3 HA RBS Abs are not efficiently elicited by vaccines Zost et al. show that most antibodies targeting the RBS of the H3N2 HAs are not broadly reactive. They identify one broadly reactive H3 HA RBS antibody that is tolerant of substitutions in adjacent antigenic sites but show that these types of antibodies are not efficiently elicited by vaccination.