Recurring and Adaptable Binding Motifs in Broadly Neutralizing Antibodies to Influenza Virus Are Encoded on the D3-9 Segment of the Ig Gene

Discovery and characterization of broadly neutralizing antibodies (bnAbs) to the influenza hemagglutinin (HA) stem have provided insights for the development of a universal flu vaccine. Identification of signature features common to bnAbs from different individuals will be key to guiding immunogen design. S9-3-37 is a bnAb isolated from a healthy H5N1 vaccinee. Here, structural characterization reveals that the D3-9 gene segment of S9-3-37 contributes most of the interaction surface with the highly conserved stem epitope on HA. Comparison with other influenza bnAb crystal structures indicates that the D3-9 segment provides a general mechanism for targeting HA stem. Interestingly, such bnAbs can approach the HA stem with vastly different angles and orientations. Moreover, D3-9 can be translated in different reading frames in different bnAbs yet still target the same HA stem pocket. Thus, the D3-9 gene segment in the human immune repertoire can provide a robust defense against influenza virus.