Committing the Oldest Sins in the Newest Kind of Ways-Antibodies Targeting the Influenza Virus Type A Hemagglutinin Globular Head.

The globular head of the trimeric influenza hemagglutinin (HA) contains the receptor-binding domain (RBD) and is the target of potently neutralizing human monoclonal antibodies (mAbs) with high in vivo activity. In general, these mAbs are induced easily by vaccination, but only infrequently display cross-neutralizing activity against antigenic drift variants or even against HA molecules from viruses of heterologous subtypes. Recently, the atomic resolution structures of several such antibodies in complex with HA have been determined by X-ray crystallography. Not surprisingly, cross-reactive globular head antibodies target, at least partially, the conserved RBD. The cross-reactive potential of such mAbs is limited by contacts of hypervariable HA residues outside the conserved RBD. The RBD of H2 HA seems especially immunogenic. Increasing the immunogenicity of the RBD of other HA subtypes may be a step toward a universal influenza vaccine. The germ line-encoded Phe54 residue of the CDR-H2 of the VH1-69 germ line sequence appears to be ideally suited not only to reach into a conserved, hydrophobic pocket on the HA stem, but also to reach into the conserved, hydrophobic pocket that is the RBD. We have cloned antibodies from different individuals that are encoded by the VH1-69 germ line gene segment that contact the universally conserved Trp153 on the bottom of the RBD. These antibodies serve as further evidence of antibody genetic sequence convergence across individuals.