A Site of Vulnerability on the Influenza Virus Hemagglutinin Head Domain Trimer Interface

Here, we describe the discovery of a naturally occurring human antibody (Ab), FluA-20, that recognizes a new site of vulnerability on the hemagglutinin (HA) head domain and reacts with most influenza A viruses. Structural characterization of FluA-20 with H1 and H3 head domains revealed a novel epitope in the HA trimer interface, suggesting previously unrecognized dynamic features of the trimeric HA protein. The critical HA residues recognized by FluA-20 remain conserved across most subtypes of influenza A viruses, which explains the Ab’s extraordinary breadth. The Ab rapidly disrupted the integrity of HA protein trimers, inhibited cell-to-cell spread of virus in culture, and protected mice against challenge with viruses of H1N1, H3N2, H5N1, or H7N9 subtypes when used as prophylaxis or therapy. The FluA-20 Ab has uncovered an exceedingly conserved protective determinant in the influenza HA head domain trimer interface that is an unexpected new target for anti-influenza therapeutics and vaccines. [Display omitted] •FluA-20 isolated from a healthy donor with extensive influenza vaccination history•FluA-20 protects against all major influenza A subtypes that infect humans•FluA-20 recognizes a unique conserved site in the trimer interface of the HA head•FluA-20 binds to the uncleaved form of HA trimer and disrupts trimer integrity Antibodies targeting a novel site in the head domain of hemagglutinin afford broad protection against influenza.