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

Authors:

• Bangaru, Sandhya
• Lang, Shanshan
• Schotsaert, Michael
• Vanderven, Hillary A.
• Zhu, Xueyong
• Kose, Nurgun
• Bombardi, Robin
• Finn, Jessica A.
• Kent, Stephen J.
• Gilchuk, Pavlo
• Gilchuk, Iuliia
• Turner, Hannah L.
• García-Sastre, Adolfo
• Li, Sheng
• Ward, Andrew B.
• Wilson, Ian A.
• Crowe, James E.

Details:

Cell, Volume 177, Issue 5, 2019-05-16

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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.