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First exposure to the pandemic H1N1 virus induced broadly neutralizing antibodies targeting hemagglutinin head epitopes

Structural and experimental determination reveals broadly neutralizing antibodies targeting conserved epitopes on the HA head of H1N1 viruses. Broad neutralization of influenza virus Protection against different strains of influenza is mediated by broadly neutralizing antibodies, which target conserved regions of the virus. Here, Guthmiller et al. demonstrated that antibodies produced by B cells responding to the 2009 pandemic H1N1 influenza virus were broadly neutralizing and were specific to one of two conserved regions of the hemagglutinin head, the lateral patch or the receptor binding site. Mice receiving passive transfer of these antibodies were protected from lethal influenza infection. Thus, vaccine strategies targeting the lateral patch and receptor binding site may provide broad protection against multiple strains of influenza. Broadly neutralizing antibodies are critical for protection against both drifted and shifted influenza viruses. Here, we reveal that first exposure to the 2009 pandemic H1N1 influenza virus recalls memory B cells that are specific to the conserved receptor-binding site (RBS) or lateral patch epitopes of the hemagglutinin (HA) head domain. Monoclonal antibodies (mAbs) generated against these epitopes are broadly neutralizing against H1N1 viruses spanning 40 years of viral evolution and provide potent protection in vivo. Lateral patch-targeting antibodies demonstrated near universal binding to H1 viruses, and RBS-binding antibodies commonly cross-reacted with H3N2 viruses and influenza B viruses. Lateral patch-targeting mAbs were restricted to expressing the variable heavy-chain gene VH3-23 with or without the variable kappa-chain gene VK1-33 and often had a Y-x-R motif within the heavy-chain complementarity determining region 3 to make key contacts with HA. Moreover, lateral patch antibodies that used both VH3-23 and VK1-33 maintained neutralizing capability with recent pH1N1 strains that acquired mutations near the lateral patch. RBS-binding mAbs used a diverse repertoire but targeted the RBS epitope similarly and made extensive contacts with the major antigenic site Sb. Together, our data indicate that RBS- and lateral patch-targeting clones are abundant within the human memory B cell pool, and universal vaccine strategies should aim to drive antibodies against both conserved head and stalk epitopes.