The RBS epitope is also immuno-subdominant, likely because the conserved residues of the RBS pocket are buried ( Schmidt et al., 2015 Ekiert et al., 2012). The HA stalk domain is immuno-subdominant relative to the HA head, potentially due to poor immunogenicity and steric hindrance ( Tan et al., 2019 Angeletti et al., 2019 Andrews et al., 2015a). In contrast, exposure to the antigenically distinct 2009 pandemic H1N1 (pH1N1) and novel avian influenza viruses, including H5N1 and H7N9, induced antibodies targeting conserved epitopes found within the HA stalk domain ( Andrews et al., 2015a Li et al., 2012 Henry Dunand et al., 2016 Ellebedy et al., 2014 Wrammert et al., 2011), which are correlated with protection against influenza virus infection in humans ( Ng et al., 2019).īroadly neutralizing antibodies against influenza viruses are rarely induced by seasonal vaccination for unclear reasons. Current seasonal influenza virus vaccines largely stimulate strain-specific antibodies targeting the polymorphic head domain of HA and provide narrow protection against circulating strains ( Andrews et al., 2015a). No universal influenza virus vaccine yet exists, and annual vaccinations against circulating strains are still recommended. The induction of broadly neutralizing antibodies is the goal of a universal vaccine that can protect against >75% of influenza A viruses ( Paules et al., 2017). Together, our data reveal that polyreactivity is a beneficial feature of antibodies targeting conserved epitopes.īroadly neutralizing antibodies targeting influenza viruses largely bind conserved epitopes found within the receptor-binding site (RBS), lateral patch, and stalk domain of the viral surface protein hemagglutinin (HA) ( Dreyfus et al., 2012 Whittle et al., 2011 Ekiert et al., 2012 Ekiert et al., 2009 Raymond et al., 2018). Lastly, we found affinity-matured polyreactive B cells were typically derived from germline polyreactive B cells that were preferentially selected to participate in B cell responses over time. Polyreactivity augmented mAb viral binding strength by increasing antibody flexibility, allowing for adaption to imperfectly conserved epitopes. Polyreactive mAbs were preferentially induced by novel viral exposures due to their broad viral binding breadth. By analyzing more than 500 monoclonal antibodies (mAbs) derived from B cells induced by numerous influenza virus vaccines and infections, we found mAbs targeting conserved neutralizing influenza virus hemagglutinin epitopes were polyreactive. However, little is known about the role of polyreactivity during anti-influenza virus antibody responses. Polyreactivity is the ability of a single antibody to bind to multiple molecularly distinct antigens and is a common feature of antibodies induced upon pathogen exposure.
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