Polyreactive Broadly Neutralizing B cells Are Selected to Provide Defense against Pandemic Threat Influenza Viruses

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. However, little is known about the role of polyreactivity during anti-influenza virus antibody responses. 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. Polyreactive mAbs were preferentially induced by novel viral exposures due to their broad viral binding breadth. Polyreactivity augmented mAb viral binding strength by increasing antibody flexibility, allowing for adaption to imperfectly conserved epitopes. 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. Together, our data reveal that polyreactivity is a beneficial feature of antibodies targeting conserved epitopes. [Display omitted] •Antibodies targeting conserved hemagglutinin epitopes are polyreactive•Polyreactive antibodies are preferentially induced by novel influenza viruses•Polyreactivity increases antibody flexibility, affinity, and neutralization potency•Polyreactive naive B cells are selected into the memory B cell pool Polyreactivity is a common feature of antibodies, but little is known about the selection, function, and role of polyreactive B cells against pathogens. Guthmiller et al. demonstrate polyreactive B cells are selected against broadly neutralizing epitopes of influenza viruses and are linked to increased viral-binding breadth, affinity, and antibody flexibility.