Identification of novel classes of broadly neutralizing antibodies against influenza virus hemagglutinin 9248

Abstract Description Influenza viruses show significant antigenic variation, highlighting the need for broadly neutralizing antibodies (bNAbs) targeting conserved regions of the hemagglutinin (HA) protein. Using single-cell RNA sequencing of PBMCs from a healthy donor, we identified B cells binding a wide array of HA subtypes. Following monoclonal antibody screening, we identified two mAbs with broad neutralization capabilities. One antibody, 228B-1358, targets the anchor epitope and exhibits enhanced binding breadth across various HA subtypes compared to existing anchor antibodies. This increased binding breadth is in part due to an N to V mutation within the binding motif “NWP” motif in the KCDR3. Revision to N in 228B-1358 or introduction of V in other anchor targeting antibodies curtails or expands binding breadth. Moreover, we identified 222B-2807, which targets a unique site near the central stalk epitope and recognizes a conserved glycosylation site on HA2 in influenza A viruses. 228B-2807 binds all influenza A virus subtypes and influenza B viruses, neutralizing group 1 influenza A viruses, and demonstrating antibody-dependent cellular toxicity activity against group 1 and group 2 influenza A viruses. These antibodies represent promising candidates for developing universal influenza therapeutics. Funding Sources This work was supported by The Howard Hughes Medical Institute (HHMI) Emerging Pathogens Initiative and Michelson Medical Research Foundation (Award No. 0000000563) Topic Categories Vaccines and Immunotherapy (VAC)