Human broadly neutralizing influenza B virus antibodies recognizing hemagglutinin computationally optimized broadly reactive antigens.

Introduction: Influenza B viruses (IBVs) are responsible for severe disease and death, similarly to influenza A viruses (IAVs), with a higher number of infections happening in children and the elderly. Despite the inclusion of an IBV component in the seasonal influenza vaccine, rates of vaccine effectiveness (VE) are still variable and low in many previous seasons. Methods: In this work, longitudinal profiling of IBV hemagglutinin (HA)-specific B-cell responses was described following influenza vaccination in 15 vaccinated participants over four consecutive influenza seasons. These individuals belonged to different age groups and monoclonal antibodies (mAbs) showing broad binding and functional antibody profiles were isolated from the plasmablasts of one individual. Results: These individuals possessed different breadths and magnitudes of antibody responses to a panel of IBV historical and more recent vaccine strains. In particular, young adults (age 23-33) showed a higher magnitude and breadth of antibody response compared to middle-aged (age 55-58) and elderly (age 65-77) participants who instead showed a lower albeit detectable antibody response. Interestingly, one of the isolated mAbs, mAb #46, had the broadest response with a broad binding and potent functional activity against historical and recent IBV strains spanning both Victoria and Yamagata lineages and including binding to IBV computationally optimized broadly reactive antigen (COBRA) HAs. Importantly, mAb #46 administration, either therapeutically or prophylactically, fully protected IBV-challenged mice. Structural characterization of the mAb #46-HA complex by cryo-electron microscopy single-particle analysis revealed that mAb #46 targets a conserved epitope within the HA receptor binding site. Discussion: This study highlights the presence of broadly neutralizing antibodies in the human repertoire that may be recalled by vaccination with COBRA HA, although this hypothesis will be confirmed in upcoming clinical trials.