Introduction: Monoclonal antibodies (mAbs) are critical tools for elucidating viral evolution, informing vaccine design, and developing antiviral therapeutics. Large-animal models, such as the pig, that closely mirror human immune responses are essential for understanding influenza immunity.

Methods: Pigs were either infected or sequentially immunized with influenza viruses and monoclonal antibodies directed against H3, H5, and H7 influenza virus haemagglutinins were isolated. Antibody specificity, breadth, epitope targeting (head versus stem), neutralizing capacity, and Fc-mediated activity were assessed across influenza subtypes.

Results: Pigs generated both strain-specific and broadly reactive mAbs targeting haemagglutinin head and stem epitopes. An H3-specific mAb (H3-57) selectively recognized the egg-adapted L194P mutation associated with reduced human vaccine effectiveness. H5 and H7 immunization induced neutralizing antibodies, including cross-group stem mAbs reactive with H1, H3, and H5 haemagglutinins. Fc-mediated activity correlated with antibody binding strength rather than epitope location.

Conclusions: These findings demonstrate that pigs mount antibody responses closely resembling those observed in humans, including recognition of conserved stem epitopes and adaptive head mutations. Porcine mAbs represent powerful new tools for dissecting influenza immunity, guiding vaccine design, and enhancing pandemic preparedness using a physiologically relevant large-animal model.