Abstract: Provided herein are methods for generating a non-naturally occurring, broadly reactive, pan-epitopic antigen derived from a pathogen, such as a virus, bacterium, and the like, that is immunogenic and is capable of eliciting a broadly reactive immune response, such as a broadly reactive neutralizing antibody response, against the pathogen following introduction into a subject. Also provided is a non-naturally occurring immunogen generated using the methods, and vaccines and compositions comprising the immunogen. Methods of generating an immune response in a subject by administering the immunogen, vaccine, or composition are provided. In particular, the immunogen comprises the hemagglutinin (HA) or neuraminidase (NA) protein of influenza virus strains.