The study introduces a novel approach to vaccine design by reorienting antigens via site-specific insertion of aspartate residues (oligoD) to control antigen orientation and enhance binding to alum. This method is demonstrated to be effective for antigens from Ebola, SARS-CoV-2, and influenza viruses, leading to enhanced neutralizing antibody responses. The researchers then apply this approach to influenza HA, specifically reorienting the H2 HA in an 'upside-down' configuration to increase the exposure and immunogenicity of the HA-stem region. The reoriented H2 HA (reoH2HA) on alum induces stem-directed antibodies that cross-react with both group 1 and group 2 influenza A subtypes. Electron microscopy polyclonal epitope mapping (EMPEM) reveals that reoH2HA elicits cross-reactive antibodies targeting group 2 HA-stems. The results highlight antigen reorientation as a generalizable approach for designing epitope-focused vaccines, offering a potential strategy to develop more broadly protective vaccines against diverse influenza strains.The study introduces a novel approach to vaccine design by reorienting antigens via site-specific insertion of aspartate residues (oligoD) to control antigen orientation and enhance binding to alum. This method is demonstrated to be effective for antigens from Ebola, SARS-CoV-2, and influenza viruses, leading to enhanced neutralizing antibody responses. The researchers then apply this approach to influenza HA, specifically reorienting the H2 HA in an 'upside-down' configuration to increase the exposure and immunogenicity of the HA-stem region. The reoriented H2 HA (reoH2HA) on alum induces stem-directed antibodies that cross-react with both group 1 and group 2 influenza A subtypes. Electron microscopy polyclonal epitope mapping (EMPEM) reveals that reoH2HA elicits cross-reactive antibodies targeting group 2 HA-stems. The results highlight antigen reorientation as a generalizable approach for designing epitope-focused vaccines, offering a potential strategy to develop more broadly protective vaccines against diverse influenza strains.