A highly conserved neutralizing epitope on group 2 influenza A viruses has been identified and characterized. The study reports the isolation and characterization of a human monoclonal antibody, CR8020, which broadly neutralizes most group 2 influenza viruses, including H3N2 and H7N7. The crystal structure of CR8020 in complex with the 1968 pandemic H3 hemagglutinin (HA) reveals a highly conserved epitope in the HA stalk distinct from the epitope recognized by the V_H1-69 group 1 antibodies. This epitope is accessible on virions and is critical for neutralizing group 2 influenza viruses. CR8020 binds to a conserved region of the HA stem, which is distinct from the epitope recognized by CR6261, a broadly neutralizing antibody against group 1 viruses. The epitope consists of two main components: the outermost strand of a 5-stranded β-sheet near the base of the stalk and the C-terminal portion of the fusion peptide. CR8020 recognizes its epitope in a conventional manner using both heavy and light chains. The epitope is highly conserved across group 2 influenza viruses, while natural variation in surrounding residues is well tolerated. CR8020 neutralizes a wide spectrum of H3N2 influenza strains as well as H7 and H10 viruses. In vivo studies show that CR8020 is effective in protecting mice against lethal challenges with H3N2 and H7N7 viruses. CR8020 also inhibits the fusogenic conformational changes in HA and blocks proteolytic activation. The study highlights the potential of CR8020 as a universal vaccine and broad-spectrum antibody therapy for influenza. The identification of CR8020 and related antibodies may lead to the development of a universal flu vaccine and broad-spectrum antibody therapies. The study also discusses the implications for therapy and vaccines, emphasizing the need for protection against both group 1 and group 2 influenza viruses. The results suggest that CR8020 may neutralize most viruses from H3, H7, and H10 subtypes, and possibly H15. The study provides insights into the mechanism of virus neutralization by CR8020, which blocks fusion by sequestering the fusion peptide and preventing its release at low pH. The findings have significant implications for the development of universal influenza vaccines and therapies.A highly conserved neutralizing epitope on group 2 influenza A viruses has been identified and characterized. The study reports the isolation and characterization of a human monoclonal antibody, CR8020, which broadly neutralizes most group 2 influenza viruses, including H3N2 and H7N7. The crystal structure of CR8020 in complex with the 1968 pandemic H3 hemagglutinin (HA) reveals a highly conserved epitope in the HA stalk distinct from the epitope recognized by the V_H1-69 group 1 antibodies. This epitope is accessible on virions and is critical for neutralizing group 2 influenza viruses. CR8020 binds to a conserved region of the HA stem, which is distinct from the epitope recognized by CR6261, a broadly neutralizing antibody against group 1 viruses. The epitope consists of two main components: the outermost strand of a 5-stranded β-sheet near the base of the stalk and the C-terminal portion of the fusion peptide. CR8020 recognizes its epitope in a conventional manner using both heavy and light chains. The epitope is highly conserved across group 2 influenza viruses, while natural variation in surrounding residues is well tolerated. CR8020 neutralizes a wide spectrum of H3N2 influenza strains as well as H7 and H10 viruses. In vivo studies show that CR8020 is effective in protecting mice against lethal challenges with H3N2 and H7N7 viruses. CR8020 also inhibits the fusogenic conformational changes in HA and blocks proteolytic activation. The study highlights the potential of CR8020 as a universal vaccine and broad-spectrum antibody therapy for influenza. The identification of CR8020 and related antibodies may lead to the development of a universal flu vaccine and broad-spectrum antibody therapies. The study also discusses the implications for therapy and vaccines, emphasizing the need for protection against both group 1 and group 2 influenza viruses. The results suggest that CR8020 may neutralize most viruses from H3, H7, and H10 subtypes, and possibly H15. The study provides insights into the mechanism of virus neutralization by CR8020, which blocks fusion by sequestering the fusion peptide and preventing its release at low pH. The findings have significant implications for the development of universal influenza vaccines and therapies.