Co-immunization with hemagglutinin stem immunogens elicits cross-group neutralizing antibodies and broad protection against influenza A viruses

Current influenza vaccines predominantly induce immunity to the hypervariable hemagglutinin (HA) head, requiring frequent vaccine reformulation. Conversely, the immunosubdominant yet conserved HA stem harbors a supersite that is targeted by broadly neutralizing antibodies (bnAbs), representing a prime target for universal vaccines. Here, we showed that the co-immunization of two HA stem immunogens derived from group 1 and 2 influenza A viruses elicits cross-group protective immunity and neutralizing antibody responses in mice, ferrets, and nonhuman primates (NHPs). Immunized mice were protected from multiple group 1 and 2 viruses, and all animal models showed broad serum-neutralizing activity. A bnAb isolated from an immunized NHP broadly neutralized and protected against diverse viruses, including H5N1 and H7N9. Genetic and structural analyses revealed strong homology between macaque and human bnAbs, illustrating common biophysical constraints for acquiring cross-group specificity. Vaccine elicitation of stem-directed cross-group-protective immunity represents a step toward the development of broadly protective influenza vaccines. [Display omitted] •Broad group 2 protective immunity was induced by H10-based group 2 HA stem immunogen•Co-immunization with group 1 and 2 HA stem immunogens elicits cross-protective antibodies•A bnAb isolated from an immunized NHP neutralizes both group 1 and 2 influenza A viruses•A common mode of HA recognition via the DH gene-encoded motif among NHP and human bnAbs Current vaccine-induced influenza immunity targets the hypervariable HA head, requiring frequent vaccine reformulation. Moin et al. show that co-immunization with HA stem immunogens of group 1 and group 2 influenza A viruses broadly elicits cross-protective antibodies in animals and leads to the discovery of a cross-group protective monoclonal antibody in a macaque, offering a blueprint for broadly protective influenza vaccines.