Elicitation of stem-directed antibodies in rhesus macaques by a conventional hemagglutinin immunogen

Because they can bind many strains of influenza, antibodies targeting the hemagglutinin (HA) stem have been attractive targets for vaccine development. Many monoclonal antibodies (mAbs) directed at the HA stem have been isolated from humans, and these mAbs have mediated broad protection in animal models. We describe here HA stem-directed mAbs isolated from rhesus macaques immunized with an "ordinary" H1 HA trimer. All immunized rhesus macaques developed high serum titers with broad reactivity to diverse H1N1 and H5N1 viruses, and 7 isolated mAbs strongly blocked canonical stem antibody CR6261 binding to H1. MAb DH726.1 robustly protected mice from lethal challenge with H1N1 and H5N1 viruses, and cryo-EM showed the binding footprint overlapped that of some human mAbs. These findings suggest that vaccination with the standard, trimeric HA immunogens may be sufficient to elicit stem antibodies at titers adequate to protect against zoonotic H5N1 influenza. In BriefEfforts to achieve broad influenza protection have largely emphasized increasingly sophisticated immunogen designs to redirect antibody responses toward conserved epitopes. Here, we show that a single, conventional HA immunogen readily elicits antibodies targeting the conserved HA stem, suggesting that routine influenza vaccination may provide broader protection than previously appreciated. HighlightsO_LIMonovalent HA immunization induces strong, stem-directed immune responses in rhesus macaques C_LIO_LIEpitope on the HA stem confirmed by Cryo-EM C_LIO_LIFc-mediated activation of immune effector cell by rhesus-derived stem mAb C_LIO_LIHA stem-directed antibody protects mice against H1N1 and H5N1 viruses C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC="FIGDIR/small/738984v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@508b9org.highwire.dtl.DTLVardef@7fabbeorg.highwire.dtl.DTLVardef@1e47b84org.highwire.dtl.DTLVardef@1693bfb_HPS_FORMAT_FIGEXP M_FIG C_FIG