EMD-44112
Hemagglutinin H1 New Caledonia 1999 in complex with monoclonal antibody Fab 43_S0008
EMD-44112
Single-particle3.09 Å
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Map released: 11/12/2024
Last modified: 11/12/2024
Sample Organism:
Influenza A virus,
Mus sp.,
Homo sapiens
Sample: Hemagglutinin H1 New Caledonia 1999 in complex with monoclonal antibody Fab 43_S0008
Fitted models: 9b2m (Avg. Q-score: 0.377)
Deposition Authors: Torrents de la Pena A, de Paiva Froes Rocha R, Ward AB, Ataca S, Kanekiyo M
Sample: Hemagglutinin H1 New Caledonia 1999 in complex with monoclonal antibody Fab 43_S0008
Fitted models: 9b2m (Avg. Q-score: 0.377)
Deposition Authors: Torrents de la Pena A, de Paiva Froes Rocha R, Ward AB, Ataca S, Kanekiyo M
Modulating the immunodominance hierarchy of immunoglobulin germline-encoded structural motifs targeting the influenza hemagglutinin stem.
Ataca S,
Sangesland M,
de Paiva Froes Rocha R,
Torrents de la Pena A,
Ronsard L,
Boyoglu-Barnum S,
Gillespie RA,
Tsybovsky Y,
Stephens T,
Moin SM,
Lederhofer J,
Creanga A,
Andrews SF,
Barnes RM,
Rohrer D,
Lonberg N,
Graham BS,
Ward AB,
Lingwood D,
Kanekiyo M
(2024) Cell Rep , 43 , 114990 - 114990
(2024) Cell Rep , 43 , 114990 - 114990
Abstract:
Antibodies targeting epitopes through germline-encoded motifs can be found in different individuals. While these public antibodies are often beneficial, they also pose hurdles for subdominant antibodies to emerge. Here, we use transgenic mice that reproduce the human IGHV1-69∗01 germline-encoded antibody response to the conserved stem epitope on group 1 hemagglutinin (HA) of influenza A virus to show that this germline-endowed response can be overridden by a subdominant yet cross-group reactive public antibody response. Immunization with a non-cognate group 2 HA stem enriched B cells harboring the IGHD3-9 gene, thereby switching from IGHV1-69- to IGHD3-9-encoded motif-dependent epitope recognition. These IGHD3-9 antibodies bound, neutralized, and conferred cross-group protection in mice against influenza A viruses. A cryoelectron microscopy (cryo-EM) structure of an IGHD3-9 antibody resembled the human broadly neutralizing antibody FI6v3, which uses IGHD3-9. Together, our findings offer insights into vaccine regimens that engage an immunoglobulin repertoire with broader cross-reactivity to influenza A viruses.
Antibodies targeting epitopes through germline-encoded motifs can be found in different individuals. While these public antibodies are often beneficial, they also pose hurdles for subdominant antibodies to emerge. Here, we use transgenic mice that reproduce the human IGHV1-69∗01 germline-encoded antibody response to the conserved stem epitope on group 1 hemagglutinin (HA) of influenza A virus to show that this germline-endowed response can be overridden by a subdominant yet cross-group reactive public antibody response. Immunization with a non-cognate group 2 HA stem enriched B cells harboring the IGHD3-9 gene, thereby switching from IGHV1-69- to IGHD3-9-encoded motif-dependent epitope recognition. These IGHD3-9 antibodies bound, neutralized, and conferred cross-group protection in mice against influenza A viruses. A cryoelectron microscopy (cryo-EM) structure of an IGHD3-9 antibody resembled the human broadly neutralizing antibody FI6v3, which uses IGHD3-9. Together, our findings offer insights into vaccine regimens that engage an immunoglobulin repertoire with broader cross-reactivity to influenza A viruses.