Modulating the immunodominance hierarchy of immunoglobulin germline-encoded structural motifs targeting the influenza hemagglutinin stem
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<sup>∗</sup>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.
Authors
- Larance Ronsard (ORCID: https://orcid.org/0000-0002-5307-1940)
- Syed M. Moin (ORCID: https://orcid.org/0000-0001-8789-9167)
- Julia Lederhofer (ORCID: https://orcid.org/0000-0001-9096-9701)
- Barney S. Graham (ORCID: https://orcid.org/0000-0001-8112-0853)
- Maya Sangesland (ORCID: https://orcid.org/0000-0001-8316-039X)
- Daniel Lingwood (ORCID: https://orcid.org/0000-0001-5631-9238)
- Daniel Rohrer (ORCID: https://orcid.org/0000-0003-2013-6370)
- Sarah F. Andrews (ORCID: https://orcid.org/0000-0002-2583-1949)
- Adrian Creanga (ORCID: https://orcid.org/0000-0002-3087-8397)
- Tyler Stephens
- Masaru Kanekiyo (ORCID: https://orcid.org/0000-0001-5767-1532)
- Seyhan Boyoglu-Barnum
- Alba Torrents de la Peña (ORCID: https://orcid.org/0000-0001-5598-1780)
- Yaroslav Tsybovsky (ORCID: https://orcid.org/0000-0002-2159-5248)
- Rebecca A. Gillespie (ORCID: https://orcid.org/0000-0001-5741-3699)
- Rebeca de Paiva Fróes Rocha (ORCID: https://orcid.org/0000-0002-5678-4006)
- Ralston M. Barnes
- Sila Ataca
- Nils Lönberg (ORCID: https://orcid.org/0000-0003-2011-6134)
- Andrew B. Ward
Institutions
- Scripps Research Institute (US)
- National Institutes of Health (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- Bristol-Myers Squibb (United States) (US)
- Frederick National Laboratory for Cancer Research (US)
- National Institute of Allergy and Infectious Diseases (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-11-22
- DOI
- https://doi.org/10.1016/j.celrep.2024.114990
- Citations
- 8
- Primary Topic
- Influenza Virus Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 3.09
Funders
- Bill and Melinda Gates Foundation
- Frederick National Laboratory for Cancer Research
- Vaccine Research Center
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases