Cross-neutralizing and potent human monoclonal antibodies against historical and emerging H5Nx influenza viruses
Highly pathogenic avian influenza H5Nx viruses are an emerging threat for global health, especially clade 2.3.4.4b H5N1 virus which causes panzootic infections. Here we describe the isolation and characterization of broadly cross-neutralizing monoclonal antibodies (mAbs) against diverse H5Nx viruses from individuals who received a monovalent H5N1 vaccine 15 years ago. By screening over 500 mAbs, we identified 5 mAbs that neutralized the majority of H5 clades including 2.3.4.4b and target three distinct conserved epitopes within the HA globular head. Cryo-electron microscopy structures of these mAbs in complex with HA, deep mutational scanning and neutralization escape studies define the sites of vulnerability of H5 HA. These mAbs mediated stronger prophylactic protection against clade 2.3.4.4b H5N1 infection in mice than the best-in-class mAb targeting the HA stem. Our study identified several highly potent broadly neutralizing H5 mAbs from humans that either alone or in combination provide a pragmatic pandemic preparedness option against the threat of panzootic H5N1 influenza.
Authors
- Jesmine Roberts-Torres
- Tongqing Zhou (ORCID: https://orcid.org/0000-0002-3935-4637)
- Grace Mantus
- Sarah D. Smith (ORCID: https://orcid.org/0009-0006-8891-0691)
- Vanessa Guerra (ORCID: https://orcid.org/0000-0001-9295-6234)
- G. L. Freeman
- Mary M. Rodgers (ORCID: https://orcid.org/0009-0005-1017-7605)
- Eli Boritz (ORCID: https://orcid.org/0000-0003-4633-4594)
- Lesia Dropulic (ORCID: https://orcid.org/0000-0003-1125-5597)
- Matthew J. Vukovich (ORCID: https://orcid.org/0000-0002-7110-9623)
- Tatsiana Bylund (ORCID: https://orcid.org/0000-0002-2065-2773)
- Daniel C. Douek (ORCID: https://orcid.org/0000-0001-5575-8634)
- Timothy S. Johnston (ORCID: https://orcid.org/0000-0001-9246-6155)
- Eun Sung Yang (ORCID: https://orcid.org/0000-0003-3161-1624)
- Sarah F. Andrews (ORCID: https://orcid.org/0000-0002-2583-1949)
- Theodore C. Pierson (ORCID: https://orcid.org/0000-0002-3795-4348)
- Adrian Creanga (ORCID: https://orcid.org/0000-0002-3087-8397)
- Masaru Kanekiyo (ORCID: https://orcid.org/0000-0001-5767-1532)
- Geoffrey D. Shimberg (ORCID: https://orcid.org/0000-0001-7986-0895)
- Ingelise J. Gordon (ORCID: https://orcid.org/0000-0001-6584-1589)
- Yaroslav Tsybovsky (ORCID: https://orcid.org/0000-0002-2159-5248)
- Douglas S. Reed (ORCID: https://orcid.org/0000-0003-0076-9023)
- Bernadeta Dadonaite (ORCID: https://orcid.org/0000-0003-0908-6982)
- Tejaswi Dittakavi (ORCID: https://orcid.org/0000-0002-7259-1386)
- Rebecca A. Gillespie (ORCID: https://orcid.org/0000-0001-5741-3699)
- Amy R. Henry
- Eleanor Walker (ORCID: https://orcid.org/0009-0005-5141-9658)
- Tek Narsingh Malla (ORCID: https://orcid.org/0000-0002-1387-0801)
- Cheng Cheng (ORCID: https://orcid.org/0000-0002-3837-9293)
- Jesse D. Bloom (ORCID: https://orcid.org/0000-0003-1267-3408)
- Alexandra A. Abu-Shmais (ORCID: https://orcid.org/0000-0001-5514-3277)
- Ankita J. Chopde
- Michelle Ravichandran (ORCID: https://orcid.org/0009-0005-9600-0551)
- Elizabeth Bardwil-Lugones (ORCID: https://orcid.org/0000-0003-3249-2815)
Institutions
- Leidos (United States) (US)
- National Institutes of Health (US)
- Howard Hughes Medical Institute (US)
- University of Pittsburgh (US)
- Fred Hutch Cancer Center (US)
- Frederick National Laboratory for Cancer Research (US)
- National Institute of Allergy and Infectious Diseases (US)
Publication Details
- Journal
- Nature Microbiology
- Published
- 2025-10-14
- DOI
- https://doi.org/10.1038/s41564-025-02137-x
- Citations
- 4
- Primary Topic
- Influenza Virus Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 5.42
Funders
- Howard Hughes Medical Institute
- U.S. Department of Health and Human Services
- Frederick National Laboratory for Cancer Research
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases
- Office of AIDS Research