A potently neutralizing and protective human antibody targeting antigenic site V on RSV and hMPV fusion glycoprotein

Alexandra A Abu-Shmais¹, Luqiang Guo², Ahmed Magdy Khalil³, Sabina E Leonard¹, Rose J Miller⁴, Alexis K Janke⁵, Matthew J Vukovich¹, Lindsay E Bass⁶, Yukthi P Suresh⁵, Scott A Rush², Rachael M Wolters¹, Nurgun Kose⁵, Robert H Carnahan⁷, James E Crowe Jr⁸, Rachel H Bonami⁹, Jarrod J Mousa¹⁰, Jason S McLellan², Ivelin S Georgiev¹¹

Affiliations

¹ Vanderbilt Center for Antibody Therapeutics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
² Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.
³ Department of Zoonotic Diseases, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt; Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA.
⁴ Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA; Center for Vaccines and Immunology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA.
⁵ Vanderbilt Center for Antibody Therapeutics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁶ Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁷ Vanderbilt Center for Antibody Therapeutics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁸ Vanderbilt Center for Antibody Therapeutics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁹ Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
¹⁰ Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA; Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA; Center for Vaccines and Immunology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA.
¹¹ Vanderbilt Center for Antibody Therapeutics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Computer Science, Vanderbilt University, Nashville, TN 37232, USA; Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, USA; Program in Computational Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: ivelin.georgiev@vanderbilt.edu.

PMID: 41547352
DOI: 10.1016/j.xcrm.2025.102564

Free article

A potently neutralizing and protective human antibody targeting antigenic site V on RSV and hMPV fusion glycoprotein

Alexandra A Abu-Shmais et al. Cell Rep Med. 2026.

Free article

. 2026 Jan 16:102564.

doi: 10.1016/j.xcrm.2025.102564. Online ahead of print.

Authors

Affiliations

¹ Vanderbilt Center for Antibody Therapeutics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
² Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.
³ Department of Zoonotic Diseases, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt; Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA.
⁴ Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA; Center for Vaccines and Immunology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA.
⁵ Vanderbilt Center for Antibody Therapeutics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁶ Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁷ Vanderbilt Center for Antibody Therapeutics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁸ Vanderbilt Center for Antibody Therapeutics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁹ Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
¹⁰ Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA; Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA; Center for Vaccines and Immunology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA.
¹¹ Vanderbilt Center for Antibody Therapeutics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Computer Science, Vanderbilt University, Nashville, TN 37232, USA; Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, USA; Program in Computational Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: ivelin.georgiev@vanderbilt.edu.

PMID: 41547352
DOI: 10.1016/j.xcrm.2025.102564

Abstract

Human respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are frequent drivers of morbidity and mortality in susceptible populations. The primary target of neutralizing antibodies is the fusion (F) glycoprotein on the surface of the RSV and hMPV virion. As a result of the structural conservation between RSV and hMPV F, three antigenic regions are known to induce cross-neutralizing responses: sites III, IV, and V. Leveraging LIBRA-seq, we identify five RSV/hMPV cross-reactive human antibodies. One antibody, RM 5-1, potently neutralizes all tested viruses from the major subgroups of RSV and hMPV and provides protection against RSV and hMPV in a mouse challenge model. Structural analysis reveals that RM 5-1 utilizes an uncommon genetic signature to bind an epitope that spans sites Ø, II, and V. These findings highlight the molecular and structural elements influencing RSV and hMPV cross-reactivity as well as the potential of antibody RM 5-1 for translational development.

Keywords: RSV; anti-viral; antibody; hMPV; in-vivo; neutralizing, monoclonal; site II; site V; site Ø.

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Conflict of interest statement

Declaration of interests A.A.A.-S. and I.S.G. are listed as inventors on patents filed describing the antibodies discovered here. I.S.G. is listed as an inventor on patent applications for the LIBRA-seq technology. I.S.G. is a co-founder of AbSeek Bio. I.S.G. has served as a consultant for Sanofi. The Georgiev laboratory at VUMC has received unrelated funding from Merck and Takeda Pharmaceuticals. J.E.C. has served as a consultant for Luna Labs USA, Merck Sharp & Dohme Corporation, and Emergent Biosolutions; is a former member of the Scientific Advisory Boards of Gigagen (Grifols), Meissa Vaccines, and BTG International; is founder of IDBiologics; and receives royalties from UpToDate. The laboratory of J.E.C. received unrelated sponsored research agreements from AstraZeneca, Takeda Vaccines, and IDBiologics during the conduct of the study.

Update of

A potently neutralizing and protective human antibody targeting antigenic site V on RSV and hMPV fusion glycoprotein.
Abu-Shmais AA, Guo L, Khalil AM, Miller RJ, Janke AK, Vukovich MJ, Bass LE, Suresh YP, Rush SA, Wolters RM, Kose N, Carnahan RH, Crowe JE Jr, Bonami RH, Mousa JJ, McLellan JS, Georgiev IS. Abu-Shmais AA, et al. bioRxiv [Preprint]. 2024 Nov 1:2024.10.31.621295. doi: 10.1101/2024.10.31.621295. bioRxiv. 2024. Update in: Cell Rep Med. 2026 Jan 16:102564. doi: 10.1016/j.xcrm.2025.102564. PMID: 39554078 Free PMC article. Updated. Preprint.

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A potently neutralizing and protective human antibody targeting antigenic site V on RSV and hMPV fusion glycoprotein

Affiliations

A potently neutralizing and protective human antibody targeting antigenic site V on RSV and hMPV fusion glycoprotein

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

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Full Text Sources

Research Materials