Structural basis for ultrapotent antibody-mediated neutralization of human metapneumovirus

Author:

Banerjee Avik1,Huang Jiachen12,Rush Scott A.3ORCID,Murray Jackelyn2,Gingerich Aaron D.1,Royer Fredejah1ORCID,Hsieh Ching-Lin3,Tripp Ralph A.2,McLellan Jason S.3,Mousa Jarrod J.124ORCID

Affiliation:

1. Center for Vaccines and Immunology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602

2. Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602

3. Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712

4. Department of Biochemistry and Molecular Biology, Franklin College of Arts and Sciences, University of Georgia, Athens, GA 30602

Abstract

Human metapneumovirus (hMPV) is a leading cause of morbidity and hospitalization among children worldwide, however, no vaccines or therapeutics are currently available for hMPV disease prevention and treatment. The hMPV fusion (F) protein is the sole target of neutralizing antibodies. To map the immunodominant epitopes on the hMPV F protein, we isolated a panel of human monoclonal antibodies (mAbs), and the mAbs were assessed for binding avidity, neutralization potency, and epitope specificity. We found the majority of the mAbs target diverse epitopes on the hMPV F protein, and we discovered multiple mAb binding approaches for antigenic site III. The most potent mAb, MPV467, which had picomolar potency, was examined in prophylactic and therapeutic mouse challenge studies, and MPV467 limited virus replication in mouse lungs when administered 24 h before or 72 h after viral infection. We determined the structure of MPV467 in complex with the hMPV F protein using cryo-electron microscopy to a resolution of 3.3 Å, which revealed a complex novel prefusion-specific epitope overlapping antigenic sites II and V on a single protomer. Overall, our data reveal insights into the immunodominant antigenic epitopes on the hMPV F protein, identify a mAb therapy for hMPV F disease prevention and treatment, and provide the discovery of a prefusion-specific epitope on the hMPV F protein.

Funder

HHS | NIH | NIAID | Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases

HHS | NIH | NIH Office of the Director

Welch Foundation

Georgia Research Alliance

HHS | NIH | National Institute of General Medical Sciences

Cancer Prevention and Research Institute of Texas

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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