{"doi":"10.1128/mbio.02122-23","title":"A neutralizing single-domain antibody that targets the trimer interface of the human metapneumovirus fusion protein","abstract":"ABSTRACT Human metapneumovirus (hMPV) is a leading cause of viral lower respiratory tract disease in children and adults. The hMPV fusion protein F is a trimeric class I fusion protein that is initially synthesized as a precursor (F 0 ) and requires proteolytic activation by a host cell protease to generate the metastable, fusion-competent prefusion conformation of F. hMPV F is considered the main target of the neutralizing antibody response against hMPV infection. We isolated single-domain antibodies (sdAbs) directed against hMPV F that potently neutralize hMPV A and B strains. One of these sdAbs, sdHMPV16, specifically bound to cleaved and uncleaved prefusion F. Co-crystal structure analysis revealed that sdHMPV16 binds to a site located at the trimer interface of prefusion F. Moreover, prophylactic treatment with a sdHMPV16-Fc fusion protein reduced viral titers in the lungs of hMPV-infected cotton rats. In summary, sdHMPV16 broadly neutralizes hMPV, can be turned into a candidate biologic that restricts hMPV replication in an in vivo model, and, unexpectedly, binds to an unconventional epitope at the prefusion F trimer interface. IMPORTANCE Human metapneumovirus (hMPV) is an important respiratory pathogen for which no licensed antivirals or vaccines exist. Single-domain antibodies represent promising antiviral biologics that can be easily produced and formatted. We describe the isolation and detailed characterization of two hMPV-neutralizing single-domain antibodies that are directed against the fusion protein F. One of these single-domain antibodies broadly neutralizes hMPV A and B strains, can prevent proteolytic maturation of F, and binds to an epitope in the F trimer interface. This suggests that hMPV pre-F undergoes trimer opening or “breathing” on infectious virions, exposing a vulnerable site for neutralizing antibodies. Finally, we show that this single-domain antibody, fused to a human IgG1 Fc, can protect cotton rats against hMPV replication, an important finding for potential future clinical applications.","journal":"mBio","year":2023,"id":347233,"datarank":0.578669959354109,"base_score":2.5649493574615367,"endowment":2.5649493574615367,"self_citation_contribution":0.38474240361923057,"citation_network_contribution":0.19392755573487844,"self_endowment_contribution":0.38474240361923057,"citer_contribution":0.19392755573487844,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":12,"citers_with_citation_signal":8,"citers_with_endowment":8,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9595,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE234589"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1089136,"name":"Revina C. van Scherpenzeel","orcid":null,"position":1,"is_corresponding":false},{"id":1089137,"name":"Teresa Delgado","orcid":null,"position":2,"is_corresponding":false},{"id":1088720,"name":"María Iglesias‐Caballero","orcid":"0000-0002-3248-4471","position":3,"is_corresponding":false},{"id":1089138,"name":"Blanca García Barreno","orcid":null,"position":4,"is_corresponding":false},{"id":1088721,"name":"S. Pandey","orcid":"0000-0003-0440-6019","position":5,"is_corresponding":false},{"id":649972,"name":"Scott A. Rush","orcid":"0000-0002-9601-5068","position":6,"is_corresponding":false},{"id":1088722,"name":"Joost A. Kolkman","orcid":"0000-0002-9621-3646","position":7,"is_corresponding":false},{"id":395045,"name":"Vicente Más","orcid":"0000-0002-0887-0743","position":8,"is_corresponding":false},{"id":87312,"name":"Jason S. McLellan","orcid":"0000-0003-3991-542X","position":9,"is_corresponding":false},{"id":630599,"name":"Xavier Saelens","orcid":"0000-0002-3861-6965","position":10,"is_corresponding":false},{"id":931968,"name":"Marlies Ballegeer","orcid":"0000-0002-4914-7455","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-19T01:11:57.720122Z","pmid":"38117059","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}