title: Structural basis for antibody cross-neutralization of respiratory syncytial virus and human metapneumovirus.
abstract: Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are two closely related viruses that cause bronchiolitis and pneumonia in infants and the elderly1, with a significant health burden2-6. There are no licensed vaccines or small-molecule antiviral treatments specific to these two viruses at present. A humanized murine monoclonal antibody (palivizumab) is approved to treat high-risk infants for RSV infection7,8, but other treatments, as well as vaccines, for both viruses are still in development. Recent epidemiological modelling suggests that cross-immunity between RSV, HMPV and human parainfluenzaviruses may contribute to their periodic outbreaks9, suggesting that a deeper understanding of host immunity to these viruses may lead to enhanced strategies for their control. Cross-reactive neutralizing antibodies to the RSV and HMPV fusion (F) proteins have been identified10,11. Here, we examine the structural basis for cross-reactive antibody binding to RSV and HMPV F protein by two related, independently isolated antibodies, MPE8 and 25P13. We solved the structure of the MPE8 antibody bound to RSV F protein and identified the 25P13 antibody from an independent blood donor. Our results indicate that both antibodies use germline residues to interact with a conserved surface on F protein that could guide the emergence of cross-reactivity. The induction of similar cross-reactive neutralizing antibodies using structural vaccinology approaches could enhance intrinsic cross-immunity to these paramyxoviruses and approaches to controlling recurring outbreaks.
authors.affiliation: Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Wen
authors.affiliation: Vanderbilt Vaccine Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Jarrod J
authors.initials: JJ
authors.lastname: Mousa
authors.affiliation: Vanderbilt Vaccine Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: John T
authors.identifier: http://orcid.org/0000-0001-5545-6871
authors.initials: JT
authors.lastname: Bates
authors.affiliation: Howard Hughes Medical Institute, Northwestern University, Evanston, Illinois 60208-3500, USA.|Department of Molecular Biosciences, Northwestern University, Evanston, Illinois 60208-3500, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Lamb
authors.affiliation: Vanderbilt Vaccine Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.|Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.|Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Crowe
authors.affiliation: Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Jardetzky
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D000914:Antibodies, Viral / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D003429:Cross Reactions; D018360:Crystallography, X-Ray; D029121:Metapneumovirus / Q000276:immunology*; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D012136:Respiratory Syncytial Viruses / Q000276:immunology*; D014760:Viral Fusion Proteins / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D014760:Viral Fusion Proteins