title: A broadly neutralizing human monoclonal antibody exhibits in vivo efficacy against both human metapneumovirus and respiratory syncytial virus.
abstract: BACKGROUND
  Human metapneumovirus (HMPV) is a leading cause of acute respiratory tract infection, with significant morbidity and mortality. No licensed vaccines or therapeutic agents exist. Monoclonal antibodies (mAbs) are effective at preventing other infectious diseases and could be used against HMPV in high-risk hosts.
  
  
  METHODS
  In vitro assays were performed to assess the neutralizing activity and affinity kinetics of human mAb 54G10. A new mouse model was developed to assess prophylactic and therapeutic efficacy in vivo. The epitope of 54G10 was identified by generating mAb-resistant mutants (MARMs).
  
  
  RESULTS
  At low concentrations, 54G10 neutralized all 4 subgroups of HMPV in vitro and had subnanomolar affinity for the fusion protein. DBA/2 mice were permissive for all 4 HMPV subgroups, and 54G10 was effective both prophylactically and therapeutically against HMPV in vivo. Sequencing of HMPV MARMs identified the 54G10 epitope, which was similar to an antigenic site on respiratory syncytial virus (RSV). 54G10 also exhibited in vitro neutralizing activity and in vivo protective and therapeutic efficacy against RSV.
  
  
  CONCLUSIONS
  Human mAb 54G10 has broad neutralizing activity against HMPV and could have prophylactic and therapeutic utility clinically. The conserved epitope could represent a structural vaccine target for HMPV and RSV.
authors.affiliation: Department of Pediatrics.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Schuster
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Reagan G
authors.initials: RG
authors.lastname: Cox
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Hastings
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Kelli L
authors.initials: KL
authors.lastname: Boyd
authors.affiliation: Crucell Vaccine Institute, San Diego.
authors.forename: Jay
authors.initials: J
authors.lastname: Wadia
authors.affiliation: Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.affiliation: Crucell Vaccine Institute, London, United Kingdom.
authors.forename: R Anthony
authors.initials: RA
authors.lastname: Williamson
authors.affiliation: Department of Pediatrics Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee.
authors.forename: John V
authors.initials: JV
authors.lastname: Williams
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000302:isolation & purification / Q000627:therapeutic use*; D057134:Antibodies, Neutralizing / Q000302:isolation & purification / Q000627:therapeutic use*; D000914:Antibodies, Viral / Q000302:isolation & purification / Q000627:therapeutic use*; D018890:Chemoprevention / Q000379:methods; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D029121:Metapneumovirus / Q000276:immunology*; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009500:Neutralization Tests; D018184:Paramyxoviridae Infections / Q000517:prevention & control / Q000628:therapy; D018357:Respiratory Syncytial Virus Infections / Q000517:prevention & control / Q000628:therapy; D018113:Respiratory Syncytial Virus, Human / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral
keywords: DBA/2 mouse; human metapneumovirus; monoclonal antibody; paramyxovirus; respiratory syncytial virus