title: A Computationally Designed Hemagglutinin Stem-Binding Protein Provides In Vivo Protection from Influenza Independent of a Host Immune Response.
abstract: Broadly neutralizing antibodies targeting a highly conserved region in the hemagglutinin (HA) stem protect against influenza infection. Here, we investigate the protective efficacy of a protein (HB36.6) computationally designed to bind with high affinity to the same region in the HA stem. We show that intranasal delivery of HB36.6 affords protection in mice lethally challenged with diverse strains of influenza independent of Fc-mediated effector functions or a host antiviral immune response. This designed protein prevents infection when given as a single dose of 6.0 mg/kg up to 48 hours before viral challenge and significantly reduces disease when administered as a daily therapeutic after challenge. A single dose of 10.0 mg/kg HB36.6 administered 1-day post-challenge resulted in substantially better protection than 10 doses of oseltamivir administered twice daily for 5 days. Thus, binding of HB36.6 to the influenza HA stem region alone, independent of a host response, is sufficient to reduce viral infection and replication in vivo. These studies demonstrate the potential of computationally designed binding proteins as a new class of antivirals for influenza.
authors: Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
authors: Merika Treants
authors: MT
authors: Koday
authors: Institute for Protein Design, Department of Biochemistry, University of Washington, Seattle, Washington, United States of America.
authors: Jorgen
authors: J
authors: Nelson
authors: Institute for Protein Design, Department of Biochemistry, University of Washington, Seattle, Washington, United States of America.
authors: Aaron
authors: A
authors: Chevalier
authors: Washington National Primate Research Center, University of Washington, Seattle, Washington, United States of America.
authors: Michael
authors: M
authors: Koday
authors: Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
authors: Hannah
authors: H
authors: Kalinoski
authors: Institute for Protein Design, Department of Biochemistry, University of Washington, Seattle, Washington, United States of America.
authors: Lance
authors: L
authors: Stewart
authors: Institute for Protein Design, Department of Biochemistry, University of Washington, Seattle, Washington, United States of America.
authors: Lauren
authors: L
authors: Carter
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors: Travis
authors: T
authors: Nieusma
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors: Peter S
authors: PS
authors: Lee
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors: Andrew B
authors: AB
authors: Ward
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America.|Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors: Ian A
authors: IA
authors: Wilson
authors: Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, Utah, United States of America.
authors: Ashley
authors: A
authors: Dagley
authors: Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, Utah, United States of America.
authors: Donald F
authors: DF
authors: Smee
authors: Institute for Protein Design, Department of Biochemistry, University of Washington, Seattle, Washington, United States of America.|Howard Hughes Medical Institute, University of Washington, Seattle, Washington, United States of America.
authors: David
authors: D
authors: Baker
authors: Department of Microbiology, University of Washington, Seattle, Washington, United States of America.|Washington National Primate Research Center, University of Washington, Seattle, Washington, United States of America.
authors: Deborah Heydenburg
authors: DH
authors: Fuller
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology*; D002352:Carrier Proteins / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology*; D006801:Humans; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology* / Q000821:virology; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D014779:Virus Replication
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D002352:Carrier Proteins; D016207:Cytokines; D019267:Hemagglutinin Glycoproteins, Influenza Virus