A Computationally Designed Hemagglutinin Stem-Binding Protein Provides In Vivo Protection from Influenza Independent of a Host Immune Response

• Published in: PLoS pathogens Vol. 12; no. 2; p. e1005409
• Main Authors: Koday, Merika Treants, Nelson, Jorgen, Chevalier, Aaron, Koday, Michael, Kalinoski, Hannah, Stewart, Lance, Carter, Lauren, Nieusma, Travis, Lee, Peter S, Ward, Andrew B, Wilson, Ian A, Dagley, Ashley, Smee, Donald F, Baker, David, Fuller, Deborah Heydenburg
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04.02.2016; Public Library of Science (PLoS)
• Subjects: Animals; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; Binding proteins; Biology and Life Sciences; Blood proteins; Carrier Proteins - chemistry; Carrier Proteins - immunology; Carrier Proteins - metabolism; Cytokines - metabolism; Development and progression; Genetic aspects; Health aspects; Hemagglutinin Glycoproteins, Influenza Virus - immunology; Humans; Immune response; Influenza; Influenza A virus - genetics; Influenza A virus - immunology; Influenza, Human - immunology; Influenza, Human - virology; Medicine and Health Sciences; Mice; Models, Molecular; Mutation; Pandemics; Research and Analysis Methods; Vaccines; Virus Replication; Viruses
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1005409

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.