A Computationally Designed Hemagglutinin Stem-Binding Protein Provides In Vivo Protection from Influenza Independent of a Host Immune Response
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 th...
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Published in | PLoS pathogens Vol. 12; no. 2; p. e1005409 |
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Main Authors | , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Public Library of Science
04.02.2016
Public Library of Science (PLoS) |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conceived and designed the experiments: MTK JN AC DB DHF. Performed the experiments: MTK JN MK HK TN PSL DFS AD. Analyzed the data: MTK JN AC DB DHF. Contributed reagents/materials/analysis tools: LS LC ABW IAW. Wrote the paper: MTK JN IAW DB DHF. I have read the journal's policy and the authors of this manuscript have the following competing interests: We declare an affiliation of Virvio, Inc. and Drs. Baker, Chevalier, Fuller and Treants (co-founders). We also declare that Drs. Baker, Chevalier, Fuller and Treants have pending patents pertinent to this article (61/968,874 and 62/028,139). We confirm that this does not alter our adherence to all PLoS Pathogens policies on sharing data and materials. |
ISSN: | 1553-7374 1553-7366 1553-7374 |
DOI: | 10.1371/journal.ppat.1005409 |