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Human Monoclonal Antibody 81.39a Effectively Neutralizes Emerging Influenza A Viruses of Group 1 and 2 Hemagglutinins

The pandemic threat posed by emerging zoonotic influenza A viruses necessitates development of antiviral agents effective against various antigenic subtypes. Human monoclonal antibody (hMAb) targeting the hemagglutinin (HA) stalk offers a promising approach to control influenza virus infections. Her...

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Autores principales: Marjuki, Henju, Mishin, Vasiliy P., Chai, Ning, Tan, Man-Wah, Newton, Elizabeth M., Tegeris, John, Erlandson, Karl, Willis, Melissa, Jones, Joyce, Davis, Todd, Stevens, James, Gubareva, Larisa V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110155/
https://www.ncbi.nlm.nih.gov/pubmed/27630240
http://dx.doi.org/10.1128/JVI.01284-16
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author Marjuki, Henju
Mishin, Vasiliy P.
Chai, Ning
Tan, Man-Wah
Newton, Elizabeth M.
Tegeris, John
Erlandson, Karl
Willis, Melissa
Jones, Joyce
Davis, Todd
Stevens, James
Gubareva, Larisa V.
author_facet Marjuki, Henju
Mishin, Vasiliy P.
Chai, Ning
Tan, Man-Wah
Newton, Elizabeth M.
Tegeris, John
Erlandson, Karl
Willis, Melissa
Jones, Joyce
Davis, Todd
Stevens, James
Gubareva, Larisa V.
author_sort Marjuki, Henju
collection PubMed
description The pandemic threat posed by emerging zoonotic influenza A viruses necessitates development of antiviral agents effective against various antigenic subtypes. Human monoclonal antibody (hMAb) targeting the hemagglutinin (HA) stalk offers a promising approach to control influenza virus infections. Here, we investigated the ability of the hMAb 81.39a to inhibit in vitro replication of human and zoonotic viruses, representing 16 HA subtypes. The majority of viruses were effectively neutralized by 81.39a at a 50% effective concentration (EC(50)) of <0.01 to 4.9 μg/ml. Among group 2 HA viruses tested, a single A(H7N9) virus was not neutralized at 50 μg/ml; it contained HA(2)-Asp19Gly, an amino acid position previously associated with resistance to neutralization by the group 2 HA-neutralizing MAb CR8020. Notably, among group 1 HA viruses, H11-H13 and H16 subtypes were not neutralized at 50 μg/ml; they shared the substitution HA(2)-Asp19Asn/Ala. Conversely, H9 viruses harboring HA(2)-Asp19Ala were fully susceptible to neutralization. Therefore, amino acid variance at HA(2)-Asp19 has subtype-specific adverse effects on in vitro neutralization. Mice given a single injection (15 or 45 mg/kg of body weight) at 24 or 48 h after infection with recently emerged A(H5N2), A(H5N8), A(H6N1), or A(H7N9) viruses were protected from mortality and showed drastically reduced lung viral titers. Furthermore, 81.39a protected mice infected with A(H7N9) harboring HA(2)-Asp19Gly, although the antiviral effect was lessened. A(H1N1)pdm09-infected ferrets receiving a single dose (25 mg/kg) had reduced viral titers and showed less lung tissue injury, despite 24- to 72-h-delayed treatment. Taken together, this study provides experimental evidence for the therapeutic potential of 81.39a against diverse influenza A viruses. IMPORTANCE Zoonotic influenza viruses, such as A(H5N1) and A(H7N9) subtypes, have caused severe disease and deaths in humans, raising public health concerns. Development of novel anti-influenza therapeutics with a broad spectrum of activity against various subtypes is necessary to mitigate disease severity. Here, we demonstrate that the hemagglutinin (HA) stalk-targeting human monoclonal antibody 81.39a effectively neutralized the majority of influenza A viruses tested, representing 16 HA subtypes. Furthermore, delayed treatment with 81.39a significantly suppressed virus replication in the lungs, prevented dramatic body weight loss, and increased survival rates of mice infected with A(H5Nx), A(H6N1), or A(H7N9) viruses. When tested in ferrets, delayed 81.39a treatment reduced viral titers, particularly in the lower respiratory tract, and substantially alleviated disease symptoms associated with severe A(H1N1)pdm09 influenza. Collectively, our data demonstrated the effectiveness of 81.39a against both seasonal and emerging influenza A viruses.
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spelling pubmed-51101552016-11-30 Human Monoclonal Antibody 81.39a Effectively Neutralizes Emerging Influenza A Viruses of Group 1 and 2 Hemagglutinins Marjuki, Henju Mishin, Vasiliy P. Chai, Ning Tan, Man-Wah Newton, Elizabeth M. Tegeris, John Erlandson, Karl Willis, Melissa Jones, Joyce Davis, Todd Stevens, James Gubareva, Larisa V. J Virol Vaccines and Antiviral Agents The pandemic threat posed by emerging zoonotic influenza A viruses necessitates development of antiviral agents effective against various antigenic subtypes. Human monoclonal antibody (hMAb) targeting the hemagglutinin (HA) stalk offers a promising approach to control influenza virus infections. Here, we investigated the ability of the hMAb 81.39a to inhibit in vitro replication of human and zoonotic viruses, representing 16 HA subtypes. The majority of viruses were effectively neutralized by 81.39a at a 50% effective concentration (EC(50)) of <0.01 to 4.9 μg/ml. Among group 2 HA viruses tested, a single A(H7N9) virus was not neutralized at 50 μg/ml; it contained HA(2)-Asp19Gly, an amino acid position previously associated with resistance to neutralization by the group 2 HA-neutralizing MAb CR8020. Notably, among group 1 HA viruses, H11-H13 and H16 subtypes were not neutralized at 50 μg/ml; they shared the substitution HA(2)-Asp19Asn/Ala. Conversely, H9 viruses harboring HA(2)-Asp19Ala were fully susceptible to neutralization. Therefore, amino acid variance at HA(2)-Asp19 has subtype-specific adverse effects on in vitro neutralization. Mice given a single injection (15 or 45 mg/kg of body weight) at 24 or 48 h after infection with recently emerged A(H5N2), A(H5N8), A(H6N1), or A(H7N9) viruses were protected from mortality and showed drastically reduced lung viral titers. Furthermore, 81.39a protected mice infected with A(H7N9) harboring HA(2)-Asp19Gly, although the antiviral effect was lessened. A(H1N1)pdm09-infected ferrets receiving a single dose (25 mg/kg) had reduced viral titers and showed less lung tissue injury, despite 24- to 72-h-delayed treatment. Taken together, this study provides experimental evidence for the therapeutic potential of 81.39a against diverse influenza A viruses. IMPORTANCE Zoonotic influenza viruses, such as A(H5N1) and A(H7N9) subtypes, have caused severe disease and deaths in humans, raising public health concerns. Development of novel anti-influenza therapeutics with a broad spectrum of activity against various subtypes is necessary to mitigate disease severity. Here, we demonstrate that the hemagglutinin (HA) stalk-targeting human monoclonal antibody 81.39a effectively neutralized the majority of influenza A viruses tested, representing 16 HA subtypes. Furthermore, delayed treatment with 81.39a significantly suppressed virus replication in the lungs, prevented dramatic body weight loss, and increased survival rates of mice infected with A(H5Nx), A(H6N1), or A(H7N9) viruses. When tested in ferrets, delayed 81.39a treatment reduced viral titers, particularly in the lower respiratory tract, and substantially alleviated disease symptoms associated with severe A(H1N1)pdm09 influenza. Collectively, our data demonstrated the effectiveness of 81.39a against both seasonal and emerging influenza A viruses. American Society for Microbiology 2016-11-14 /pmc/articles/PMC5110155/ /pubmed/27630240 http://dx.doi.org/10.1128/JVI.01284-16 Text en Copyright © 2016 Marjuki et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Vaccines and Antiviral Agents
Marjuki, Henju
Mishin, Vasiliy P.
Chai, Ning
Tan, Man-Wah
Newton, Elizabeth M.
Tegeris, John
Erlandson, Karl
Willis, Melissa
Jones, Joyce
Davis, Todd
Stevens, James
Gubareva, Larisa V.
Human Monoclonal Antibody 81.39a Effectively Neutralizes Emerging Influenza A Viruses of Group 1 and 2 Hemagglutinins
title Human Monoclonal Antibody 81.39a Effectively Neutralizes Emerging Influenza A Viruses of Group 1 and 2 Hemagglutinins
title_full Human Monoclonal Antibody 81.39a Effectively Neutralizes Emerging Influenza A Viruses of Group 1 and 2 Hemagglutinins
title_fullStr Human Monoclonal Antibody 81.39a Effectively Neutralizes Emerging Influenza A Viruses of Group 1 and 2 Hemagglutinins
title_full_unstemmed Human Monoclonal Antibody 81.39a Effectively Neutralizes Emerging Influenza A Viruses of Group 1 and 2 Hemagglutinins
title_short Human Monoclonal Antibody 81.39a Effectively Neutralizes Emerging Influenza A Viruses of Group 1 and 2 Hemagglutinins
title_sort human monoclonal antibody 81.39a effectively neutralizes emerging influenza a viruses of group 1 and 2 hemagglutinins
topic Vaccines and Antiviral Agents
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110155/
https://www.ncbi.nlm.nih.gov/pubmed/27630240
http://dx.doi.org/10.1128/JVI.01284-16
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