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

Henju Marjuki; Vasiliy P Mishin; Ning Chai; Man-Wah Tan; Elizabeth M Newton; John Tegeris; Karl Erlandson; Melissa Willis; Joyce Jones; Todd Davis; James Stevens; Larisa V Gubareva

doi:10.1128/JVI.01284-16

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

Journal article

Open access

Peer reviewed

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

Henju Marjuki, Vasiliy P Mishin, Ning Chai, Man-Wah Tan, Elizabeth M Newton, John Tegeris, Karl Erlandson, Melissa Willis, Joyce Jones, Todd Davis, …

Journal of virology, Vol.90(23), pp.10446-10458

12/01/2016

DOI: 10.1128/JVI.01284-16

PMCID: PMC5110155

PMID: 27630240

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Abstract

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 ) 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 -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 -Asp19Asn/Ala. Conversely, H9 viruses harboring HA -Asp19Ala were fully susceptible to neutralization. Therefore, amino acid variance at HA -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 -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. 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.

Animals

Antibodies, Monoclonal - immunology

Antibodies, Monoclonal - therapeutic use

Antibodies, Neutralizing - immunology

Antibodies, Neutralizing - therapeutic use

Antibodies, Viral - immunology

Antibodies, Viral - therapeutic use

Antigenic Variation - genetics

Antigenic Variation - immunology

Female

Ferrets

Hemagglutinin Glycoproteins, Influenza Virus - classification

Hemagglutinin Glycoproteins, Influenza Virus - genetics

Hemagglutinin Glycoproteins, Influenza Virus - immunology

Humans

In Vitro Techniques

Influenza A virus - classification

Influenza A virus - genetics

Influenza A virus - immunology

Influenza, Human - immunology

Influenza, Human - virology

Lung - pathology

Lung - virology

Male

Mice

Mice, Inbred BALB C

Orthomyxoviridae Infections - immunology

Orthomyxoviridae Infections - therapy

Orthomyxoviridae Infections - virology

Treatment Outcome

Details

Title: Subtitle: Human Monoclonal Antibody 81.39a Effectively Neutralizes Emerging Influenza A Viruses of Group 1 and 2 Hemagglutinins
Creators: Henju Marjuki - National Center for Immunization and Respiratory Diseases
Vasiliy P Mishin - National Center for Immunization and Respiratory Diseases
Ning Chai - Genentech
Man-Wah Tan - Genentech
Elizabeth M Newton - Genentech
John Tegeris - Biomedical Advanced Research and Development Authority
Karl Erlandson - Biomedical Advanced Research and Development Authority
Melissa Willis - Biomedical Advanced Research and Development Authority
Joyce Jones - National Center for Immunization and Respiratory Diseases
Todd Davis - National Center for Immunization and Respiratory Diseases
James Stevens - National Center for Immunization and Respiratory Diseases
Larisa V Gubareva - National Center for Immunization and Respiratory Diseases
Resource Type: Journal article
Publication Details: Journal of virology, Vol.90(23), pp.10446-10458
DOI: 10.1128/JVI.01284-16
PMID: 27630240
PMCID: PMC5110155
NLM abbreviation: J Virol
ISSN: 0022-538X
eISSN: 1098-5514
Grant note: name: CDC Influenza Division
Language: English
Date published: 12/01/2016
Academic Unit: Dermatology
Record Identifier: 9984296311002771

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