Human Monoclonal Antibody 81.39a Effectively Neutralizes Emerging Influenza A Viruses of Group 1 and 2 Hemagglutinins
| Autor: | Henju Marjuki, Joyce Jones, Larisa V. Gubareva, Man-Wah Tan, Karl J. Erlandson, Elizabeth M. Newton, Vasiliy P. Mishin, Melissa Willis, Todd Davis, Ning Chai, John Tegeris, James Stevens |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male medicine.drug_class 030106 microbiology Immunology Hemagglutinin (influenza) Hemagglutinin Glycoproteins Influenza Virus In Vitro Techniques Monoclonal antibody medicine.disease_cause Antibodies Viral Microbiology Virus Neutralization 03 medical and health sciences Mice Orthomyxoviridae Infections Virology Influenza Human Vaccines and Antiviral Agents medicine Influenza A virus Animals Humans Lung Mice Inbred BALB C biology Ferrets Antibodies Monoclonal Antibodies Neutralizing Antigenic Variation Influenza A virus subtype H5N1 030104 developmental biology Treatment Outcome Viral replication Insect Science biology.protein Female Antibody |
| Zdroj: | Journal of Virology |
| ISSN: | 1098-5514 |
| Popis: | 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 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. |
| Databáze: | OpenAIRE |
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