A Site of #Vulnerability on the #Influenza Virus #Hemagglutinin Head Domain Trimer Interface (Cell, abstract)

[Source: Cell, full page: (LINK). Abstract, edited.]

Cell. 2019 May 16;177(5):1136-1152.e18. doi: 10.1016/j.cell.2019.04.011.

A Site of Vulnerability on the Influenza Virus Hemagglutinin Head Domain Trimer Interface.

Bangaru S1, Lang S2, Schotsaert M3, Vanderven HA4, Zhu X2, Kose N5, Bombardi R5, Finn JA1, Kent SJ4, Gilchuk P5, Gilchuk I5, Turner HL2, García-Sastre A6, Li S7, Ward AB2, Wilson IA8, Crowe JE Jr9.

Author information: 1 Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. 2 Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. 3 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. 4 Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia. 5 The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA. 6 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. 7 Department of Medicine and Biomedical Sciences, School of Medicine, University of California, San Diego, CA 92093, USA. 8 Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: wilson@scripps.edu. 9 Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: james.crowe@vanderbilt.edu.

 

Abstract

Here, we describe the discovery of a naturally occurring human antibody (Ab), FluA-20, that recognizes a new site of vulnerability on the hemagglutinin (HA) head domain and reacts with most influenza A viruses. Structural characterization of FluA-20 with H1 and H3 head domains revealed a novel epitope in the HA trimer interface, suggesting previously unrecognized dynamic features of the trimeric HA protein. The critical HA residues recognized by FluA-20 remain conserved across most subtypes of influenza A viruses, which explains the Ab’s extraordinary breadth. The Ab rapidly disrupted the integrity of HA protein trimers, inhibited cell-to-cell spread of virus in culture, and protected mice against challenge with viruses of H1N1, H3N2, H5N1, or H7N9 subtypes when used as prophylaxis or therapy. The FluA-20 Ab has uncovered an exceedingly conserved protective determinant in the influenza HA head domain trimer interface that is an unexpected new target for anti-influenza therapeutics and vaccines.

Copyright © 2019 Elsevier Inc. All rights reserved.

KEYWORDS: B-lymphocytes; antibodies; antibody-dependent cell cytotoxicity; antigen-antibody reactions; hemagglutinin glycoproteins; influenza A virus; influenza virus; monoclonal; viral

PMID: 31100268 DOI: 10.1016/j.cell.2019.04.011

Keywords: Influenza A; H1N1; H3N2; H5N1; H7N9; Monoclonal antibodies; Animal models.

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Unlocking #pandemic #potential: #prevalence and spatial #patterns of key substitutions in #avian #influenza #H5N1 in #Egyptian isolates (BMC Infect Dis., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

BMC Infect Dis. 2018 Jul 6;18(1):314. doi: 10.1186/s12879-018-3222-6.

Unlocking pandemic potential: prevalence and spatial patterns of key substitutions in avian influenza H5N1 in Egyptian isolates.

Young SG1, Kitchen A2, Kayali G3,4, Carrel M5,6.

Author information: 1 Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR, USA. SGYoung@uams.edu. 2 Department of Anthropology, University of Iowa, Iowa City, IA, USA. 3 Department of Epidemiology, Human Genetics, and Environmental Sciences, University of Texas Health Sciences Center, Houston, TX, USA. 4 Department of Scientific Research, Human Link, Hazmieh, Lebanon. 5 Department of Geographical and Sustainability Sciences, University of Iowa, Iowa City, IA, USA. 6 Department of Epidemiology, University of Iowa, Iowa City, IA, USA.

 

Abstract

BACKGROUND:

Avian influenza H5N1 has a high human case fatality rate, but is not yet well-adapted to human hosts. Amino acid substitutions currently circulating in avian populations may enhance viral fitness in, and thus viral adaptation to, human hosts. Substitutions which could increase the risk of a human pandemic (through changes to host specificity, virulence, replication ability, transmissibility, or drug susceptibility) are termed key substitutions (KS). Egypt represents the epicenter of human H5N1 infections, with more confirmed cases than any other country. To date, however, there have not been any spatial analyses of KS in Egypt.

METHODS:

Using 925 viral samples of H5N1 from Egypt, we aligned protein sequences and scanned for KS. We geocoded isolates using dasymetric mapping, then carried out geospatial hot spot analyses to identify spatial clusters of high KS detection rates. KS prevalence and spatial clusters were evaluated for all detected KS, as well as when stratified by phenotypic consequence.

RESULTS:

A total of 39 distinct KS were detected in the wild, including 17 not previously reported in Egypt. KS were detected in 874 samples (94.5%). Detection rates varied by viral protein with most KS observed in the surface hemagglutinin (HA) and neuraminidase (NA) proteins, as well as the interior non-structural 1 (NS1) protein. The most frequently detected KS were associated with increased viral binding to mammalian cells and virulence. Samples with high overall detection rates of KS exhibited statistically significant spatial clustering in two governorates in the northwestern Nile delta, Alexandria and Beheira.

CONCLUSIONS:

KS provide a possible mechanism by which avian influenza H5N1 could evolve into a pandemic candidate. With numerous KS circulating in Egypt, and non-random spatial clustering of KS detection rates, these findings suggest the need for increased surveillance in these areas.

KEYWORDS: Avian influenza; Egypt; Landscape genetics; Poultry

PMID: 29980172 PMCID: PMC6035396 DOI: 10.1186/s12879-018-3222-6 [Indexed for MEDLINE]  Free PMC Article

Keywords: Avian Influenza; H5N1; Pandemic Preparedness; Egypt.

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Continuing #evolution of highly pathogenic #H5N1 viruses in #Bangladeshi live #poultry #markets (Emerg Microbes Infect., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Emerg Microbes Infect. 2019;8(1):650-661. doi: 10.1080/22221751.2019.1605845.

Continuing evolution of highly pathogenic H5N1 viruses in Bangladeshi live poultry markets.

Barman S1, Turner JCM1, Hasan MK2, Akhtar S2, El-Shesheny R1,3, Franks J1, Walker D1, Seiler P1, Friedman K1, Kercher L1, Jeevan T1, McKenzie P1, Webby RJ1, Webster RG1, Feeroz MM2.

Author information: 1a Department of Infectious Diseases , St. Jude Children’s Research Hospital , Memphis , TN , USA. 2 b Department of Zoology , Jahangirnagar University , Dhaka , Bangladesh. 3 c Center of Scientific Excellence for Influenza Viruses , National Research Centre , Giza , Egypt.

 

Abstract

Since November 2008, we have conducted active avian influenza surveillance in Bangladesh. Clades 2.2.2, 2.3.4.2, and 2.3.2.1a of highly pathogenic avian influenza H5N1 viruses have all been identified in Bangladeshi live poultry markets (LPMs), although, since the end of 2014, H5N1 viruses have been exclusively from clade 2.3.2.1a. In June 2015, a new reassortant H5N1 virus (H5N1-R1) from clade 2.3.2.1a was identified, containing haemagglutinin, neuraminidase, and matrix genes of H5N1 viruses circulating in Bangladesh since 2011, plus five other genes of Eurasian-lineage low pathogenic avian influenza A (LPAI) viruses. Here we report the status of circulating avian influenza A viruses in Bangladeshi LPMs from March 2016 to January 2018. Until April 2017, H5N1 viruses exclusively belonged to H5N1-R1 clade 2.3.2.1a. However, in May 2017, we identified another reassortant H5N1 (H5N1-R2), also of clade 2.3.2.1a, wherein the PA gene segment of H5N1-R1 was replaced by that of another Eurasian-lineage LPAI virus related to A/duck/Bangladesh/30828/2016 (H3N8), detected in Bangladeshi LPM in September 2016. Currently, both reassortant H5N1-R1 and H5N1-R2 co-circulate in Bangladeshi LPMs. Furthermore, some LPAI viruses isolated from LPMs during 2016-2017 were closely related to those from ducks in free-range farms and wild birds in Tanguar haor, a wetland region of Bangladesh where ducks have frequent contact with migratory birds. These data support a hypothesis where Tanguar haor-like ecosystems provide a mechanism for movement of LPAI viruses to LPMs where reassortment with poultry viruses occurs adding to the diversity of viruses at this human-animal interface.

KEYWORDS: Bangladesh; H9N2 viruses; avian influenza A virus; domestic ducks; highly pathogenic H5N1 viruses; live poultry market; reassortment; surveillance

PMID: 31014196 DOI: 10.1080/22221751.2019.1605845

Keywords: Avian Influenza; H5N1; Reassortant Strain; Poultry; Live poultry markets; Bangladesh.

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Safety and Immunogenicity of #MF59-Adjuvanted Cell Culture-Derived A/ #H5N1 Subunit #Influenza Virus #Vaccine: Dose-Finding Clinical Trials in Adults and the Elderly (Open Forum Infect Dis., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Open Forum Infect Dis. 2019 Mar 1;6(4):ofz107. doi: 10.1093/ofid/ofz107. eCollection 2019 Apr.

Safety and Immunogenicity of MF59-Adjuvanted Cell Culture-Derived A/H5N1 Subunit Influenza Virus Vaccine: Dose-Finding Clinical Trials in Adults and the Elderly.

Frey SE1, Shakib S2, Chanthavanich P3, Richmond P4, Smith T5, Tantawichien T6, Kittel C7, Jaehnig P7, Mojares Z8, Verma B9, Kanesa-Thasan N9, Hohenboken M10.

Author information: 1 School of Medicine, Saint Louis University, St. Louis, Missouri. 2 CMAX Clinical Research Pty Ltd., Adelaide, SA, Australia. 3 Department of Tropical Pediatrics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. 4 Division of Paediatrics, School of Medicine, University of Western Australia, and Vaccine Trials Group, Telethon Kids Institute, Subiaco, WA, Australia. 5 Mercy Health Research, St. Louis, Missouri. 6 Department of Medicine, Faculty of Medicine, Chulalongkorn University and Queen Saovabha Memorial Institute, Bangkok, Thailand. 7 GlaxoSmithKline Vaccines GmbH, Marburg, Germany. 8 GlaxoSmithKline Pte Ltd., Singapore, Singapore. 9 GlaxoSmithKline Vaccines LLC, Rockville, Maryland. 10 Seqirus Inc., Cambridge, Massachusetts.

 

Abstract

BACKGROUND:

A/H5N1 influenza viruses have high pandemic potential; consequently, vaccines need to be produced rapidly. MF59® adjuvant reduces the antigen required per dose, allowing for dose sparing and more rapid vaccine availability.

METHODS:

Two multicenter, phase II trials were conducted to evaluate the safety and immunogenicity of an MF59-adjuvanted, cell culture-derived, A/H5N1 vaccine (aH5N1c) among 979 adult (18-64 years old) and 1393 elderly (≥65 years old) subjects. Participants were equally randomized to receive 2 full-dose (7.5 μg of hemagglutinin antigen per dose) or 2 half-dose aH5N1c vaccinations 3 weeks apart. Outcomes were based on Center for Biologics Evaluation Research and Review (CBER) and Committee for Medicinal Products for Human Use (CHMP) licensure criteria (titers ≥1:40 and seroconversions on day 43). Solicited reactions and adverse events were assessed (www.clinicaltrials.gov: NCT01776541 and NCT01766921).

RESULTS:

CBER and CHMP criteria were met by both age groups. CBER criteria for hemagglutination titers were met for the full-dose formulation. Solicited reaction frequencies tended to be higher in the full-dose group and were of mild to moderate intensity. No vaccine-related serious adverse events occurred.

CONCLUSIONS:

In adult and elderly participants, the full-dose aH5N1c vaccine formulation was well tolerated and met US and European licensure criteria for pandemic vaccines.

KEYWORDS: H5N1 subunit vaccine; MF59 adjuvant; pandemic influenza; cell culture–derived vaccine; influenza; phase II

PMID: 30968056 PMCID: PMC6446137 DOI: 10.1093/ofid/ofz107

Keywords: Avian Influenza; H5N1; Vaccines.

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Efficacy of #laninamivir octanoate in mice with advanced #inflammation stage caused by #infection of highly #lethal #influenza virus (J Infect Chemother., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

J Infect Chemother. 2019 Mar 29. pii: S1341-321X(19)30067-4. doi: 10.1016/j.jiac.2019.02.023. [Epub ahead of print]

Efficacy of laninamivir octanoate in mice with advanced inflammation stage caused by infection of highly lethal influenza virus.

Tomozawa T1, Hoshino K1, Yamashita M2, Kubo S3.

Author information: 1 Vaccine Research Institute, Kitasato Daiichi Sankyo Vaccine Co. Ltd., 1-16-13, Kitakasai, Edogawa-ku, Tokyo, Japan. 2 Division of Virology, Institute of Medical Science, University of Tokyo, Japan. 3 Vaccine Research Institute, Kitasato Daiichi Sankyo Vaccine Co. Ltd., 1-16-13, Kitakasai, Edogawa-ku, Tokyo, Japan. Electronic address: kubo.shuku.pe@daiichisankyo.co.jp.

 

Abstract

Four neuraminidase (NA) inhibitors and an RNA synthesis inhibitor were recently approved and are currently in clinical use for influenza. Among NA inhibitors, oseltamivir phosphate (OSE, Tamiflu®) and zanamivir are approved worldwide, whereas peramivir and laninamivir octanoate (LAN, Inavir®) are regionally approved for human use. Therefore, OSE has been used to treat infections of highly pathogenic influenza viruses, such as H5N1 and H7N9, which caused epidemic in southeast Asia and Egypt, and China, respectively. Generally, OSE is administered twice daily for 5 days by oral administration, and LAN once by inhalation for completing influenza therapy. In this study, we compared the efficacy of OSE and LAN administered according to the regimens in mice infected with highly lethal influenza viruses. The drugs were administered at the early and late stages of infection, which correspond to mild and severe inflammation in the lungs, respectively. Based on the drugs’ regimens for human, a single administration of LAN at both stages of inflammation showed superior efficacy to repeated administration of OSE. LAN, as in OSE, could also be efficacious in treating severe influenza in humans.

Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

KEYWORDS: Inflamed stage; Influenza virus; Laninamivir; Mouse; Oseltamivir; Treatment

PMID: 30935767 DOI: 10.1016/j.jiac.2019.02.023

Keywords: Influenza A; Avian Influenza; H5N1; H7N9; Antivirals; Laninamivir; Animal models.

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Characterization of three clade 2.3.4.4 #H5 highly pathogenic #avian #influenza viruses isolated from #wildbirds (J Infect., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

J Infect. 2019 Mar 27. pii: S0163-4453(19)30096-9. doi: 10.1016/j.jinf.2019.03.011. [Epub ahead of print]

Characterization of three clade 2.3.4.4 H5 highly pathogenic avian influenza viruses isolated from wild birds.

Qiu Y1, Li Y2, Li J2, Hou G2, Wang S2, Zhuang Q2, Peng C2, Zhao X1, Jiang W3, Zou F4.

Author information: 1 Guangdong Institute of Applied Biological Resources, Guangzhou, China. 2 China Animal Health and Epidemiology Center, Qingdao, China. 3 China Animal Health and Epidemiology Center, Qingdao, China. Electronic address: civcul@163.com. 4 Guangdong Institute of Applied Biological Resources, Guangzhou, China. Electronic address: zoufs@giabr.gd.cn.

 

Abstract

We isolated and characterized three H5 HPAIVs with different NA subtypes (N1, N6 and N8) during avian influenza virus (AIV) surveillance in wild birds during 2015-2016. The P126/H5N1, P560/H5N6 and ST/H5N8 viruses were highly pathogenic to chickens and ducks. Furthermore, P126/H5N1 and P560/H5N6 showed high pathogenicity in mice. Continued circulation of these influenza virus strains clearly poses a significant potential health threat to poultry and human populations.

Copyright © 2019. Published by Elsevier Ltd.

KEYWORDS: Chickens; Ducks; H5; Highly pathogenic; Mice; Pathogenicity

PMID: 30928558 DOI: 10.1016/j.jinf.2019.03.011

Keywords: Avian Influenza; H5N1; H5N6; H5N8; Poultry; Wild Birds; China.

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#Viral #Factors Important for Efficient #Replication of #Influenza A Viruses in Cells of the #CNS (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Viral Factors Important for Efficient Replication of Influenza A Viruses in Cells of the Central Nervous System

Jurre Y. Siegers, Marco W.G. van de Bildt, Zhanmin Lin, Lonneke M. Leijten, Rémon A.M. Lavrijssen, Theo Bestebroer, Monique I.J. Spronken, Chris I. De Zeeuw, Zhenyu Gao,Eefje J.A. Schrauwen, Thijs Kuiken, Debby van Riel

DOI: 10.1128/JVI.02273-18

 

ABSTRACT

Central nervous system (CNS) disease is one of the most common extra-respiratory tract complication of influenza A virus infections. Remarkably, zoonotic H5N1 virus infections are more frequently associated with CNS disease than seasonal or pandemic viruses. Little is known about the interaction between influenza A viruses and cells of the CNS, and therefore it is currently unknown which viral factors are important for efficient replication. Here, we determined the replication kinetics of a seasonal, pandemic, zoonotic, and lab-adapted influenza A virus in human neuron-like (SK-N-SH), astrocyte-like (U87-MG) cells and primary mouse cortex neurons. In general, highly pathogenic avian influenza (HPAI) H5N1 virus replicated most efficiently in all cells which was associated with efficient attachment and infection. Seasonal H3N2 virus and to a lesser extent pandemic H1N1 replicated trypsin-dependent in SK-N-SH but not in U87-MG cells. In the absence of trypsin, only HPAI H5N1 and WSN viruses replicated. Removal of the multi-basic cleavage site (MBCS) from HPAI H5N1 virus attenuated, but did not abrogate replication. Taken together, we showed that the MBCS and to a lesser extent ability to attach and are important determinants for efficient replication of HPAI H5N1 virus in cells of the CNS. This suggests that both an alternative HA cleavage mechanism and preference for α-2,3 linked sialic acids allowing efficient attachment, contribute to the ability of influenza A viruses to replicate efficiently in cells of the CNS. This study further improves our knowledge on potential viral factors important for the neurotropic potential of influenza A viruses.

 

IMPORTANCE

Central nervous system (CNS) disease is one of the most common extra-respiratory tract complications of influenza A virus infections and frequency and severity differ between seasonal, pandemic and zoonotic viruses. However, little is known about the interaction of these viruses with cells of CNS. Differences among seasonal, pandemic and zoonotic viruses in replication efficacy and cleavability in CNS cells partially explain the higher frequency and severity of zoonotic viruses. Identifying important viral factors and detailed knowledge of the interaction between influenza virus and CNS cells are important to prevent and treat this potentially lethal CNS disease.

Copyright © 2019 Siegers et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Influenza A; H3N2; H1N1; H5N1; Avian Influenza; Neuroinvasion.

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