#Outcomes and #Adverse Effects With #Peramivir for the #Treatment of #Influenza #H1N1 in Critically Ill #Pediatric Patients (J Pediatr Pharmacol Ther., abstract)

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

J Pediatr Pharmacol Ther. 2019 Nov-Dec;24(6):497-503. doi: 10.5863/1551-6776-24.6.497.

Outcomes and Adverse Effects With Peramivir for the Treatment of Influenza H1N1 in Critically Ill Pediatric Patients.

Witcher R, Tracy J, Santos L, Chopra A.

 

Abstract

OBJECTIVES:

Influenza is an environmental pathogen and infection presents as a range from asymptomatic to fulminant illness. Though treatment is supportive, antiviral agents have a role in the management of infection. Pediatric use of peramivir is largely based on reports and extrapolations of pharmacokinetic data. We seek to describe efficacy and safety of peramivir in critically ill pediatric patients.

METHODS:

This is a retrospective, institutional review board-approved chart review of all patients under 21 years of age, admitted to the PICU, and treated with peramivir for influenza H1N1 infection between January 1, 2016, and March 31, 2016, at a single-center, 12-bed PICU. The primary outcome was time to sustained resolution of fever; secondary outcomes included dose, duration, and adverse effects of peramivir therapy.

RESULTS:

Seven patients were included with median age of 3.7 years. Median time to sustained resolution of fever was 49.3 hours, median duration of mechanical ventilation was 14.2 days, median ICU LOS was 18.7 days, and hospital LOS was 24.7 days. No patients suffered mortality. Three patients experienced leukopenia, one of which experienced a concurrent neutropenia. Three patients experienced hyperglycemia, 2 experienced hypertension, 1 experienced increased aspartate aminotransferase and increased alanine aminotransferase, and 1 experienced diarrhea. All adverse events assessed were classified as possible using published adverse event causality assessments.

CONCLUSIONS:

Peramivir has been shown to be an effective therapy for the treatment of influenza H1N1 in critically ill pediatric patients. In our experience with 7 pediatric patients, peramivir was well tolerated at typical durations of therapy; however, increased vigilance is warranted during prolonged courses or in patients with reasons for altered pharmacokinetics and pharmacodynamics.

Copyright Published by the Pediatric Pharmacy Association. All rights reserved. For permissions, email: mhelms@pediatricpharmacy.org 2019.

KEYWORDS: adverse drug events; critical care; influenza; pediatric; safety

PMID: 31719811 PMCID: PMC6836703 DOI: 10.5863/1551-6776-24.6.497

Keywords: Seasonal Influenza; H1N1; Antivirals; Drugs safety; Peramivir; Pediatrics.

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#HA #stability regulates #H1N1 #influenza virus #replication and #pathogenicity in mice by modulating type I #interferon responses in dendritic cells (J Virol., abstract)

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

HA stability regulates H1N1 influenza virus replication and pathogenicity in mice by modulating type I interferon responses in dendritic cells

Marion Russier, Guohua Yang, Benoit Briard, Victoria Meliopoulos, Sean Cherry, Thirumala-Devi Kanneganti, Stacey Schultz-Cherry, Peter Vogel, Charles J. Russell

DOI: 10.1128/JVI.01423-19

 

ABSTRACT

Hemagglutinin (HA) stability, or the pH at which HA is activated to cause membrane fusion, has been associated with the replication, pathogenicity, transmissibility, and interspecies adaptation of influenza A viruses. Here, we investigated mechanisms by which a destabilizing HA mutation, Y17H (activation pH 6.0), attenuates virus replication and pathogenicity in DBA/2 mice, compared to wild-type (WT; activation pH 5.5). Extracellular lung pH was measured to be near neutral (pH 6.9–7.5). WT and Y17H viruses had similar environmental stability at pH 7.0; thus, extracellular inactivation was unlikely to attenuate Y17H virus. The Y17H virus had accelerated replication kinetics in MDCK, A549, and Raw264.7 cells when inoculated at an MOI of 3 PFU/cell. The destabilizing mutation also increased early infectivity and type I interferon (IFN) responses in mouse bone marrow–derived dendritic cells (DCs). In contrast, the HA-Y17H mutation reduced replication in murine airway mNEC and mTEC cultures and attenuated virus replication, virus spread, severity of infection, and cellular infiltration in the lungs of mice. Normalizing virus infection and weight loss in mice by inoculating them with Y17H virus at a dose 500-fold higher than that of WT virus revealed that the destabilized mutant virus triggered the upregulation of more host genes and increased type I IFN responses and cytokine expression in DBA/2 mouse lungs. Overall, HA destabilization decreased virulence in mice by boosting early infection in DCs, resulting in greater activation of antiviral responses, including type I IFN. These studies reveal HA stability may regulate pathogenicity by modulating IFN responses.

 

Importance

Diverse influenza A viruses circulate in wild aquatic birds, occasionally infecting farm animals. Rarely, an avian- or swine-origin influenza virus adapts to humans and starts a pandemic. Seasonal and many universal influenza vaccines target the HA surface protein, which is a key component of pandemic influenza. Understanding HA properties needed for replication and pathogenicity in mammals may guide response efforts to control influenza. Some antiviral drugs and broadly reactive influenza vaccines that target the HA protein have suffered resistance due to destabilizing HA mutations that do not compromise replicative fitness in cell culture. Here, we show that despite not compromising fitness in standard cell cultures, a destabilizing H1N1 HA stalk mutation greatly diminishes viral replication and pathogenicity in vivo by modulating type I IFN responses. This encourages targeting the HA stalk with antiviral drugs and vaccines as well as reevaluating previous candidates that were susceptible to destabilizing resistance mutations.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Influenza A; H1N1; Viral pathogenesis; Interferons.

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#Oseltamivir Is Effective against 1918 #Influenza Virus Infection of #Macaques but Vulnerable to Escape (mBio, abstract)

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

Oseltamivir Is Effective against 1918 Influenza Virus Infection of Macaques but Vulnerable to Escape

Friederike Feldmann, Darwyn Kobasa, Carissa Embury-Hyatt, Allen Grolla, Tracy Taylor, Maki Kiso, Satoshi Kakugawa, Jason Gren, Steven M. Jones, Yoshihiro Kawaoka, Heinz Feldmann

Diane E. Griffin, Editor

DOI: 10.1128/mBio.02059-19

 

ABSTRACT

The 1918 influenza virus, subtype H1N1, was the causative agent of the most devastating pandemic in the history of infectious diseases. In vitro studies have confirmed that extreme virulence is an inherent property of this virus. Here, we utilized the macaque model for evaluating the efficacy of oseltamivir phosphate against the fully reconstructed 1918 influenza virus in a highly susceptible and relevant disease model. Our findings demonstrate that oseltamivir phosphate is effective in preventing severe disease in macaques but vulnerable to virus escape through emergence of resistant mutants, especially if given in a treatment regimen. Nevertheless, we conclude that oseltamivir would be highly beneficial to reduce the morbidity and mortality rates caused by a highly pathogenic influenza virus although it would be predicted that resistance would likely emerge with sustained use of the drug.

 

IMPORTANCE

Oseltamivir phosphate is used as a first line of defense in the event of an influenza pandemic prior to vaccine administration. Treatment failure through selection and replication of drug-resistant viruses is a known complication in the field and was also demonstrated in our study with spread of resistant 1918 influenza virus in multiple respiratory tissues. This emphasizes the importance of early treatment and the possibility that noncompliance may exacerbate treatment effectiveness. It also demonstrates the importance of implementing combination therapy and vaccination strategies as soon as possible in a pandemic situation.

Keywords: Antivirals; Drugs Resistance; Oseltamivir; Animal models; H1N1; Pandemic Influenza; Spanish flu.

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MDCK-B4GalNT2 cells disclose a α2,3-sialic acid requirement for the 2009 #pandemic #H1N1 A/California/04/2009 and NA aid entry of A/WSN/33 (Emerg Microbes Infect., abstract)

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

Emerg Microbes Infect. 2019;8(1):1428-1437. doi: 10.1080/22221751.2019.1665971.

MDCK-B4GalNT2 cells disclose a α2,3-sialic acid requirement for the 2009 pandemic H1N1 A/California/04/2009 and NA aid entry of A/WSN/33.

Wong HH1,2, Fung K1, Nicholls JM1.

Author information: 1 Department of Pathology, University of Hong Kong , Hong Kong. 2 HKU-Pasteur Research Pole, University of Hong Kong , Hong Kong.

 

Abstract

Switching of receptor binding preference has been widely considered as one of the necessary mutations for avian influenza viruses, enabling efficient transmissions between human hosts. By stably overexpressing B4GalNT2 gene in MDCK cells, surface α2,3-siallylactose receptors were modified without affecting α2,6-receptor expression. The cell line MDCK-B4GalNT2 was used as a tool to screen for α2,3-receptor requirements in a panel of influenza viruses with previously characterized glycan array data. Infection of viruses with α2,3-receptor binding capability was inhibited in MDCK-B4GalNT2 cells, with the exception of A/WSN/33 (WSN). Infection with the 2009 pandemic H1N1 strains, A/California/04/2009 (Cal04) and A/Hong Kong/415742/2009 (HK09), despite showing α2,6-receptor binding, was also found to be inhibited. Further investigation showed that viral inhibition was due to a reduction in viral entry rate and viral attachment. Recombinant WSN virus with the neuraminidase (NA) gene swapped to A/Puerto Rico/8/1934 (PR8) and Cal04 resulted in a significant viral inhibition in MDCK-B4GalNT2 cells. With oseltamivir, the NA active site was found to be important for the replication results of WSN, but not Cal04.

KEYWORDS: B4GalNT2; Influenza; MDCK; Madin-Darby Canine Kidney cell; Sda; receptor; sialic acid; β-1,4-N-Acetyl-Galactosaminyltransferase 2

PMID: 31560252 DOI: 10.1080/22221751.2019.1665971

Keywords: Pandemic Influenza; Seasonal Influenza; H1N1; H1N1pdm09; Viral pathogenesis.

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A novel #reassortant #influenza A (#H1N1) virus #infection in #swine in #Shandong Province, eastern #China (Transbound Emerg Dis., abstract)

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

Transbound Emerg Dis. 2019 Sep 19. doi: 10.1111/tbed.13360. [Epub ahead of print]

A novel reassortant influenza A (H1N1) virus infection in swine in Shandong Province, eastern China.

Yu Z1,2,3, Cheng K4, He H5, Wu J1,2,3.

Author information: 1 Poultry Institute, Shandong Academy of Agricultural Sciences, Jinan, 250023, China. 2 Shandong Provincial Key Laboratory of Poultry Diseases Diagnosis and Immunology. 3 Poultry Breeding Engineering Technology Center of Shandong Province. 4 Dairy Cattle Research Center, Shandong Academy of Agricultural Sciences, Jinan, 250132, China. 5 College of Life Sciences, Shandong Normal University, Jinan, 250014, China.

 

Abstract

Influenza A (H1N1) viruses are distributed worldwide and pose a threat to public health. Swine, as a natural host and mixing vessel of influenza A (H1N1) virus, play a critical role in the transmission of this virus to humans. Furthermore, swine influenza A (H1N1) viruses have provided all eight genes or some genes to the genomes of influenza strains that historically have caused human pandemics. Hence, persistent surveillance of influenza A (H1N1) virus in swine herds could contribute to the prevention and control of this virus. Here, we report a novel reassortant influenza A (H1N1) virus generated by reassortment between 2009 pandemic H1N1 viruses and swine viruses. We also found that this virus is prevalent in swine herds in Shandong Province, eastern China. Our findings suggest that surveillance of the emergence of the novel reassortant influenza A (H1N1) virus in swine is imperative.

© 2019 Blackwell Verlag GmbH.

KEYWORDS: H1N1; human; influenza; reassortant; swine

PMID: 31535780 DOI: 10.1111/tbed.13360

Keywords: Seasonal Influenza; Swine Influenza; H1N1; H1N1pdm09; Pigs; Reassortant strain; Shandong; China.

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#Mucosal #CD8+ T cell responses induced by an MCMV based #vaccine #vector confer protection against #influenza challenge (PLoS Pathog., abstract)

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

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Mucosal CD8+ T cell responses induced by an MCMV based vaccine vector confer protection against influenza challenge

Xiaoyan Zheng, Jennifer D. Oduro, Julia D. Boehme, Lisa Borkner, Thomas Ebensen, Ulrike Heise, Marcus Gereke, Marina C. Pils, Astrid Krmpotic, Carlos A. Guzmán, Dunja Bruder, Luka Čičin-Šain

Published: September 16, 2019 / DOI: https://doi.org/10.1371/journal.ppat.1008036 / This is an uncorrected proof.

 

Abstract

Cytomegalovirus (CMV) is a ubiquitous β-herpesvirus that establishes life-long latent infection in a high percentage of the population worldwide. CMV induces the strongest and most durable CD8+ T cell response known in human clinical medicine. Due to its unique properties, the virus represents a promising candidate vaccine vector for the induction of persistent cellular immunity. To take advantage of this, we constructed a recombinant murine CMV (MCMV) expressing an MHC-I restricted epitope from influenza A virus (IAV) H1N1 within the immediate early 2 (ie2) gene. Only mice that were immunized intranasally (i.n.) were capable of controlling IAV infection, despite the greater potency of the intraperitoneally (i.p.) vaccination in inducing a systemic IAV-specific CD8+ T cell response. The protective capacity of the i.n. immunization was associated with its ability to induce IAV-specific tissue-resident memory CD8+ T (CD8TRM) cells in the lungs. Our data demonstrate that the protective effect exerted by the i.n. immunization was critically mediated by antigen-specific CD8+ T cells. CD8TRM cells promoted the induction of IFNγ and chemokines that facilitate the recruitment of antigen-specific CD8+ T cells to the lungs. Overall, our results showed that locally applied MCMV vectors could induce mucosal immunity at sites of entry, providing superior immune protection against respiratory infections.

 

Author summary

Vaccines against influenza typically induce immune responses based on antibodies, small molecules that recognize the virus particles outside of cells and neutralize them before they infect a cell. However, influenza rapidly evolves, escaping immune recognition, and the fastest evolution is seen in the part of the virus that is recognized by antibodies. Therefore, every year we are confronted with new flu strains that are not recognized by our antibodies against the strains from previous years. The other branch of the immune system is made of killer T cells, which recognize infected cells and target them for killing. Influenza does not rapidly evolve to escape T cell killing; thus, vaccines inducing T-cell responses to influenza might provide long-term protection. We introduced an antigen from influenza into the murine cytomegalovirus (MCMV) and used it as a vaccine vector inducing killer T-cell responses of unparalleled strength. Our vector controls influenza replication and provides relief to infected mice, but only if we administered it through the nose, to activate killer T cells that will persist in the lungs close to the airways. Therefore, our data show that the subset of lung-resident killer T cells is sufficient to protect against influenza.

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Citation: Zheng X, Oduro JD, Boehme JD, Borkner L, Ebensen T, Heise U, et al. (2019) Mucosal CD8+ T cell responses induced by an MCMV based vaccine vector confer protection against influenza challenge. PLoS Pathog 15(9): e1008036. https://doi.org/10.1371/journal.ppat.1008036

Editor: Christopher M. Snyder, Thomas Jefferson University, UNITED STATES

Received: July 17, 2019; Accepted: August 21, 2019; Published: September 16, 2019

Copyright: © 2019 Zheng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: This study was supported by the European Research Council through the ERC Starting Grant 260934 to LCS and the Helmholtz Association through the Helmholtz EU Partnering Grant PIE-008 to LCS. XZ was supported by a scholarship from the Chinese Research Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Keywords: Influenza A; CMV; Vaccines; Animal models.

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#Growth activation of #influenza virus by #trypsin and effect of T-705 (#favipiravir) on trypsin-optimized growth condition (Acta Virol., abstract)

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

Acta Virol. 2019;63(3):309-315. doi: 10.4149/av_2019_311.

Growth activation of influenza virus by trypsin and effect of T-705 (favipiravir) on trypsin-optimized growth condition.

Daikoku T, Okuda T, Kawai M, Morita N, Tanaka T, Takemoto M, Fukuda Y, Takahashi K, Nomura N, Shiraki K.

 

Abstract

Influenza virus is activated by proteolytic cleavage of hemagglutinin by trypsin. After determining the optimal trypsin concentration, intracellular and extracellular influenza A/PR/8/34 (H1N1) and A/Victoria/361/2011 (H3N2) virus productions were compared in cultures treated with T-705 (favipiravir) and GS 4071 (an active form of oseltamivir). Although both drugs efficiently inhibited extracellular viral RNA release in a dose-dependent manner, T-705 inhibited it to the level of the inoculum without trypsin treatment, while GS 4071 inhibited it to a final level 10 times higher than that without trypsin. T-705 inhibited intracellular viral RNA production to the level of input virus in both trypsin-treated and untreated cells. In contrast, GS 4071 dose-dependently inhibited intracellular viral RNA production in cells treated with trypsin but allowed viral RNA synthesis. The level of maximum inhibition by GS 4071 was 10 times higher than that of cells without trypsin and 1,000 times greater than the inoculum titer in cells without trypsin. T-705 inhibited both intracellular and extracellular virus production 1,000 and 10 times more strongly, respectively, than GS 4071. T-705 has powerful anti-influenza activity in the absence of trypsin and even in the trypsin-optimized growth condition, suggesting the therapeutic advantage in treatment of influenza complicated with bacterial pneumonia.

Keywords: influenza; T-705; Tamiflu; trypsin; bacterial trypsin-like protease.

PMID: 31507197 DOI: 10.4149/av_2019_311

Keywords: Influenza A; H1N1; H3N2; Antivirals; Favipiravir; Oseltamivir.

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