Optimizing T-705 (#favipiravir) #treatment of #severe #influenza B virus infection in the immunocompromised mouse model (J Antimicrob Chemother., abstract)

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

Optimizing T-705 (favipiravir) treatment of severe influenza B virus infection in the immunocompromised mouse model

Philippe Noriel, Q Pascua, Bindumadhav M Marathe, Peter Vogel, Richard J Webby, Elena A Govorkova

Journal of Antimicrobial Chemotherapy, dky560, https://doi.org/10.1093/jac/dky560

Published: 30 January 2019

 

Abstract

Background

Influenza B virus infections remain insufficiently studied and antiviral management in immunocompromised patients is not well defined. The treatment regimens for these high-risk patients, which have elevated risk of severe disease-associated complications, require optimization and can be partly addressed via animal models.

Methods

We examined the efficacy of monotherapy with the RNA-dependent RNA polymerase inhibitor T-705 (favipiravir) in protecting genetically modified, permanently immunocompromised BALB scid mice against lethal infection with B/Brisbane/60/2008 (BR/08) virus. Beginning at 24 h post-infection, BALB scidmice received oral T-705 twice daily (10, 50 or 250 mg/kg/day) for 5 or 10 days.

Results

T-705 had a dose-dependent effect on survival after BR/08 challenge, resulting in 100% protection at the highest dosages. With the 5 day regimens, dosages of 50 or 250 mg/kg/day reduced the peak lung viral titres within the treatment window, but could not efficiently clear the virus after completion of treatment. With the 10 day regimens, dosages of 50 or 250 mg/kg/day significantly suppressed virus replication in the lungs, particularly at 45 days post-infection, limiting viral spread and pulmonary pathology. No T-705 regimen decreased virus growth in the nasal turbinates of mice, which potentially contributed to the viral dynamics in the lungs. The susceptibility of influenza B viruses isolated from T-705-treated mice remained comparable to that of viruses from untreated control animals.

Conclusions

T-705 treatment is efficacious against lethal challenge with BR/08 virus in immunocompromised mice. The antiviral benefit was greatest when longer T-705 treatment was combined with higher dosages.

Issue Section: ORIGINAL RESEARCH

© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Seasonal Influenza; Influenza B; Antivirals; Favipiravir; Animal models.

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In Vitro Properties and #Virulence of Contemporary #Recombinant #Influenza B Viruses Harboring #Mutations of Cross- #Resistance to #Neuraminidase Inhibitors (Viruses, abstract)

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

Viruses. 2018 Dec 22;11(1). pii: E6. doi: 10.3390/v11010006.

In Vitro Properties and Virulence of Contemporary Recombinant Influenza B Viruses Harboring Mutations of Cross-Resistance to Neuraminidase Inhibitors.

Fage C1, Abed Y2, Checkmahomed L3, Venable MC4, Boivin G5.

Author information: 1 Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, 2705 Boulevard Laurier, Québec City, QC G1V 4G2, Canada. Clement.Fage2@crchudequebec.ulaval.ca. 2 Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, 2705 Boulevard Laurier, Québec City, QC G1V 4G2, Canada. yacine.abed@crchudequebec.ulaval.ca. 3 Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, 2705 Boulevard Laurier, Québec City, QC G1V 4G2, Canada. liva.checkmahomed@crchudequebec.ulaval.ca. 4 Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, 2705 Boulevard Laurier, Québec City, QC G1V 4G2, Canada. marie-christine.venable@crchudequebec.ulaval.ca. 5 Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, 2705 Boulevard Laurier, Québec City, QC G1V 4G2, Canada. guy.boivin@crchudequebec.ulaval.ca.

 

Abstract

Three neuraminidase inhibitors (NAIs: Oseltamivir, zanamivir and peramivir) are currently approved in many countries for the treatment of influenza A and B infections. The emergence of influenza B viruses (IBVs) containing mutations of cross-resistance to these NAIs constitutes a serious clinical threat. Herein, we used a reverse genetics system for the current B/Phuket/3073/2013 vaccine strain to investigate the impact on in vitro properties and virulence of H136N, R152K, D198E/N, I222T and N294S NA substitutions (N2 numbering), reported by the World Health Organization (WHO) as clinical markers of reduced or highly-reduced inhibition (RI/HRI) to multiple NAIs. Recombinant viruses were tested by NA inhibition assays. Their replicative capacity and virulence were evaluated in ST6GalI-MDCK cells and BALB/c mice, respectively. All NA mutants (excepted D198E/N) showed RI/HRI phenotypes against ≥ 2 NAIs. These mutants grew to comparable titers of the recombinant wild-type (WT) IBV in vitro, and some of them (H136N, I222T and N294S mutants) induced more weight loss and mortality in BALB/c mice in comparison to the recombinant WT IBV. These results demonstrate that, in contemporary IBVs, some NA mutations may confer RI/HRI phenotypes to existing NAIs without altering the viral fitness. This reinforces the need for development of novel antiviral strategies with different mechanisms of action.

KEYWORDS: fitness; influenza B; mouse model and neuraminidase mutation; resistance

PMID: 30583488 DOI: 10.3390/v11010006

Keywords: Influenza B; Antivirals; Drugs Resistance; Oseltamivir; Zanamivir; Peramivir.

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In Vitro #Properties and #Virulence of Contemporary Recombinant #Influenza B Viruses Harboring Mutations of Cross- #Resistance to #Neuraminidase Inhibitors (Viruses, abstract)

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

Viruses. 2018 Dec 22;11(1). pii: E6. doi: 10.3390/v11010006.

In Vitro Properties and Virulence of Contemporary Recombinant Influenza B Viruses Harboring Mutations of Cross-Resistance to Neuraminidase Inhibitors.

Fage C1, Abed Y2, Checkmahomed L3, Venable MC4, Boivin G5.

Author information: 1 Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, 2705 Boulevard Laurier, Québec City, QC G1V 4G2, Canada. Clement.Fage2@crchudequebec.ulaval.ca. 2 Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, 2705 Boulevard Laurier, Québec City, QC G1V 4G2, Canada. yacine.abed@crchudequebec.ulaval.ca. 3 Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, 2705 Boulevard Laurier, Québec City, QC G1V 4G2, Canada. liva.checkmahomed@crchudequebec.ulaval.ca. 4 Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, 2705 Boulevard Laurier, Québec City, QC G1V 4G2, Canada. marie-christine.venable@crchudequebec.ulaval.ca. 5 Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, 2705 Boulevard Laurier, Québec City, QC G1V 4G2, Canada. guy.boivin@crchudequebec.ulaval.ca.

 

Abstract

Three neuraminidase inhibitors (NAIs: Oseltamivir, zanamivir and peramivir) are currently approved in many countries for the treatment of influenza A and B infections. The emergence of influenza B viruses (IBVs) containing mutations of cross-resistance to these NAIs constitutes a serious clinical threat. Herein, we used a reverse genetics system for the current B/Phuket/3073/2013 vaccine strain to investigate the impact on in vitro properties and virulence of H136N, R152K, D198E/N, I222T and N294S NA substitutions (N2 numbering), reported by the World Health Organization (WHO) as clinical markers of reduced or highly-reduced inhibition (RI/HRI) to multiple NAIs. Recombinant viruses were tested by NA inhibition assays. Their replicative capacity and virulence were evaluated in ST6GalI-MDCK cells and BALB/c mice, respectively. All NA mutants (excepted D198E/N) showed RI/HRI phenotypes against ≥ 2 NAIs. These mutants grew to comparable titers of the recombinant wild-type (WT) IBV in vitro, and some of them (H136N, I222T and N294S mutants) induced more weight loss and mortality in BALB/c mice in comparison to the recombinant WT IBV. These results demonstrate that, in contemporary IBVs, some NA mutations may confer RI/HRI phenotypes to existing NAIs without altering the viral fitness. This reinforces the need for development of novel antiviral strategies with different mechanisms of action.

KEYWORDS: fitness; influenza B; mouse model and neuraminidase mutation; resistance

PMID: 30583488 DOI: 10.3390/v11010006

Keywords: Influenza B; Antivirals; Drugs Resistance; Oseltamivir; Zanamivir; Peramivir.

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Consecutive #influenza #surveillance of #neuraminidase #mutations and neuraminidase inhibitor #resistance in #Japan (Influenza Other Respir Viruses, abstract)

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

Influenza Other Respir Viruses. 2018 Dec 11. doi: 10.1111/irv.12624. [Epub ahead of print]

Consecutive influenza surveillance of neuraminidase mutations and neuraminidase inhibitor resistance in Japan.

Chong Y1, Matsumoto S2, Kang D2,3, Ikematsu H4.

Author information: 1 Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. 2 Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Hospital, Fukuoka, Japan. 3 Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 4 Japan Physicians Association, Influenza Study Group, Tokyo, Japan.

 

Abstract

BACKGROUND:

The large consumption of neuraminidase (NA) inhibitors (NAIs) for the treatment of influenza virus infections places Japan at risk of becoming the epicenter of the global spread of NAI-resistant viruses.

OBJECTIVE:

To clarify NA amino acid mutations of epidemic influenza viruses in Japan and their related NAI resistance METHODS: A total of 1791 samples, including 396 A/H1N1pdm09, 1117 A/H3N2, and 278 B isolates, were collected to determine of their 50% inhibitory concentration (IC50 ) values by NAIs (oseltamivir, zanamivir, peramivir, and laninamivir) during the Japanese seasons from 2011-12 to 2016-17. Then, 380 samples including 49 A/H1N1pdm09, 251 A/H3N2, and 80 B isolates, were sequenced for the entire NA genes.

RESULTS:

NAI-resistant A/H1N1pdm09 viruses were detected at a frequency of 1.3% (5/396 isolates) in the epidemic seasons. None of the A/H3N2 and B viruses developed resistance to any of the four NAIs during the six seasons. Only five and 13 AA mutations were detected in the NA catalytic sites of A/H1N1pdm09 and A/H3N2 viruses, respectively. No mutations were observed in the catalytic sites of B viruses. Four of the five mutations in the catalytic sites of A/H1N1pdm09 consisted of H275Y, which was related to high resistance to oseltamivir and peramivir. Most (10/13) of the catalytic site mutations in A/H3N2 were associated with MDCK-passaged induction (D151G/N). Finally, no mutations related to substantial NAI resistance were detected in the A/H3N2 and B viruses examined.

CONCLUSION:

These findings suggest that the NA catalytic sites of influenza viruses are well preserved. Even in Japan, no spread of NAI-resistant viruses has been observed, and A/H1N1pdm09 viruses carrying H275Y remain limited.

This article is protected by copyright. All rights reserved.

KEYWORDS: Influenza; mutation; neuraminidase; neuraminidase inhibitor; resistance

PMID: 30548432 DOI: 10.1111/irv.12624

Keywords: Antivirals; Drugs Resistance; Oseltamivir; Zanamivir; Peramivir; Laninamivir; H1N1pdm09; H3N2; Seasonal Influenza.

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Broadly protective #influenza #vaccines: design and production platforms (Curr Opin Virol., abstract)

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

Curr Opin Virol. 2018 Nov 26;34:1-9. doi: 10.1016/j.coviro.2018.11.005. [Epub ahead of print]

Broadly protective influenza vaccines: design and production platforms.

Elbahesh H1, Saletti G1, Gerlach T1, Rimmelzwaan GF2.

Author information: 1 University of Veterinary Medicine (TiHo), Research Center for Emerging Infections and Zoonoses (RIZ), Bünteweg 17, 30559 Hannover, Germany. 2 University of Veterinary Medicine (TiHo), Research Center for Emerging Infections and Zoonoses (RIZ), Bünteweg 17, 30559 Hannover, Germany. Electronic address: Guus.Rimmelzwaan@tiho-hannover.de.

 

Abstract

Effective vaccines are the cornerstone of our defenses against acute influenza virus infections that result in ∼500 000 annual deaths worldwide. For decades, an on-going concerted effort has been to develop a universal influenza vaccine to combat the looming threat of potentially pandemic emerging and re-emerging influenza viruses. To address the need for rapid efficacious vaccines that could mitigate the impact of seasonal and future pandemics, multiple platforms are under development and/or investigation. What is clear is that any universal vaccine must provide long-lasting cross-protective immunity that can induce both B and T cell responses. This review will explore some of the universal influenza vaccine platforms in the contexts of their ability to induce long-lasting and cross-protective T cell immunity.

PMID: 30497050 DOI: 10.1016/j.coviro.2018.11.005

Keywords: Influenza A; Influenza B; Vaccines.

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Duration of #fever and other symptoms after the inhalation of #laninamivir octanoate hydrate in the 2016/17 #Japanese #influenza season; comparison with the 2011/12 to 2015/16 seasons (J Infect Chemother., abstract)

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

J Infect Chemother. 2018 Sep;24(9):718-724. doi: 10.1016/j.jiac.2018.04.013. Epub 2018 Jun 1.

Duration of fever and other symptoms after the inhalation of laninamivir octanoate hydrate in the 2016/17 Japanese influenza season; comparison with the 2011/12 to 2015/16 seasons.

Ikematsu H1, Kawai N2, Iwaki N2, Kashiwagi S2, Ishikawa Y3, Yamaguchi H3, Shiosakai K3.

Author information: 1 Japan Physicians Association, Tokyo, Japan. Electronic address: ikematsu@gray.plala.or.jp. 2 Japan Physicians Association, Tokyo, Japan. 3 Daiichi Sankyo Co., Ltd, Tokyo, Japan.

 

Abstract

The duration of fever and symptoms after laninamivir octanoate hydrate (laninamivir) inhalation were investigated in the Japanese 2016/17 influenza season and the results were compared with those of the 2011/12 to 2015/16 seasons. A total of 1278 patients were evaluated for the duration of fever and symptoms in the six studied seasons. In the 2016/17 season, the influenza types/subtypes of the patients were 6 A (H1N1)pdm09 (2.9%), 183 A (H3N2) (87.6%), and 20 B (9.6%). The respective median durations of fever for A (H1N1)pdm09, A (H3N2), and B were 38.0, 33.0, and 38.5 h, without significant difference (p = 0.9201), and the median durations of symptoms were 86.5, 73.0, and 99.0 h, with significant difference (p = 0.0342). The median durations of fever and symptoms after laninamivir inhalation were quite consistent for the six studied seasons for A (H1N1)pdm09, A (H3N2), and B, without any significant differences. The percentage of patients with unresolved fever patients displayed a similar pattern through the six studied seasons for all these virus types. There was no significant difference in the duration of fever or symptoms between the Victoria and Yamagata lineages in the 2016/17 season and those of the previous studied seasons. Over the seasons tested, ten adverse drug reactions (ADRs) were reported from 1341 patients. The most frequent ADR was diarrhea and all ADRs were self-resolving and not serious. These results indicate the continuing clinical effectiveness of laninamivir against influenza A (H1N1)pdm09, A (H3N2), and B, with no safety issues.

KEYWORDS: Fever; Influenza; Laninamivir; Neuraminidase inhibitor; Symptom

PMID: 29861186 DOI: 10.1016/j.jiac.2018.04.013 [Indexed for MEDLINE]  Free full text

Keywords: Seasonal Influenza; H1N1pdm09; H3N2; Antivirals; Laninamivir; Japan.

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A broadly protective #therapeutic #antibody against #influenza B virus with two mechanisms of action (Nat Commun., abstract)

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

Nat Commun. 2017 Jan 19;8:14234. doi: 10.1038/ncomms14234.

A broadly protective therapeutic antibody against influenza B virus with two mechanisms of action.

Chai N1, Swem LR1, Park S2, Nakamura G3, Chiang N3, Estevez A4, Fong R4, Kamen L5, Kho E5, Reichelt M6, Lin Z2, Chiu H7, Skippington E8, Modrusan Z9, Stinson J9, Xu M2, Lupardus P4, Ciferri C4, Tan MW1.

Author information: 1 Department of Infectious Diseases, Genentech, South San Francisco, California 94080, USA. 2 Department of Translational Immunology, Genentech, South San Francisco, California 94080, USA. 3 Department of Antibody Engineering, Genentech, South San Francisco, California 94080, USA. 4 Department of Structural Biology, Genentech, South San Francisco, California 94080, USA. 5 Department of BioAnalytical Sciences, Genentech, South San Francisco, California 94080, USA. 6 Department of Pathology, Genentech, South San Francisco, California 94080, USA. 7 Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, California 94080, USA. 8 Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, California 94080, USA. 9 Department of Molecular Biology, Genentech, South San Francisco, California 94080, USA.

 

Abstract

Influenza B virus (IBV) causes annual influenza epidemics around the world. Here we use an in vivo plasmablast enrichment technique to isolate a human monoclonal antibody, 46B8 that neutralizes all IBVs tested in vitro and protects mice against lethal challenge of all IBVs tested when administered 72 h post infection. 46B8 demonstrates a superior therapeutic benefit over Tamiflu and has an additive antiviral effect in combination with Tamiflu. 46B8 binds to a conserved epitope in the vestigial esterase domain of hemagglutinin (HA) and blocks HA-mediated membrane fusion. After passage of the B/Brisbane/60/2008 virus in the presence of 46B8, we isolated three resistant clones, all harbouring the same mutation (Ser301Phe) in HA that abolishes 46B8 binding to HA at low pH. Interestingly, 46B8 is still able to protect mice against lethal challenge of the mutant viruses, possibly owing to its ability to mediate antibody-dependent cellular cytotoxicity (ADCC).

PMID: 28102191 PMCID: PMC5253702 DOI: 10.1038/ncomms14234 [Indexed for MEDLINE]  Free PMC Article

Keywords: Seasonal Influenza; Influenza B; Monoclonal Antibodies.

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