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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#Universal #protection against #influenza #infection by a multidomain #antibody to influenza #hemagglutinin (Science, abstract)

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

Universal protection against influenza infection by a multidomain antibody to influenza hemagglutinin

Nick S. Laursen1,*, Robert H. E. Friesen2,†, Xueyong Zhu1, Mandy Jongeneelen3, Sven Blokland3, Jan Vermond4, Alida van Eijgen4, Chan Tang3, Harry van Diepen4, Galina Obmolova2, Marijn van der Neut Kolfschoten3, David Zuijdgeest3, Roel Straetemans5, Ryan M. B. Hoffman1, Travis Nieusma1, Jesper Pallesen1, Hannah L. Turner1, Steffen M. Bernard1, Andrew B. Ward1, Jinquan Luo2, Leo L. M. Poon6, Anna P. Tretiakova7,‡, James M. Wilson7, Maria P. Limberis7, Ronald Vogels3, Boerries Brandenburg3, Joost A. Kolkman8,§, Ian A. Wilson1,9,§

1 Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. 2 Janssen Research and Development, Spring House, PA 19002, USA. 3 Janssen Vaccines and Prevention, Archimedesweg 4-6, 2333 CN, Leiden, Netherlands. 4 Janssen Prevention Center, Archimedesweg 6, 2333 CN, Leiden, Netherlands.  5 Quantitative Sciences, Janssen Pharmaceutical Companies of Johnson and Johnson, Turnhoutseweg 30, 2340 Beerse, Belgium. 6 Center of Influenza Research and School of Public Health, The University of Hong Kong, Hong Kong SAR, China. 7 Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. 8 Janssen Infectious Diseases, Turnhoutseweg 30, 2340, Beerse, Belgium. 9 Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

§Corresponding author. Email: wilson@scripps.edu (I.A.W.); jkolkman@its.jnj.com (J.A.K.)

* Present address: Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10, 8000 Aarhus C, Denmark.

† Present address: Ablynx, a Sanofi company, Technologiepark 21, 9052 Zwijnaarde, Belgium.

‡ Present address: Pfizer, Rare Disease Research Unit, 610 Main Street, Cambridge, MA 02139, USA.

Science  02 Nov 2018: Vol. 362, Issue 6414, pp. 598-602 / DOI: 10.1126/science.aaq0620

 

Durable influenza protection

Vaccines are indispensable for the control and prevention of influenza, but there are several challenges to efficacy. Some individuals respond poorly to vaccination, and virus variation makes targeting optimal antigens difficult. Broadly neutralizing antibodies are one solution, but they have their own pitfalls, including limited cross-reactivity to both influenza A and B strains and the need for repeated injections. Now, Laursen et al. have developed multidomain antibodies with breadth and potency. Administered intranasally to mice with an adenovirus vector, the antibodies provided durable and continuous protection from a panoply of influenza strains.

Science, this issue p. 598

 

Abstract

Broadly neutralizing antibodies against highly variable pathogens have stimulated the design of vaccines and therapeutics. We report the use of diverse camelid single-domain antibodies to influenza virus hemagglutinin to generate multidomain antibodies with impressive breadth and potency. Multidomain antibody MD3606 protects mice against influenza A and B infection when administered intravenously or expressed locally from a recombinant adeno-associated virus vector. Crystal and single-particle electron microscopy structures of these antibodies with hemagglutinins from influenza A and B viruses reveal binding to highly conserved epitopes. Collectively, our findings demonstrate that multidomain antibodies targeting multiple epitopes exhibit enhanced virus cross-reactivity and potency. In combination with adeno-associated virus–mediated gene delivery, they may provide an effective strategy to prevent infection with influenza virus and other highly variable pathogens.

Keywords: Influenza A; Influenza B; Monoclonal Antibodies; Animal Models.

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N-Glycosylation of Seasonal #Influenza #Vaccine #Hemagglutinins: Implication for potency testing and immune processing (J Virol., abstract)

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

N-Glycosylation of Seasonal Influenza Vaccine Hemagglutinins: Implication for potency testing and immune processing

Yanming An, Lisa M. Parsons, Ewa Jankowska, Darya Melnyk, Manju Joshi, John F. Cipollo

DOI: 10.1128/JVI.01693-18

 

ABSTRACT

Prior to each annual flu season, health authorities recommend three or four virus strains for inclusion in the annual influenza vaccine: a Type A:H1N1, a Type A:H3N2, and one or two Type B viruses. Antigenic differences between strains are found in the glycosylation patterns of the major influenza antigen, hemagglutinin (HA). Here we examine the glycosylation patterns of seven reference antigens containing HA used in influenza vaccine potency testing. These reagents are supplied by the Center for Biologics Evaluation and Research (CBER) or the National Institute for Biological Standards and Control (NIBSC) for use in vaccine testing. Those produced in hen egg, Madin Darby Canine Kidney (MDCK), and insect (Sf9) expression systems were examined. They are closely related or identical to antigens used in commercial vaccine. Reference antigens studied were used in the 2014-2015 influenza season and included A/California/07/2009 H1N1, A/Texas/50/2012 H3N2 and B/Massachusetts/02/2012. Released glycan and HA specific glycopeptide glycosylation patterns were examined. Also examined was the sensitivity of the Single Radial Immunodiffusion Assay (SRID) potency test to differences in HA antigen glycosylation. The SRID assay was not sensitive to any HA antigen glycosylation status from any cell system based on deglycosylation studies as applied using standard assay procedures. Mapping of glycosites with their occupying glycan to functional regions, including antigenic sites, lectin interaction regions and fusion domains was performed and has implications for immune processing, immune response and antigenic shielding. Differences in glycosylation patterns, as dictated by cell system used in expression, may impact on these functions.

 

IMPORTANCE

Here the glycosylation patterns of the 2014-2015 influenza vaccine season standard antigens A/California/07/2009 H1N1, A/Texas/50/2012 H3N2, and B/Massachusetts/02/2012 were revealed and sensitivity of the Single Radial Immunodiffusion Assay (SRID) potency test glycosylation was tested. Differences in hemagglutinin glycosylation site composition and heterogeneity seen in antigen produced in different cell substrates suggests differences in processing and downstream immune response. The SRID potency test used in vaccine release, is not sensitive to differences in glycosylation when applied under standard use conditions. This work reveals important differences in vaccine antigens and may point toward areas where improvements may be made concerning vaccine antigen preparation, immune processing and testing.

This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.

Keywords: Seasonal Influenza; H1N1pdm09; H3N2; Influenza B; Vaccines.

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In vitro characterization of #baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the #influenza virus #polymerase PA subunit (Antiviral Res., abstract)

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

Antiviral Res. 2018 Oct 11. pii: S0166-3542(18)30363-2. doi: 10.1016/j.antiviral.2018.10.008. [Epub ahead of print]

In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit.

Noshi T1, Kitano M1, Taniguchi K2, Yamamoto A1, Omoto S1, Baba K1, Hashimoto T1, Ishida K1, Kushima Y1, Hattori K1, Kawai M1, Yoshida R1, Kobayashi M1, Yoshinaga T1, Sato A3, Okamatsu M4, Sakoda Y4, Kida H5, Shishido T6, Naito A1.

Author information: 1 Shionogi & Co., Ltd, Osaka, Japan. 2 Shionogi & Co., Ltd, Osaka, Japan; Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Japan. 3 Shionogi & Co., Ltd, Osaka, Japan; Research Center for Zoonosis Control, Hokkaido University, Japan. 4 Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Japan. 5 Research Center for Zoonosis Control, Hokkaido University, Japan. 6 Shionogi & Co., Ltd, Osaka, Japan. Electronic address: takao.shishido@shionogi.co.jp.

 

Abstract

Cap-dependent endonuclease (CEN) resides in the PA subunit of the influenza virus and mediates the critical “cap-snatching” step of viral RNA transcription, which is considered to be a promising anti-influenza target. Here, we describe in vitro characterization of a novel CEN inhibitor, baloxavir acid (BXA), the active form of baloxavir marboxil (BXM). BXA inhibits viral RNA transcription via selective inhibition of CEN activity in enzymatic assays, and inhibits viral replication in infected cells without cytotoxicity in cytopathic effect assays. The antiviral activity of BXA is also confirmed in yield reduction assays with seasonal type A and B viruses, including neuraminidase inhibitor-resistant strains. Furthermore, BXA shows broad potency against various subtypes of influenza A viruses (H1N2, H5N1, H5N2, H5N6, H7N9 and H9N2). Additionally, serial passages of the viruses in the presence of BXA result in isolation of PA/I38T variants with reduced BXA susceptibility. Phenotypic and genotypic analyses with reverse genetics demonstrate the mechanism of BXA action via CEN inhibition in infected cells. These results reveal the in vitro characteristics of BXA and support clinical use of BXM to treat influenza.

KEYWORDS: Baloxavir acid; Baloxavir marboxil; Cap-dependent endonuclease; Influenza virus

PMID: 30316915 DOI: 10.1016/j.antiviral.2018.10.008

Keywords: Influenza A; Influenza B; H1N1pdm09; H3N2; H1N2; H5N1; H5N6; H7N9; H9N2; H5N2; Antivirals; Baloxavir.

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#Replacement of #NAIs susceptible #influenza A(#H1N1) with #resistant phenotype in 2008 and circulation of susceptible influenza A and B viruses during 2009-2013, #ZA (Influenza Other Respir Viruses, abstract)

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

Influenza Other Respir Viruses. 2018 Sep 14. doi: 10.1111/irv.12611. [Epub ahead of print]

Replacement of neuraminidase inhibitor susceptible influenza A(H1N1) with resistant phenotype in 2008 and circulation of susceptible influenza A and B viruses during 2009-2013, South Africa.

Treurnicht FK1, Buys A1, Tempia S2,3, Seleka M1, Cohen AL2,4, Walaza S1,5, Glass AJ6, Rossouw I7, McAnerney J1, Blumberg L8,5, Cohen C1,5, Venter M9,10.

Author information:  1 Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa. 2 Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia, USA. 3 Influenza Program, Centers for Disease Control and Prevention, Pretoria, South Africa. 4 Global Immunization Monitoring and Surveillance, Expanded Programme on Immunization, Department of Immunization, Vaccines and Biologicals, World Health Organization, Geneva, Switzerland. 5 School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. 6 Department of Molecular Pathology, Lancet Laboratories, Johannesburg, South Africa. 7 PathCare Laboratories, PathCare Park, N1 City, Cape Town, South Africa. 8 Division of Public Health Surveillance and Response, National Institute of Communicable Diseases, Sandringham, Johannesburg, South Africa. 9 Emerging Arbo-and Respiratory virus Program, Department of Medical Virology, University of Pretoria, Pretoria, South Africa. 10 Tshwane Academic Division, National Health Laboratory Service, Pretoria, South Africa.

 

Abstract

BACKGROUND:

Data on the susceptibility of influenza viruses from South Africa to neuraminidase inhibitors (NAIs) is scarce, and no extensive analysis was done.

OBJECTIVES:

We aimed to determine oseltamivir and zanamivir susceptibility of influenza A and B virus neuraminidases (NAs), 2007-2013, South Africa.

PATIENTS/METHODS:

We enrolled participants through national influenza-like illness surveillance, 2007-2013. Influenza diagnosis was by virus isolation and real-time polymerase chain reaction (qPCR). Drug susceptibility was determined by chemilluminescence-based NA-STAR/NA-XTD assay. Sanger sequencing was used to determine molecular markers of NAI resistance.

RESULTS:

Forty percent (6,341/15,985) of participants were positive for influenza viruses using virus isolation (2007-2009) and qPCR (2009-2013) methods. 1,236/6,341 (19.5%) virus isolates were generated of which 307/1,236 (25%) were tested for drug susceptibility. During 2007-2008 the median 50% inhibitory concentration (IC50 ) of oseltamivir for seasonal influenza A(H1N1) increased from of 0.08 nM (range 0.01-3.60) in 2007 to 73 nM (range 1.56-305 nM) in 2008. Influenza A isolates from 2009-2013 were susceptible to oseltamivir [A(H3N2) median IC50 = 0.05 nM (range 0.01-0.08); A(H1N1)pdm09= 0.11 nM (range 0.01-0.78)] and zanamivir [A(H3N2) median IC50 = 0.56 nM (range 0.47-0.66); A(H1N1)pdm09= 0.35 nM (range 0.27-0.533)]. Influenza B viruses were susceptible to both NAIs. NAI resistance-associated substitutions H275Y, E119V, and R150K (N1 numbering) were not detected in influenza A viruses that circulated in 2009-2013.

CONCLUSIONS:

We confirm replacement of NAI susceptible by resistant phenotype influenza A(H1N1) in 2008. Influenza A and B viruses (2009-2013) remained susceptible to NAIs; therefore these drugs are useful for treating influenza-infected patients.

This article is protected by copyright. All rights reserved.

KEYWORDS: South Africa; influenza; oseltamivir; susceptibility

PMID: 30218485 DOI: 10.1111/irv.12611

Keywords: Seasonal Influenza; H1N1; H1N1pdm09; H3N2; Influenza B; Antivirals; Drugs Resistance; South Africa; Oseltamivir.

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