Evaluation of a dry powder delivery system for laninamivir in a ferret model of influenza infection

Panozzo, Jacqueline; Oh, Ding Yuan; Margo, Kenneth; Morton, David Alexander Vodden; Piedrafita, David; Mosse, Jennifer; Hurt, Aeron C.

doi:10.1016/j.antiviral.2015.05.007

Cited by 7 publications

(5 citation statements)

References 26 publications

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“…Inflammation and cell recruitment relies on the presence of replicating influenza virus [ 24 ]. Thus, laboratory indicators of inflammation at the nasal cavity of ferrets were also investigated as potential parameter for influenza B virus pathogenicity as previously done with influenza A viruses [ 33 – 38 ]. For these, the elevations of white blood cells (WBCs), neutrophils, lymphocytes, and total protein counts in nasal washes were examined.…”

Section: Resultsmentioning

confidence: 99%

Competitive Fitness of Influenza B Viruses Possessing E119A and H274Y Neuraminidase Inhibitor Resistance–Associated Substitutions in Ferrets

et al. 2016

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Neuraminidase (NA) inhibitors (NAIs) are the only antiviral drugs recommended for influenza treatment and prophylaxis. Although NAI-resistant influenza B viruses that could pose a threat to public health have been reported in the field, their fitness is poorly understood. We evaluated in ferrets the pathogenicity and relative fitness of reverse genetics (rg)–generated influenza B/Yamanashi/166/1998-like viruses containing E119A or H274Y NA substitutions (N2 numbering). Ferrets inoculated with NAI-susceptible rg–wild-type (rg-WT) or NAI-resistant (rg-E119A or rg-H274Y) viruses developed mild infections. Growth of rg-E119A virus in the nasal cavities was delayed, but the high titers at 3 days post-inoculation (dpi) were comparable to those of the rg-WT and rg-H274Y viruses (3.6–4.1 log10TCID50/mL). No virus persisted beyond 5 dpi and replication did not extend to the trachea or lungs. Positive virus antigen-staining of the nasal turbinate epithelium was intermittent with the rg-WT and rg-H274Y viruses; whereas antigen-staining for the rg-E119A virus was more diffuse. Virus populations in ferrets coinoculated with NAI-susceptible and -resistant viruses (1:1 mixture) remained heterogeneous at 5 dpi but were predominantly rg-WT (>70%). Although the E119A substitution was associated with delayed replication in ferrets, the H274Y substitution did not measurably affect viral growth properties. These data suggest that rg-H274Y has undiminished fitness in single virus inoculations, but neither rg-E119A nor rg-H274Y gained a fitness advantage over rg-WT in direct competition experiments without antiviral drug pressure. Taken together, our data suggest the following order of relative fitness in a ferret animal model: rg-WT > rg-H274Y > rg-E119A.

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Section: Resultsmentioning

confidence: 99%

Competitive Fitness of Influenza B Viruses Possessing E119A and H274Y Neuraminidase Inhibitor Resistance–Associated Substitutions in Ferrets

et al. 2016

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“…Furthermore, the virus transmits easily among ferrets [88], recapitulating virus spread in humans. Given the similarity of the physiological response to influenza virus between ferrets and humans, ferrets have been used to study influenza proteins [94,95] and to assess the effectiveness of anti-viral compounds at ameliorating disease progression [89,[96][97][98]. However, the limitation of ferrets is that while they are highly susceptible to infection, intramuscular or other immunization routes with noninfectious antigen results in the poor antibody response.…”

Section: Ferretsmentioning

confidence: 99%

Alternative Experimental Models for Studying Influenza Proteins, Host–Virus Interactions and Anti-Influenza Drugs

Chua

Engelberg

et al. 2019

Pharmaceuticals

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Ninety years after the discovery of the virus causing the influenza disease, this malady remains one of the biggest public health threats to mankind. Currently available drugs and vaccines only partially reduce deaths and hospitalizations. Some of the reasons for this disturbing situation stem from the sophistication of the viral machinery, but another reason is the lack of a complete understanding of the molecular and physiological basis of viral infections and host-pathogen interactions. Even the functions of the influenza proteins, their mechanisms of action and interaction with host proteins have not been fully revealed. These questions have traditionally been studied in mammalian animal models, mainly ferrets and mice (as well as pigs and non-human primates) and in cell lines. Although obviously relevant as models to humans, these experimental systems are very complex and are not conveniently accessible to various genetic, molecular and biochemical approaches. The fact that influenza remains an unsolved problem, in combination with the limitations of the conventional experimental models, motivated increasing attempts to use the power of other models, such as low eukaryotes, including invertebrate, and primary cell cultures. In this review, we summarized the efforts to study influenza in yeast, Drosophila, zebrafish and primary human tissue cultures and the major contributions these studies have made toward a better understanding of the disease. We feel that these models are still under-utilized and we highlight the unique potential each model has for better comprehending virus-host interactions and viral protein function.

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“…Insuﬄators are devices that have been widely used as a non-invasive method to administer powdered drugs for drug deposition studies in small animals such as mice or rats ( Nahar et al, 2013 ), but have been less commonly used in larger animals such as ferrets. To bridge this unmet need for a delivery system for powdered antivirals such as laninamivir, we recently characterized the usage of a dry powder insuﬄator to deliver laninamivir octanoate (LO) to ferrets prior to influenza infection ( Panozzo et al, 2015 ). In vitro laser diffraction analysis showed that ∼80% LO together with its lactose carrier can be effectively discharged from the device and intratracheal administration of LO in anesthetized ferrets can be easily performed ( Panozzo et al, 2015 ).…”

Section: Drug Administrationmentioning

confidence: 99%

“…To bridge this unmet need for a delivery system for powdered antivirals such as laninamivir, we recently characterized the usage of a dry powder insuﬄator to deliver laninamivir octanoate (LO) to ferrets prior to influenza infection ( Panozzo et al, 2015 ). In vitro laser diffraction analysis showed that ∼80% LO together with its lactose carrier can be effectively discharged from the device and intratracheal administration of LO in anesthetized ferrets can be easily performed ( Panozzo et al, 2015 ). For LO where a single dose is sufficient, the method is highly applicable, but repeated dosing would be difficult due to the need for regular anesthesia.…”

Section: Drug Administrationmentioning

confidence: 99%

“…Recently, the report of an annotated ferret transcriptome during influenza infection has also opened up an avenue for interrogating the global host gene expression to further understand host immunity toward influenza infection ( Leon et al, 2013 ). In addition, simple immunological analysis such as measuring total cell count or protein concentration in nasal wash samples can also be useful as a determinant of inflammation ( Govorkova et al, 2007 , 2011 ; Marriott et al, 2014 ; Oh et al, 2015 ; Panozzo et al, 2015 ). Other basic immune measurements include differential staining of various leukocytes populations in the BAL or blood, and also clinical chemistry of different proteins in blood post influenza infection ( Kim et al, 2013 ; Stark et al, 2013 ; Table 4 ).…”

Section: Parameters To Assess the Effectiveness Of Antiviral Treatmenmentioning

confidence: 99%

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Using the Ferret as an Animal Model for Investigating Influenza Antiviral Effectiveness

Hurt

2016

Front. Microbiol.

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The concern of the emergence of a pandemic influenza virus has sparked an increased effort toward the development and testing of novel influenza antivirals. Central to this is the animal model of influenza infection, which has played an important role in understanding treatment effectiveness and the effect of antivirals on host immune responses. Among the different animal models of influenza, ferrets can be considered the most suitable for antiviral studies as they display most of the human-like symptoms following influenza infections, they can be infected with human influenza virus without prior viral adaptation and have the ability to transmit influenza virus efficiently between one another. However, an accurate assessment of the effectiveness of an antiviral treatment in ferrets is dependent on three major experimental considerations encompassing firstly, the volume and titer of virus, and the route of viral inoculation. Secondly, the route and dose of drug administration, and lastly, the different methods used to assess clinical symptoms, viral shedding kinetics and host immune responses in the ferrets. A good understanding of these areas is necessary to achieve data that can accurately inform the human use of influenza antivirals. In this review, we discuss the current progress and the challenges faced in these three major areas when using the ferret model to measure influenza antiviral effectiveness.

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Evaluation of a dry powder delivery system for laninamivir in a ferret model of influenza infection

Cited by 7 publications

References 26 publications

Competitive Fitness of Influenza B Viruses Possessing E119A and H274Y Neuraminidase Inhibitor Resistance–Associated Substitutions in Ferrets

Competitive Fitness of Influenza B Viruses Possessing E119A and H274Y Neuraminidase Inhibitor Resistance–Associated Substitutions in Ferrets

Alternative Experimental Models for Studying Influenza Proteins, Host–Virus Interactions and Anti-Influenza Drugs

Using the Ferret as an Animal Model for Investigating Influenza Antiviral Effectiveness

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