Abstract
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.
Highlights
Reviewed by: Paul Horwood, Institut Pasteur in Cambodia, Cambodia Barry Rockx, Rijksinstituut voor Volksgezondheid en Milieu, Netherlands
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
The continuous risks posed by the emergence of neuraminidase inhibitors (NAIs)-resistant viruses (Takashita et al, 2015) and the pandemic potential of avian influenza viruses, such as A(H5N1) (Nguyen et al, 2013) and A(H7N9) (Hu et al, 2013), has sparked a major effort to develop new antivirals for human use
Summary
The neuraminidase inhibitors (NAIs) are the only licensed class of antiviral drugs effective against currently circulating influenza viruses. The choice of the animal model for assessing the effectiveness of these influenza antivirals becomes critical as it provides pre-clinical data that can inform the decision for progression toward clinical trials. In the majority of human clinical trials of influenza antivirals, the primary endpoint used to assess the drug efficacy is the time to alleviation of clinical symptoms, such as cough, fever, sore throat, myalgia, lethargy, nasal congestion, and headaches, whereas other aspects, including the ability to reduce viral shedding, are considered secondary endpoints (Hayden et al, 1997; The MIST, 1998; Makela et al, 2000; Nicholson et al, 2000; Treanor et al, 2000; Haffizulla et al, 2014). The pros and cons of the different animal models of influenza to investigate disease pathogenesis, transmission, and vaccine development have been well-described in several published reviews and are summarized here in Table 1 (Bouvier and Lowen, 2010; Lowen et al, 2014; Margine and Krammer, 2014; Thangavel and Bouvier, 2014; Davis et al, 2015; Enkirch and von Messling, 2015)
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