Postexposure Protective Efficacy of T-705 (Favipiravir) Against Sudan Virus Infection in Guinea Pigs

Rahim, Niaz; Zhang, Z; He, Shulin; Zhu, Weiliang; Banadyga, Logan; Safronetz, Dave; Qiu, Xiaoqing

doi:10.1093/infdis/jiy303

Cited by 10 publications

(8 citation statements)

References 31 publications

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“…Alterations of some of these hematology and blood chemistry parameters were also found in guinea pigs [ 27 ], ferrets [ 61 , 62 ], IFNAR [ 43 ] and IFNAGR [ 39 ] mice on a C57BL/6J background, and in our study with STAT-1 KO mice. Consistent with previous observations in EBOV-infected IFNAGR KO mice [ 39 ] and human patients [ 63 ], we observed neutrophilia following SUDV challenge in our STAT-1 KO mice. Histopathology findings indicated that SUDV replicated in the liver and spleen of mice in our study, similar to NHPs [ 56 , 57 , 58 , 59 , 60 ], guinea pigs [ 27 , 64 ], and IFNAR KO mice [ 43 ], with features somewhat consistent with those described in the corresponding organs of EBOV-infected patients [ 65 ].…”

Section: Discussionsupporting

confidence: 93%

STAT-1 Knockout Mice as a Model for Wild-Type Sudan Virus (SUDV)

Escaffre

Juelich

Neef³

et al. 2021

Viruses

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Currently there is no FDA-licensed vaccine or therapeutic against Sudan ebolavirus (SUDV) infections. The largest ever reported 2014–2016 West Africa outbreak, as well as the 2021 outbreak in the Democratic Republic of Congo, highlight the critical need for countermeasures against filovirus infections. A well-characterized small animal model that is susceptible to wild-type filoviruses would greatly add to the screening of antivirals and vaccines. Here, we infected signal transducer and activator of transcription-1 knock out (STAT-1 KO) mice with five different wildtype filoviruses to determine susceptibility. SUDV and Marburg virus (MARV) were the most virulent, and caused 100% or 80% lethality, respectively. Zaire ebolavirus (EBOV), Bundibugyo ebolavirus (BDBV), and Taï Forest ebolavirus (TAFV) caused 40%, 20%, and no mortality, respectively. Further characterization of SUDV in STAT-1 KO mice demonstrated lethality down to 3.1 × 101 pfu. Viral genomic material was detectable in serum as early as 1 to 2 days post-challenge. The onset of viremia was closely followed by significant changes in total white blood cells and proportion of neutrophils and lymphocytes, as well as by an influx of neutrophils in the liver and spleen. Concomitant significant fluctuations in blood glucose, albumin, globulin, and alanine aminotransferase were also noted, altogether consistent with other models of filovirus infection. Finally, favipiravir treatment fully protected STAT-1 KO mice from lethal SUDV challenge, suggesting that this may be an appropriate small animal model to screen anti-SUDV countermeasures.

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Section: Discussionsupporting

confidence: 93%

STAT-1 Knockout Mice as a Model for Wild-Type Sudan Virus (SUDV)

Escaffre

Juelich

Neef³

et al. 2021

Viruses

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“…It is unclear what effect EBOV infection would have on the metabolic enzymes such as the P450’s in the guinea pig. To our knowledge, favipiravir has not previously been tested orally against EBOV in guinea pig (though it has demonstrated survival rates of 83-100% in Sudan virus-infected guinea pigs (35)), and in this study we now demonstrate efficacy on a par with what was observed in non-human primates (41, 42). In comparison, survival after pyronaridine (300 and 600 mg/kg) treatment was not significantly different from oral-administered favipiravir in the guinea pig model ((Log-rank (Mantel-Cox) test), suggesting a similar efficacy.…”

Section: Discussionsupporting

confidence: 55%

“…Favipiravir has been shown to protect guinea pigs from adapted Sudan Virus (35) however in our study it protected ∼44% of the animals against gpa-EBOV, with deaths starting on study day 6 and continuing until study day 14 (Fig. 3A).…”

Section: Resultsmentioning

confidence: 59%

Pyronaridine Tetraphosphate Efficacy Against Ebola Virus Infection in Guinea Pig

Lane

Massey²,

Comer³

et al. 2020

Preprint

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31The recent outbreaks of the Ebola virus (EBOV) in Africa have brought global visibility to 32 the shortage of available therapeutic options to treat patients infected with this or closely 33 related viruses. We have recently computationally identified three molecules which have 34 all demonstrated statistically significant efficacy in the mouse model of infection with 35 mouse adapted Ebola virus (ma-EBOV). One of these molecules is the antimalarial 36 pyronaridine tetraphosphate (IC 50 range of 0.82-1.30 µM against three strains of EBOV 37 and IC 50 range of 1.01-2.72 µM against two strains of Marburg virus (MARV)) which is 38 an approved drug in the European Union and used in combination with artesunate. To 39 date, no small molecule drugs have shown statistically significant efficacy in the guinea 40 pig model of EBOV infection. Pharmacokinetics and range-finding studies in guinea pigs 41 directed us to a single 300mg/kg or 600mg/kg oral dose of pyronaridine 1hr after 42 infection. Pyronaridine resulted in statistically significant survival of 40% at 300mg/kg 43 and protected from a lethal challenge with EBOV. In comparison, oral favipiravir (300 44 mg/kg dosed once a day) had 43.5 % survival. The in vitro metabolism and metabolite 45 identification of pyronaridine and another of our EBOV active molecules, tilorone, which 46 suggests significant species differences which may account for the efficacy or lack 47 thereof, respectively in guinea pig. In summary, our studies with pyronaridine 48 demonstrates its utility for repurposing as an antiviral against EBOV and MARV, 49 providing justification for future testing in non-human primates. 50 51 52 4 Importance 53There is currently no antiviral small molecule drug approved for treating Ebola Virus 54 infection. We have previously used machine learning models to identify new uses for 55 approved drugs and demonstrated their activity against the Ebola virus in vitro and in 56 vivo. We now describe the pharmacokinetic properties of the antimalarial pyronaridine in 57 the guinea pig. In addition, we show that this drug is effective against multiple strains of 58 EBOV and MARV in vitro and in the guinea pig model of Ebola virus infection. These 59 combined efforts indicate the need to further test this molecule in larger animal efficacy 60 studies prior to clinical use in humans. These findings also may be useful for 61 repurposing this drug for use against other viruses in future. 62 63

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“…To determine the usefulness of IFNAGR KO mice as a screening model for anti-filovirus countermeasures, we treated challenged mice with the antiviral Favipiravir. Indeed, Favipiravir was previously shown to be effective against wild-type EBOV in IFN-α/β receptor KO mouse models [ 45 , 46 , 47 ], mouse-adapted EBOV and MARV in respectively C57BL/6 or BALB/c mouse model [ 47 , 48 , 49 ], guinea pig-adapted SUDV in the guinea pig model [ 50 ] and wild-type EBOV or MARV in the NHP models [ 51 , 52 ]. Here, Favipiravir treatment was initiated 1 hour post-infection and infected mice were treated twice daily for 8 days.…”

Section: Resultsmentioning

confidence: 99%

Filovirus Virulence in Interferon α/β and γ Double Knockout Mice, and Treatment with Favipiravir

Comer

Escaffre

Neef

et al. 2019

Viruses

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The 2014 Ebolavirus outbreak in West Africa highlighted the need for vaccines and therapeutics to prevent and treat filovirus infections. A well-characterized small animal model that is susceptible to wild-type filoviruses would facilitate the screening of anti-filovirus agents. To that end, we characterized knockout mice lacking α/β and γ interferon receptors (IFNAGR KO) as a model for wild-type filovirus infection. Intraperitoneal challenge of IFNAGR KO mice with several known human pathogenic species from the genus Ebolavirus and Marburgvirus, except Bundibugyo ebolavirus and Taï Forest ebolavirus, caused variable mortality rate. Further characterization of the prototype Ebola virus Kikwit isolate infection in this KO mouse model showed 100% lethality down to a dilution equivalent to 1.0 × 10−1 pfu with all deaths occurring between 7 and 9 days post-challenge. Viral RNA was detectable in serum after challenge with 1.0 × 102 pfu as early as one day after infection. Changes in hematology and serum chemistry became pronounced as the disease progressed and mirrored the histological changes in the spleen and liver that were also consistent with those described for patients with Ebola virus disease. In a proof-of-principle study, treatment of Ebola virus infected IFNAGR KO mice with favipiravir resulted in 83% protection. Taken together, the data suggest that IFNAGR KO mice may be a useful model for early screening of anti-filovirus medical countermeasures.

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Postexposure Protective Efficacy of T-705 (Favipiravir) Against Sudan Virus Infection in Guinea Pigs

Cited by 10 publications

References 31 publications

STAT-1 Knockout Mice as a Model for Wild-Type Sudan Virus (SUDV)

STAT-1 Knockout Mice as a Model for Wild-Type Sudan Virus (SUDV)

Pyronaridine Tetraphosphate Efficacy Against Ebola Virus Infection in Guinea Pig

Filovirus Virulence in Interferon α/β and γ Double Knockout Mice, and Treatment with Favipiravir

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