Baloxavir treatment of ferrets infected with influenza A(H1N1)pdm09 virus reduces onward transmission

Abstract

Influenza viruses cause seasonal outbreaks and pose a continuous pandemic threat. Although vaccines are available for influenza control, their efficacy varies each season and a vaccine for a novel pandemic virus manufactured using current technology will not be available fast enough to mitigate the effect of the first pandemic wave. Antivirals can be effective against many different influenza viruses but have not thus far been used extensively for outbreak control. Baloxavir, a recently licensed antiviral drug that targets the influenza virus endonuclease, has been shown to reduce virus shedding more effectively than oseltamivir, a widely used neuraminidase inhibitor drug. Thus it is possible that treatment with baloxavir might also interrupt onward virus transmission. To test this, we utilized the ferret model, which is the most commonly used animal model to study influenza virus transmission. We established a subcutaneous baloxavir administration method in ferrets which achieved similar pharmacokinetics to the approved human oral dose. Transmission studies were then conducted in two different locations with different experimental setups to compare the onward transmission of A(H1N1)pdm09 virus from infected ferrets treated with baloxavir, oseltamivir or placebo to naïve sentinel ferrets exposed either indirectly in adjacent cages or directly by co-housing. We found that baloxavir treatment reduced infectious viral shedding in the upper respiratory tract of ferrets compared to placebo, and reduced the frequency of transmission amongst sentinels in both experimental setups, even when treatment was delayed until 2 days post-infection. In contrast, oseltamivir treatment did not substantially affect viral shedding or transmission compared to placebo. We did not detect the emergence of baloxavir-resistant variants in treated animals or in untreated sentinels.

Pharmacokinetic and pharmacodynamic analysis of baloxavir marboxil, a novel cap-dependent endonuclease inhibitor, in a murine model of influenza virus infection

“…The model may have utility in future studies for evaluating residual virus burden following antiviral treatment and thus the potential for transmission. 35 Symptom resolution was faster with baloxavir marboxil than placebo, but not oseltamivir phosphate, in type A virus infections. 25 , 34 These clinical findings suggest that our PK/PD analysis based on virus titre reduction in the murine model could be useful in predicting potent viral load reduction in patients, but might be limited in predicting a shorter time to symptom resolution in otherwise healthy influenza patients.…”

Baloxavir Treatment in Adolescents With Acute Influenza: Subgroup Analysis From the CAPSTONE-1 Trial

“…Children and adolescents play a major role in influenza transmission in the household. Our ferret study has shown a possibility of interrupting onward transmission with baloxavir treatment [ 17 ], and a clinical trial in a household-based transmission (ClinicalTrials.gov: NCT03969212) is underway to determine to what extent treatment can reduce the risk of transmission to close contacts.…”

Fitness of influenza A and B viruses with reduced susceptibility to baloxavir: A mini‐review

“…26 More recently, the potential of BXM to impact influenza virus transmission was assessed in ferrets experimentally infected with influenza A (H1N1) pdm09 virus. 28 The authors reported that administration of a single dose of BXM (4 mg/kg) reduced viral shedding in the upper respiratory tract of ferrets compared to placebo and also reduced the frequency of airborne and contact transmission of virus to healthy ferrets, even when treatment was delayed until 2 days p.i. 28…”