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. Our results support the concept that antivirals which decrease viral shedding could also reduce influenza transmission in the community.

Author summary

During seasonal influenza outbreaks and global pandemics, influenza can cause significant morbidity and mortality and spread rapidly. Influenza viruses constantly change, and the effectiveness of vaccination can be low if the match between the vaccine and circulating viruses is poor. However, antiviral drugs target conserved parts of the virus and therefore typically remain effective against new seasonal or pandemic strains of influenza. The new antiviral baloxavir is more effective than existing drugs, such as oseltamivir, in reducing the amount of virus particles produced by infected people, suggesting it might reduce the onward spread of influenza viruses to others. To test this, we developed an effective way to deliver baloxavir to ferrets, the best available animal model of influenza virus transmission. We then treated influenza-infected ferrets with baloxavir to determine if they were less likely to pass their virus onto healthy ferrets housed in the same cage, or in the adjacent cage. In both cases, we found that compared to oseltamivir or placebo treatment, infected ferrets treated with baloxavir produced fewer virus particles and were less likely to transmit virus to healthy ferrets. Our results suggest baloxavir can contribute to the early control of influenza outbreaks by limiting community-based viral spread.