Influenza: New treatment reduces spread of virus

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A large international collaboration in an animal model (ferrets) found that baloxavir reduced the transmission of influenza across all settings, and did so immediately, while oseltamivir (Tamiflu) did not.

Researchers at the World Health Organisation (WHO) Collaborating Centre for Reference and Research on Influenza at the Peter Doherty Institute for Infection and Immunity (Doherty Institute – a joint venture between the University of Melbourne and Royal Melbourne Hospital) and Imperial College London tested whether baloxavir could prevent the spread of influenza virus in an animal model in conditions that mimicked household settings, including direct and indirect contact. They also compared the treatment to oseltamivir (tradename Tamiflu), a widely prescribed influenza antiviral.

A detailed report of the study, which was conducted in ferrets – considered the gold standard animal model for evaluating influenza – detailed how baloxavir reduced the transmission of influenza across all settings, and did so immediately. Conversely, oseltamivir did not reduce the transmission of influenza to other ferrets.

First author Leo Yi Yang Lee, a medical scientist at the WHO Collaborating Centre for Reference and Research on Influenza, believes the results are an important breakthrough in our understanding of managing the influenza virus.

"Our research provides evidence that baloxavir can have a dramatic dual effect: a single dose reduces the length of influenza illness, while simultaneously reducing the chance of passing it on to others," Lee said.

"This is very important, because current antiviral drugs only treat influenza illness in the infected patient. If you want to reduce the spread of influenza to others, people in close contact need to take antiviral drugs themselves to stave off infection."

Senior author Professor Wendy Barclay, head of the department of infectious disease at Imperial College London, said if the results of the study were replicated in humans, the discovery could be a game changer in stemming outbreaks of influenza, particularly amongst vulnerable groups.

"We know that influenza can have serious and devastating outcomes for people with compromised immune systems, such as those in care facilities and hospitals, where finding more ways to reduce transmission is essential," Barclay said.

A first-of-its-kind clinical trial is currently underway to test the effectiveness of baloxavir in reducing transmission amongst human household contacts by treating individuals infected with influenza and monitoring for infection in household members.

"If further trials prove successful, baloxavir could dramatically change how we manage seasonal influenza outbreaks and pandemic influenza in the future," Barclay said.

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.

Authors
Leo Yi Yang Lee, Jie Zhou, Rebecca Frise, Daniel H. Goldhill, Paulina Koszalka, Edin J Mifsud, Kaoru Baba, Takahiro Noda, Yoshinori Ando, Kenji Sato, Aoe-Ishikawa Yuki, Takao Shishido, Takeki Uehara, Steffen Wildum, Elke Zwanziger, Neil Collinson, Klaus Kuhlbusch, Barry Clinch, Aeron C Hurt, Wendy S Barclay

University of Melbourne material

PLOS Pathogens abstract

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