Antiviral-antibody combination improves influenza outcomes in mice

By Nick Paul Taylor, The Science Advisory Board contributing writer

August 17, 2022 -- Researchers at McMaster University found in a mouse study that combining a class of well-known antiviral drugs and neutralizing antibodies was more effective than either approach alone, which they contend could be used to treat seasonal influenza and help prevent the next flu pandemic.

In an August 16 article in the journal Cell Reports Medicine, the researchers describe the testing of hemagglutinin stalk-binding antibodies in combination with neuraminidase inhibitors. The drug cocktail was more effective than either treatment as a single agent.

The research suggests that an individual's titers of stalk-binding antibodies may influence the effects of neuraminidase inhibitors such as oseltamivir, an antiviral sold by Roche under the brand name Tamiflu.

Currently, physicians use antiviral drugs to treat influenza in people at risk of serious complications. The response to COVID-19 suggested there may also be a role for neutralizing antibodies. While variants of COVID-19 reduced the efficacy of some anti-SARS-CoV-2 antibodies, the initial data against the ancestral form of the virus validated the concept of using the modality to treat infectious diseases.

To assess how best to use antibodies in response to seasonal and pandemic flu, researchers at McMaster looked at the effect of giving oseltamivir and a hemagglutinin stalk-binding antibody to mice, both as single agents and in combination. The study focused on antibodies that bind to the hemagglutinin stalk because the domain is more conserved between flu strains than other parts of the virus and as such may remain effective even as the pathogen changes.

In a study of the ability of the molecules to protect against infection, the researchers administered the drugs to mice and then infected them with influenza. Mice continued to receive the molecules tested in their cohorts twice a day. Mice that received the combination therapy suffered minimal weight loss, unlike their counterparts in the control and oseltamivir cohorts.

Some mice received the antibody with a mutation that stops Fc-FcR interactions. Adding the mutated antibody to oseltamivir resulted in similar disease progression to the antiviral as a single agent, showing the importance of Fc-FcR interactions to the effects of the combination therapy.

"The mechanism behind how the drug and the antibody therapies work together is very unique and surprising," Ali Zhang, lead author of the research paper and a doctoral student at McMaster, said in a statement. "This approach allows us to both disable a crucial component of the virus and also boost our own immune system to better track down and prevent the spread of the infection."

Based on the findings, the researchers argue clinical trials that assess whether preexisting antibody titers predict the effectiveness of neuraminidase inhibitor treatment could help inform selection of the most appropriate antiviral treatments for individuals with influenza.

"We really need to have better strategies to protect people from flu pandemics because right now we don't have anything," said Matthew Miller, PhD, director of McMaster's Michael G. DeGroote Institute for Infectious Disease Research. "Our seasonal vaccines don't protect us. And we've learned that we can't make them quickly enough to vaccinate everybody if a new pandemic were to emerge."

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