Targeting two flu proteins sharply reduces airborne spread, study finds

A long-running debate in vaccine design revolves around whether a vaccine should be optimized to prevent the virus from replicating inside an infected host or prevent the virus from transmitting to others. New research led by Penn State scientists suggests there may not have to be a tradeoff.

Animal study reveals dual benefits

The study in animal models, published in the journal Science Advances, demonstrates a way to stop the influenza virus from leaping from one host to the next while continuing to keep the virus from replicating inside the host.

The findings reveal that the body’s defenses against two proteins on the surface of the virus—hemagglutinin (HA) and neuraminidase (NA)—can work to reduce the chance of airborne spread in a measurable way.

“This suggests that intentionally targeting these two proteins together in future vaccines could help curb spread,” said Troy Sutton, who led the study and serves as Huck Early Career Chair in Virology and associate professor of immunology and infectious disease at Penn State.

“Critically, transmission was reduced without accelerating viral evolution inside the host, which is a key concern in vaccine design.”

Why H1N1 and ferrets were chosen

The researchers used ferrets as models to test how different types of immunity (from either vaccination or prior infection) against an influenza H1N1 virus, a strain that causes annual outbreaks in the fall or winter months, affected both viral replication and the likelihood of airborne transmission.

“The virus used in our study is considered representative of seasonal influenza viruses, or viruses that cause outbreaks every fall and winter,” Sutton said.

Infection with an H1N1 influenza virus causes symptoms like fever, cough and fatigue and can lead to severe respiratory illness or even death, particularly in high-risk groups like children, the elderly, and those with weakened immunity.

In fact, the World Health Organization estimates that seasonal influenza viruses, such as the H1N1 virus studied by Sutton’s team, infect up to 1 billion people worldwide each year. As a result, 3–5 million people develop severe disease and as many as 650,000 people die from influenza infections each year.

Ferrets, which have remarkably similar respiratory systems to humans, closely mimic how humans become infected with and transmit influenza viruses like H1N1.

How targeting HA and NA cut spread

By pairing infected “donor” ferrets with uninfected “contact” ferrets in shared-air cages, the team could directly measure how immunity to hemagglutinin, neuraminidase, or both influenced viral transmission. The controlled environment allowed the researchers to track viral shedding, transmission rates, and viral evolution to develop an understanding of how specific immune responses shaped influenza transmission.

Across every scenario, animals with immunity to both proteins were consistently less likely to pass the virus on to nearby, uninfected ferrets. Transmission dropped by half, an effect Sutton described not as synergistic but additive, meaning immune responses to both of the HA and NA proteins equally contributed to the overall reduction in transmission.

The team also identified a measurable threshold for effectiveness. When viral levels dipped below a certain point early in infection, the likelihood of spreading the virus fell below 50%.

“That insight could help guide future vaccine design, especially efforts that aim not only to prevent severe illness but to limit viral transmission itself,” Sutton said.

Implications for future flu vaccines

Critically, he added, the team found no evidence that the virus evolved to evade the body’s immunity to the two proteins. Across dozens of animal models, no consistent escape variants—virus mutations that evolve to evade immune protection—emerged, suggesting that targeting both HA and NA does not appear to drive rapid viral adaptation.

“Our work strengthens the growing consensus among experts that influenza vaccines need to target multiple influenza virus proteins to be maximally effective,” Sutton said. “Vaccines of the future may need to do more than trigger strong antibody responses. They may need to blunt spread at the source and that may mean doubling up on the immune targets the virus relies on most.”