UNIVERSITY PARK, Pa. — The fatality rate for H5N1 highly pathogenic avian influenza in humans historically has been high, with more than half of people dying. Why, then, is the current H5N1 bird flu outbreak — which has caused massive die-offs in wild birds, farmed poultry and even wild mammals — causing mostly mild symptoms in the people it has infected? New research, led by scientists at Penn State and the University of Pittsburgh and published today (July 23) in the journal Science Translational Medicine, indicates that immunity to a seasonal influenza virus known as pandemic H1N1 that began circulating in 2009, provides protection from severe illness from H5N1 in a laboratory animal model.
"Every person has been exposed to H1N1 as the virus caused a pandemic in 2009 and is now the predominant circulating influenza strain in 1 out of every 3-4 years" said lead author Troy Sutton, associate professor of veterinary and biomedical sciences at Penn State. "Our findings suggest that this immunity is protective against the more recent H5N1 strain and may explain why we're seeing fewer cases and less severe disease than we would expect."
H5N1 viruses from clade 2.3.4.4b emerged in 2020 and were carried around the world by wild migratory birds, where they have since infected farmed poultry, wild mammals and, most recently, dairy cattle. As of June 2025, 70 human cases of H5N1 have been confirmed in the United States with one death. Most of the individuals were exposed to dairy cows or poultry and exhibited mild symptoms of conjunctivitis, fever and cough, among others. By contrast, previous human infections with H5N1 resulted in far more severe symptoms, such as seizures and respiratory failure, and some infected people died from the infection or related complications.
"We wanted to know why H5N1 2.3.4.4b was not causing severe outcomes so we investigated whether pre-existing immunity to seasonal influenza could be providing protection," said Katherine Restori, assistant research professor of veterinary and biomedical sciences, Penn State. Restori explained that this research was conducted in ferrets, which are widely recognized as one of the best animal models for studying influenza virus infections.
To conduct their study, Sutton and his colleagues, including Valerie LeSage, research assistant professor, University of Pittsburgh, who co-led the research, studied ferrets with immunity to three common types of seasonal flu: Influenza B, H1N1 and H3N2. They also studied a control group of ferrets that had no immunity to flu. Ninety days after infecting the ferrets with these common seasonal flu viruses, the team confirmed immunity by testing the animals' blood for antibodies. Next, the team exposed the ferrets through an inoculation in the nose to a version of the H5N1 virus that caused an outbreak on mink farms in Spain in 2022.
They found that all the ferrets without immunity to the seasonal flu viruses, as well as those with immunity to Influenza B, became sick, lost weight and reached a humane endpoint. The H3N2-immune ferrets lost 10% of their body weight but all survived. In contrast, the ferrets with immunity to H1N1 did not lose any weight and all survived.
Next, the team studied the potential protective effects of the same three seasonal influenza viruses against the more recent H5N1 virus that has been circulating in dairy cattle. This time, instead of inoculating the ferrets with H5N1 in the nose, the team exposed ferrets with immunity to H1N1, H3N2, or without immunity to a seasonal virus, to ferrets already infected with an H5N1 virus from dairy cows. Sutton said by examining exposure to H5N1-infected ferrets, the team could assess the transmissibility of the virus in addition to the effects of pre-existing immunity.
The researchers found that upon exposure to ferrets with dairy cow H5N1 infections, ferrets without any influenza immunity rapidly developed severe and lethal disease. When exposed to H5N1-infected ferrets, all the ferrets with pre-existing immunity to H3N2 became infected and replicating H5N1 virus was detected in their noses. These ferrets lost weight and half of them reached a humane endpoint. In contrast, only half of the ferrets previously infected with the 2009 H1N1 virus became infected, and the infected animals were protected against disease and had very low levels of viral replication in the nose.
"These findings demonstrate that pre-existing immunity to the 2009 H1N1 virus or H3N2 virus reduces the severity of H5N1 disease, with H1N1 providing even greater protection than H3N2," Sutton said. "This study provides a potential explanation for the mostly mild disease we are seeing in humans, as humans already have immunity to H1N1." However, Sutton noted, as the H5N1 virus continues to circulate in animals, it has opportunities to evolve to become more dangerous.
Experiments using the mink H5N1 and dairy cattle H5N1 viruses were performed in Penn State's biosafety level 3 Eva J. Pell Laboratory for Advanced Biological Research. This facility is approved by the Centers for Disease Control and Prevention and United States of Department of Agriculture for work with highly pathogenic avian influenza. All experiments were performed in compliance with all local, state and federal rules and regulations.
Other Penn State authors on the paper include Veronika Weaver, research technologist; Devanshi Patel, graduate student; Kayla Septer, graduate student; Cassandra Field, graduate student; Michael J. Bernabe, graduate student; Ethan Kronthal, graduate student; Allen Minns, research technician; and Scott Lindner, associate professor of biochemistry and molecular biology. Grace Merrbach, laboratory research technician, University of Pittsburgh, and Seema Lakdawala, associate professor of microbiology and immunology, Emory University, also are authors of the paper.
The National Institutes of Health, Centers of Excellence for Influenza Research and Response (CEIRR) and United States of Department of Agriculture supported this research.
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