By Brian Doctrow, Ph.D., National Institutes of Health

At a Glance

• An H5N1 flu virus from an infected farm worker could transmit through airborne droplets and was lethal in mice and ferrets.
• The findings emphasize the risks from the current H5N1 outbreak and the need for continued monitoring and testing.

A highly pathogenic avian influenza (HPAI) H5N1 outbreak in U.S. dairy cattle began in early 2024. As of early November, infections have been confirmed in hundreds of cattle in 15 states. More than 40 human cases have also been reported. Most of the human cases were in farm workers who had mild respiratory symptoms or conjunctivitis (“pink eye”). The CDC currently considers the public to be at low risk.

A research team led by Dr. Yoshihiro Kawaoka at the University of Wisconsin-Madison previously studied an HPAI H5N1 virus found in the milk of an infected cow. That virus could infect mice and ferrets but didn’t spread efficiently through the air. The team recently did a similar study of a virus from one of the infected farm workers. Results from the study, which was funded in part by NIH, appeared in Nature on October 28, 2024.

The scientists found that the virus infected and replicated efficiently in cultured human lung cells. It could also infect cultured cells from the human cornea, albeit less efficiently than in lung cells.

The virus caused lethal infections in all infected mice and ferrets. This is not unusual for an H5N1 virus. However, the cow virus studied before killed only 1 in 4 infected ferrets and required a much higher dose to kill mice. Virus was found not just in the respiratory tract, but in many tissues throughout the body, including blood, spleen, and liver.

The researchers next housed uninfected ferrets in cages next to infected ones to test whether the virus could spread through the air via respiratory droplets. They performed four separate experiments using ferrets infected with varying doses of the virus. Between 1 in 6 and 1 in 3 infected ferrets transmitted the virus to uninfected neighbors. Five of the six ferrets who became infected in this way died. This suggests that the human virus may transmit more efficiently via droplets than the cow virus, although its transmission efficiency was still limited.

The human virus contained a particular mutation that is known to promote replication in mammals. HPAI H5N1 viruses from cattle don’t have this mutation, but they do have another mutation at a nearby site. The team found that both of these mutations enhance viral replication in human cells. Notably, they also found that the cow-derived viruses were susceptible to a class of antiviral drugs called polymerase inhibitors. This suggests a potential treatment strategy for people who contract one of these viruses.

The findings support those of the earlier study suggesting that HPAI H5N1 viruses from cows could potentially transmit via respiratory droplets to infect humans. The virus from the current study only caused mild disease in the person it was isolated from. Yet its ability to cause severe disease in mice and ferrets compared to the previously studied cow virus is concerning.

Fortunately, the mutation that may contribute in part to this strain being so pathogenic hasn’t been detected in other cow viruses. “So, there are no extremely pathogenic H5N1 viruses currently circulating in cows,” Kawaoka says. “However, if a currently circulating cow H5N1 virus acquires that mutation, then that would be an issue.”

A companion paper by CDC researchers confirmed many of these findings. They studied the same virus strain and found it to be similarly lethal in ferrets. Besides respiratory droplets, they showed virus spread through direct contact and through contact with contaminated surfaces. They also detected virus particles in respiratory droplets shed by infected ferrets.

The researchers emphasize the importance of containing outbreaks in cattle to minimize the chances of more virus strains jumping to humans. Continued monitoring of H5N1 viruses circulating in dairy cattle, humans, and other animal hosts is needed.