Why hasn't an avian flu pandemic broken out yet?

Since 2021, a new clade of the highly pathogenic avian influenza H5N1 virus - 2.3.4.4b - has been circulating among birds worldwide. The virus was first detected in cattle in Texas about a year ago and has since spread to hundreds of farms across the United States. Dozens of people have been infected in North America. In some cases, the virus exhibits mutations that make it better at infecting and replicating in human cells.

A series of recent findings suggest that the current H5N1 subtype may pose a higher risk of causing a pandemic in cattle and birds than previously thought. One study analyzed blood samples from H5N1-infected dairy farm workers in the US states of Michigan and Colorado and found that many human infections went undetected. Each infection provides more opportunities for the virus to adapt to humans. A preprint released last week showed that the currently circulating H5N12.3.4.4b clade binds to human respiratory epithelial cells more readily than previous versions of H5N1. In addition, a study published in the journal Science by The Scripps Research Institute (TSRI) pointed out that a single mutation at hemagglutinin site 226L in the 2.3.4.4b virus is enough to switch the virus from avian cell surface receptors to human cell surface receptors. Although many scientists believe that viruses typically require more than two mutations to fully adapt to humans, this finding suggests that just one mutation can significantly increase the risk of transmission.

So why hasn’t H5N1 caused a pandemic yet? A simple answer might be that the virus has not yet acquired the full mix of mutations needed to trigger a pandemic. To date, viruses isolated from birds, cattle, and humans have shown no signs of carrying the 226L hemagglutinin mutation, which may significantly improve the virus's ability to attach to human receptors. The researchers speculate that this mutation may negatively affect other properties of the virus, requiring a second mutation to compensate for its disadvantages. The two mutations may also need to appear in a specific order.

Overall, to cause a human pandemic, the H5N1 virus's genome would need to acquire a series of mutations that alter a variety of key proteins. Currently, although some mutations have been observed in some viruses that infect humans, these viruses have not yet been found to be able to spread effectively.