Is Gain-of-Function Responsible for the Bird Flu Jump to Cows and Humans? – Yuhong Dong, M.D., Ph.D. and Xiaoxu Sean Lin, M.D., Ph.D. 5/29/24


In the past six months, bird flu has surprised scientists at least twice.

Bird flu viruses have circulated mainly in birds for a long time. However, in early December 2023, an outbreak occurred in U.S. dairy cows, even though cattle are not typically susceptible to avian influenza A, the bird flu virus.

In late March, a U.S. dairy farm worker was infected by a H5N1 virus from a cow.

On May 22, a second human case of H5N1 infection was reported with prior exposure to infected dairy cows in Michigan.

On the same day in May, an Australian child was infected by an H7 strain,  another subtype of influenza A  known to cause human infections.

Since bird flu infections in humans are rare, these incidents have raised significant concern among scientists.

Why is this happening, and how concerned should we be?

This article aims to avoid unnecessary fear about a potential future pandemic. Instead, we encourage people to think rationally and make appropriate adjustments for the future.

Rapid Spread in Birds

The history of the H5N1 virus family can be traced back to 1996 when it was first discovered in a sick goose in the Guangdong province of China.

H5N1 has evolved, resulting in different genetic lineages (clades) as they mutate, similar to a typical pattern of behavior for RNA viruses such as the ever-emerging COVID-19 variants. In 2013, the H5N1 clade emerged. Since then, it has spread rapidly to nearly 100 countries across Asia, Europe, Africa, and America, becoming the most dominant clade and causing significant losses to the poultry industry.

In December 2021, this particular clade, was first identified in wild birds in the United States.

The clade quickly mixed with other circulating influenza A viruses in wild birds in North America. This resulted in viral reassortment and recombination of genes and exhibiting diverse characteristics. Many of these variants cause severe illnesses in mammals, significantly affecting their nervous system.

The Jump to Cows

The avian influenza virus, commonly called the bird flu virus, belongs to the flu virus family. Flu viruses have many natural hosts, including ducks, geese, swans, gulls, terns, waders, pigs, and horses.

Certain types of flu viruses typically infect specific hosts and do not usually jump from one host to another.

There is a wide variety of bird flu viruses, ranging from H1 to H19, but they have mostly remained in birds and animals, rarely affecting humans.

This changed with the H5N1 clade

This clade became concerning because of their frequent spillover events. A spillover event occurs when a virus from one normal host reservoir jumps into a new or different host species, for example, jumping from a bird to a horse or cattle.

Since December 2023, the highly pathogenic H5N1 clade viruses have been reported to spread in dairy cows in multiple U.S. states, according to the U.S. Department of Agriculture (USDA) and Centers for Disease Control.

From early this year, some cows have been producing less milk and eating less. It was later confirmed that the H5Nx clade viruses were present in both the cows’ milk and nasal samples. The USDA reported an outbreak in this clade in cows for the first time.

The December USDA preprint reveals that the same viral strain was found in dairy cows that have no known connection to the infected herds. This suggests that the transmission in cows has already started quietly, and asymptomatic cows likely contributed to the rapid spread of the virus.

As of May 28, there were 67 herds infected by the H5N1 virus in nine states. Despite the low number of infected herds, this could indicate that it is no longer just a spillover event, but rather a significant expansion of host tropism. The concern is when a large-scale outbreak might occur.

Furthermore, as dairy cows often live in close proximity to humans, infections in cows may also impact human health.

The Likely Jump to Humans

Although bird flu infections in humans have been rare, they can happen.

In the past 20 years, there have been sporadic human infections with the H5N1 virus. There have been 888 infected patients, resulting in 463 deaths reported across 23 countries. The majority of cases have occurred in Egypt, Indonesia, and Vietnam. These cases have resulted in a cumulative case fatality rate of more than 50 percent, based on data collected by the World Health Organization.

Since these cases are mostly scattered throughout Asia, they haven’t received much public attention in Western countries until recently.

In April 2022, a case was confirmed in a Colorado poultry worker who has since recovered. This was the first known case of H5N1 infection transmitted from poultry to a human in the United States.

The second human case in the United States didn’t occur until late March. A dairy farm worker in Texas showed symptoms of hemorrhagic conjunctivitis in both eyes and was confirmed to be infected by the H5N1 clade He had no respiratory symptoms and fully recovered within a few days.

However, this person reported no contact with sick or dead birds but had close exposure to sick dairy cows. The cows showed decreased milk production, reduced appetite, fever, and dehydration, suggesting H5N1 infection.

This was the first report in the United States of the highly pathogenic avian influenza H5N1 virus suspected of transmitting from a mammalian animal species to a human.

These cases have alerted scientists, as they suggest that the virus may have acquired the ability to spread between mammals and potentially infect humans.

If a highly pathogenic H5N1 virus were to develop the ability to spread easily among humans, including through human-to-human transmission, it could have a significant impact on the human population, given the high mortality rate observed in previous cases.

Since these are the only two confirmed U.S. cases of cow-to-human transmission, the full extent of similar infections and the mortality rate remain unknown.

The spillover from one species to another typically happens naturally through the food chain. For instance, it can happen when infected birds are eaten by another species. These events generally occur on a small scale, unlike the widespread occurrences seen in U.S. cattle.

What caused the recent jump to cows from another species? Was it a natural, random event as in the past, or were other factors involved?

Gained the Ability to Spread via Aerosols

The original avian H5N1 viruses were not easily transmissible between mammals.

About a decade ago, two virologists, Yoshihiro Kawaoka from the University of Wisconsin in Madison and Ron Fouchier of Erasmus Medical Center in the Netherlands, alarmed the world by conducting high-risk gain-of-function studies on H5N1.

The process was complex. For example, a mutant H5N1 virus was created carrying the specific gene mutation PB2 E627K. It was then passed through ferrets 10 times. After gaining a total of five mutations, the mutant H5N1 virus gained the ability to be transmitted via aerosols or respiratory droplets….

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