New H5N1 ferret study suggests higher viral shedding with current bird flu virus compared to older strains

“Interestingly, whereas in older studies A(H5) viruses . . . were never transmitted via the air between ferrets, low levels of transmission have lately been observed for recently emerged clade 2.3.4.4b A(H5) viruses isolated from a European polecat, mink and dairy cows. These observations raise concerns regarding the evolution of an A(H5N1) towards mammalian, and possibly human, adaptation.”

There has been a lot of news about some recent bird flu studies involving ferrets.  The scientific community is always on alert for new flu strains that may pose a risk to human health.  This is especially the case for bird flu.  They use studies to evaluate the level of that risk, where ferrets and other small mammals are used to test things like pathogenicity and the transmissibility of bird flu viruses.  

Ferrets have been the “go to” model for experiments involving influenza (lucky them).  This is because ferrets experience flu symptoms similar to humans.  It’s not a perfect model, but we typically don’t use human subjects for flu virus experiments.   

H5N1 was first discovered in 1996 in Hong Kong.  This “vintage” H5N1 has been the subject of countless scientific studies.  But what we have seen in the past 4 years is a very different H5N1.  Indeed, the current clade 2.3.4.4b H5N1 bird flu virus that is circulating globally, infecting dairy cows and other mammals as well as humans, is a far cry from “vintage” H5N1.  It has been around for more than two decades and, in that time, has spread widely and undergone constant change.  Like all influenza viruses, H5N1 mutates fast and some of those mutations help it adapt to new hosts.  

We are seeing this in full force today, as H5N1 has infected more species of wild birds than ever before, and more species of mammals than ever before.  No one really knows why.  Why is this version of H5N1 able to do what it has done?  How can infect so many different species of birds let alone mammals?  How has it been able to transmit through some mammalian populations? 

That’s where the studies come in: to attempt to answer these types of questions.  Transmission studies look at whether a particular H5N1 strain is able to transmit from one infected ferret in the lab to another ferret, with the results being used to inform the state of the science and public health.  In the past, if a study reported any form of transmission, however small or limited, it was big news.  It would set off alarm bells. Perhaps the most famous example of this is two ferret transmission studies published in 2012:

• In the first study, published in May 2012, a laboratory-generated H5N1 reassortment virus was found to be “capable of respiratory droplet transmission in ferrets.” 

• In the second study, published in June 2012, a genetically modified H5N1 virus was found to be “airborne-transmissible” between ferrets.  

These 2012 H5N1 studies set off alarm bells because they showed the possibility of airborne transmission of H5N1 viruses between mammals.  (They also involved modifying H5N1 viruses in the lab in order to make them more infectious and transmissible to see what would happen.  But that is beyond the scope here today, suffice to say it ignited a debate about whether that type of thing is a good idea.).

More recent studies with the current clade H5N1 viruses have shown, at least what feels like to me, to be increased transmission ability between ferrets.  For example:

• A pre-print published in April 2023, used an H5N1 clade 2.3.4.4b virus from a hawk that was naturally infected in Canada, finding this virus was “efficiently transmitted by direct contact between ferrets, resulting in lethal outcomes.” 

That is a result that gave me pause. An H5N1 of the clade currently circulating around the globe was transmitted between mammals in a lab and was highly virulent. Even the authors of the study were surprised.  And this was a year before H5N1 started infecting cows.  Indeed, this type of mammal-to-mammal transmission in the lab has only seemed to increase with the H5N1 viruses from dairy cattle:

• A CDC study published in November 2024 used the H5N1 virus from the human case in Texas.  The study found that this virus spread to 3/3 direct contact ferrets and spread by respiratory droplets to 4/6 airborne contact ferrets.  

• Another study using the same Texas human H5N1 virus, published in October 2024, found that the virus spread by respiratory droplets between ferrets.  The study examined transmission in four experiments, finding that the H5N1 virus “transmitted by respiratory droplets in 17–33% of transmission pairs” with fatal results, as “five of six exposed ferrets that became infected died.”  Tissue samples of the deceased ferrets showed high levels of virus in the respiratory system.

This brings me to a recent ferret study, published on December 2, 2024, that is getting some attention.  While not a transmission study, it focuses on H5N1 aerosols produced from infected ferrets and whether different H5N1 viruses lead to different levels of viral shedding.  The study, Influenza A(H5N1) shedding in air corresponds to transmissibility in mammals, is an interesting read.  (Of note, the main author of the June 2012 study mentioned above, Ron Fouchier, is also an author of this current study.).

In order to evaluate the potential risks to public health from the current clade of H5N1, the study was designed to measure how much an infected ferret would shed the H5N1 virus.  Ferrets were placed in cages connected to air-sampling machines meant to capture virus aerosols produced from infected animals. The underlying idea here was that “the absence of transmission observed for earlier A(H5N1) viruses was due to a lack of infectious virus shedding in the air, rather than the absence of necessary mammalian adaptation mutations.”

That’s an interesting (also alarming) thought: that H5N1 clade 2.3.4.4b viruses are somehow more easily and efficiently expelled from infected animals into the air than their “vintage” H5N1 counterparts.

This does seem to correspond with current H5N1’s ability to spread more widely and readily through different species of mammals.  It is this massive increase in mammalian infections that the authors of the study specifically point to as evidence of viral evolution, stating that such “suggests selection of viruses that transmit well in mammals.” 

So as H5N1 has continued to spread and to infect new species, it has evolved; and as it evolves, genetic adaptations that make H5N1 more fit to infect these species, including mammals, are favored.  It’s evolution in real time.  The CDC even noted that H5N1 has shown a change in its transmissibility in its November 2024 ferret study (“The observed capacity of avian influenza A(H5) virus to transmit via respiratory droplets in ferrets has not been frequently reported in the past.”). 

The evolution of H5N1 has been on my mind since it spread like wildfire through a mink farm in Spain back in 2022.  At that time, the idea of H5N1 directly transmitting mammal-to-mammal was unheard of and was approached cautiously even in the face of clear evidence from the mink farm.  It’s only been two years and we have seen much more likely transmission events.  It makes sense that this couldn’t be solely due to viral mutations and mammalian adaptations but would be a culmination of multiple different factors.  As this most recent ferret study suggests, one of these factors could be that this more “fit” H5N1 virus circulating through dairy cattle today somehow allows for greater expulsion of infectious aerosols, which would necessarily lead to higher transmission amongst mammals. 

If that is the case, there could be greater risks for all those involved closely at the cattle/human interface, most notably dairy farm workers.  The same would apply to poultry farm workers.  Indeed, the authors conclude the study as follows:

“Our results indicate that recent A(H5N1) viruses exhibit a low but increased level of infectious virus shedding into the air as compared with older A(H5N1) viruses. Given the ongoing epizootic in cattle and the high risk of exposure for farm and dairy workers and domestic and wild mammals to infected cows and contaminated milk, it is crucial for effective outbreak control and public health safety to understand how this virus spreads among cattle, its potential for mammalian adaptation and its capacity for airborne transmission.”

It will be interesting to see what further studies are done in this area.  I would love some work on what molecular features may drive this increase in virus expulsion from infected ferrets, and if there is a correlation with the known mutations that indicate bird flu adaptation to mammals.  

The fact remains that H5N1 continues to evolve.  The more opportunities there are for this virus to infect mammals, especially mammals that are in close proximity to humans (like dairy cattle), the more opportunities this bird flu virus has to adapt.  Nature is conducting her own transmission experiments.

Until next time.