#18,388
Last June the CDC released a preliminary study (see CDC: Results of Ferret Transmission Studies on Texas H5N1 Virus) on the transmissibility and pathogenicity of a human isolate of the Texas `Bovine' H5N1 virus (A/Texas/37/2024) in influenza naive ferrets.
This early sample contained two mutations we've not seen in other B3.13 genotypes (PB2-E627K and PA-K142E), both of which have been linked to increased replication in mammals.
The CDC's Summary from the first report was reasonably reassuring:
- The A(H5N1) virus from the human case in Texas caused severe illness and death in ferrets. A(H5N1) infection in ferrets has been fatal in the past. This is different from what is seen with seasonal flu, which makes ferrets sick, but is not lethal.
- The A(H5N1) virus from the human case in Texas spread efficiently between ferrets in direct contact but did not spread efficiently between ferrets via respiratory droplets. This is different from what is seen with seasonal flu, which infects 100% of ferrets via respiratory droplets.
- These findings are not surprising and do not change CDC's risk assessment for most people, which is low. The results do reinforce the need for people who have exposure to infected animals to take precautions and for public health and agriculture communities to continue to work together to prevent the spread of the virus to additional dairy herds and people.
This week the Journal Nature published two concerning studies on H5N1 in ferrets.
The first, which I covered in Nature: A Human Isolate of Bovine H5N1 is Transmissible and Lethal in Animal Models, found the virus was lethal in mice and ferrets, and that it `. . .could be transmitted through the air between separated ferrets and might be capable of binding to and replicating in human respiratory tract cells.'
A second study, which repeats the animals experiments described last June, was titled:
Transmission of a human isolate of clade 2.3.4.4b A(H5N1) virus in ferrets
Yesterday the CDC published a summary of findings from this repeated research which provides additional details and somewhat different results (e.g. 66% droplet transmission between ferrets vs. 33% in the original report).
I've reproduced their summary below (bolding mine). I'll have a brief postscript after the break.
CDC Reports Additional Avian Influenza A(H5N1) Ferret Study Results
WHAT TO KNOW
The results of CDC's first study looking at the effects on ferrets of an avian influenza A(H5N1) virus from a human case in Texas have been published in Nature. CDC first shared preliminary findings from this study, which were instrumental in informing early risk assessments related to this outbreak, in June 2024. Ferrets are used as a model to assess the disease and spread characteristics of specific influenza (flu) viruses in people.
The initial study was subsequently replicated to confirm the findings, and this publication summarizes all the findings from the ferret experiments using the isolate from the case human case in Texas. Results of subsequent similar studies using different viruses from the same outbreak have differed.
Summary of cumulative findings
These ferret study findings are now available in the peer reviewed literature in Nature.
The study used an avian influenza A(H5N1) virus from the first human case associated with the current outbreak in U.S. dairy cattle and poultry, which occurred in Texas (A/Texas/37/2024).
That virus caused severe illness and death in 100% of infected ferrets causing more severe disease compared to other avian influenza A(H5N1) viruses in the same genetic group isolated prior to the 2024 dairy cow outbreaks. This also is different from what is seen with seasonal influenza viruses, which make ferrets sick, but are not fatal to ferrets.
The A/Texas/37/2024 virus spread efficiently between ferrets in direct contact (100%) but did not spread efficiently between ferrets via respiratory droplets (i.e., droplets containing virus released into the air from coughs or sneezes) or by fomites (i.e., contaminated surfaces) (66%). This is different from what is seen with seasonal influenza viruses, which do spread efficiently via respiratory droplets and fomites in ferrets (100%).
Results from this ferret study helped inform CDC's early risk assessments of the potential impact of these viruses on human health.
The results suggest this virus has the potential to cause severe illness in people and reinforce the importance of protective measures among people with exposure to infected animals and for public health and agriculture communities to continue to work together to contain this outbreak.
The preliminary results of this study reported in June 2024, are available at CDC Reports A(H5N1) Ferret Study Results | Bird Flu | CDC.
CDC researchers used a ferret model 1 to better understand the severity of illness and efficiency of transmission of A/Texas/37/2024, the avian influenza A(H5N1) virus isolated from a sick dairy cow worker in Texas on April 1, 2024. This was the first human case associated with the ongoing multistate outbreak of H5 bird flu among dairy cows and poultry. CDC researchers subsequently repeated parts of the study using additional animals to confirm the findings. (Like humans, different ferrets can respond differently to infection, and some ferrets may spread more virus than others. This is why a series of experiments are conducted and the results are combined.)
Severity of Disease
Similar to the preliminary results in six ferrets, all six infected ferrets in confirmatory testing experienced severe disease and died, highlighting the potential for this virus to cause severe disease in humans. The results are consistent with findings from other studies of ferrets infected with avian influenza A(H5N1) viruses, including two published studies conducted during the past year. Ferrets infected with avian influenza A(H5N1) viruses from mink in Spain (A/mink/Spain/3691-8_22VIR10586-10/2022) and from a person in Chile (A/Chile/25945/2023) had severe illness that was either fatal or required euthanasia.
However, subsequent studies at CDC using A(H5N1) viruses from Michigan, have differed, with ferrets experiencing milder illness. None of the ferrets infected with the A/Michigan/90/2024 virus died or had to be euthanized because of severe illness.
Spread via Direct Contact
The initial study found that the A/Texas/37/2024 virus spread easily among ferrets (3 of 3 ferrets, or 100%) in direct contact with infected ferrets placed in the same enclosure.
Spread via Respiratory Droplets
The virus was less capable of spreading by respiratory droplets compared to seasonal influenza viruses. This was tested by placing infected ferrets in enclosures next to healthy ferrets (with shared air but without direct contact). In that situation, 4 of 6 ferrets (66%) became infected, and there was a one- or two-day delay in transmission with the A/Texas/37/2024 virus compared to transmission with seasonal influenza viruses. 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 last time this level of transmission was observed was a ferret study done on A/Hong Kong/486/97, an avian influenza A(H5N1) virus isolated from a human in 1997. That study also found respiratory droplet spread occurred in 2 of the 3 ferrets (66%). The older 1997 avian influenza A(H5N1) virus did not result in efficient spread among people, and person-to-person spread has not been observed with avian influenza A(H5N1) viruses since 2007. This suggests that A/Texas/37/2024-like viruses would need to undergo changes to spread efficiently by droplets through the air, such as from coughs and sneezes like in the way seasonal influenza viruses spread.
Spread via Fomites
These ferret experiments also tested the ability of the virus to spread in a fomite transmission model (contaminated surfaces). When healthy ferrets were placed in a contaminated cage (with contaminated bedding, food, water, etc.), 1 out of 3 became infected. With a seasonal influenza virus, 3 out of 3 ferrets were positive in the fomite transmission model.
Exhaled Virus Measurements
The ferret experiments also measured the amount of virus exhaled from infected ferrets into the air. Ferrets infected with A/Texas/37/2004 exhaled comparatively more virus into the air than was observed with A/Michigan/90/2024 and A/Chile/25945/2023.
Genetic Characteristics of the Virus
The A/Texas/37/2024 virus is a genetic outlier of this group of avian influenza A(H5N1) viruses. It has two mammalian adaptive mutations not seen in the other A(H5N1) viruses that have been genetically sequenced in association with the current outbreak in dairy cows. Sequencing showed changes in two polymerase proteins, the PB2 gene at position E627K and the PA gene at position K142E:
- The polymerase PB2 E627K mutation has been previously identified to cause greater virus replication in mammals and more severe disease.
- The polymerase PA K142E gene change has been previously associated with enhanced virulence in mammalian hosts when combined with the PB2-627 mutation.
Changes like those seen in the A/Texas/37/2024 virus may help the virus replicate better in mammals and humans. The results of these experiments were used to inform an ongoing, broader CDC-led influenza risk assessment (IRAT) on A/Texas/37/2024.
Limitations of ferret experiments
For decades, CDC has conducted these types of studies to inform risk assessments of influenza viruses with pandemic potential. The use of robust and genetically diverse animal models as subjects is preferred in many areas of research. The ferrets used in our studies are outbred (bred to have genetic diversity) animals whose response to influenza virus infection is generally very similar to that of humans; therefore, it is expected that there will be some variability in disease outcomes and immune responses. This is why the experiments were repeated. The major benefit of using an outbred ferret model is that it better mimics the human population, which is genetically diverse. The conclusions obtained from studies using outbred animal models are more representative and generalizable across different experimental conditions and populations. Even as a well-documented and commonly used research model for human illness and transmission, there are limitations to ferret experiments.Conclusion and risk assessment
- Animals did not possess any antibodies to influenza A virus before infection, so this does not capture any potential/unknown contributions of pre-existing immunity that may be present in human populations at large.
- Ferrets in this study were deliberately administered a large quantity of virus. While the virus is transmitted in the respiratory droplet model when administered in a large quantity, it's unclear whether similar transmission levels would be observed following lower amounts of virus.
- The conclusions obtained from studies using outbred animal models are more representative and generalizable across different experimental conditions and populations.
- The number of animals used in the studies could be considered a limitation; however, CDC researchers comply with the 3Rs (Replace, Reduce, Refine) principles that govern ethical and humane animal research. Therefore, CDC studies use only the smallest possible number of animals necessary to meet research goals.
Overall, the cumulative results of studies in ferrets using the A(H5N1) virus from a human case in Texas suggest the virus still is not capable of spreading efficiently among people via respiratory droplets compared to seasonal influenza viruses. These findings highlight the importance of continued surveillance to monitor these kinds of changes in circulating A(H5N1) viruses. More information on ferret studies is available at CDC Reports A(H5N1) Ferret Study Results | Bird Flu | CDC.
This updated report, along with the findings from the other Nature study this week, paint a picture of an H5N1 virus better adapted than what we've seen reported from other states. This first Texas case is admittedly a bit of an outlier, in that the PB2-E627K and PA-K142E mutations have not been reported since.
Nothing says they couldn't turn up tomorrow in another case, but for now (as far as we know) this tag-team of mutations has not been repeated.
But every time the virus infects a new host (avian or mammalian) it has another opportunity to toss the genetic dice - and the more chances we allow it - the greater the chances are it will come up a winner.
Which is why - even though it may be presenting as a mild illness in humans today - we can't assume it will remain mild forever.
