A strain of the H5N1 subtype of avian influenza has been found to effectively transmit between ferrets, causing deadly illness in the mammals, according to a new pre-print study by Canadian researchers.
The study has not yet been peer-reviewed but has been submitted to the Nature Portfolio journal for review.
In the past two years, large outbreaks of the H5N1 subtype have spread across Europe and the Americas, with additional outbreaks reported across the world. In recent months, increasing numbers of mammals have been found to be infected with the virus, with mass die-offs of seals and sea lions reported in Russia and the Americas and dozens of foxes, skunks, dolphins, raccoons and cats found to be infected as well.
The researchers noted that last spring, they started to observe reassortments of the 2.3.4.4b clade of the H5N1 subtype with North American influenza A viruses in samples collected from domestic and wild birds, as well as mammals.
The researchers isolated five distinct H5N1 viruses from infected wild animals in Canada, three from birds and two from red foxes. Some of the samples included a mutation that is known to increase virulence in mammals.
One of the samples, taken from a red-tailed hawk, resulted in lethal disease and efficient transmission in ferrets, with some evidence of airborne transmission between the ferrets.
The researchers noted that these results show that H5N1 viruses could acquire adaptions through sustained transmission in mammals to spread more effectively in mammals, including humans.
Ferrets are seen as an important animal model for analyzing how viruses could affect humans as they can be infected by human influenza viruses and exhibit similar symptoms to humans.
First time H5N1 has been shown to transmit between ferrets
In past studies, H5N1 has usually not been transmitted efficiently between ferrets, although it has been shown to sometimes cause lethal illness. In the new study, the researchers infected the ferrets with the five virus samples, with only one of the ferrets surviving after infection.
Some of the most severe illness was seen in the ferrets infected with the sample from the red-tailed hawk and ferrets placed in the cages with those infected with the strain showed signs of direct transmission and severe illness, requiring euthanasia within 8-12 days after coming into contact with the originally infected ferrets. Another one of the ferrets that came into contact with a ferret infected with a sample from a red fox also showed signs of possible transmission, but it did not have an infectious virus in any tissues examined.
The researchers conducted a follow-up experiment to further examine the transmission potential of the red-tailed hawk sample in ferrets, including indirect transmission by aerosols or droplets. Four ferrets were infected with the sample and then an additional, noninfected ferret was added to each ferret's cage and a noninfected ferret was placed downwind from the directional airflow of the cage system a day later. The ferret placed downwind of each ferret was separated from the other two ferrets in the trio by a double steel mesh screen, preventing direct contact but allowing airflow.
The infected ferrets quickly developed severe symptoms, requiring euthanasia within five days of infection. Despite the quick progression of the virus, three of the four ferrets placed in the cages of the four infected ferrets were also infected. None of the four ferrets placed downwind of the other ferrets developed symptoms, but one of the ferrets did test positive on a nasal swab. The researchers ended the experiment after eight days in order to allow the collection of tissue samples at a set time point.
Further research needed on possible airborne transmission
In all four of the downwind ferrets, viral RNA was found in nasal and lung tissue samples, with the researchers stating that this showed that the animals were likely infected during the experiment, but the study was ended before significant viral replication occurred. The researchers added that this shows that additional experiments to assess the potential for airborne transmission are a priority.
The researchers stressed that while there has not as of yet been evidence of sustained transmission between mammals in the wild, the results of the study may show the potential of H5N1 to cause mammalian outbreaks. The researchers pointed to a recent H5N1 outbreak in farmed minks in Spain.
The researchers additionally noted that the virus sample isolated from the red-tailed hawk contained signs of adaptation to mammals, suggesting that the hawk may have been infected by eating mammalian carrion. Its passage through multiple species may have contributed to its enhanced transmissibility in ferrets as well.
"Our research has determined that certain, as yet uncharacterized, genetic signatures may be important determinants of mammalian adaptation and pathogenicity of these viruses," wrote the researchers in the study. "Ongoing surveillance of circulating HPAI A(H5N1) viruses across species, including humans, should be a top priority so as to promptly identify viruses that may have pandemic or outbreak potential in mammals."
'Largest-ever' outbreak of bird flu continues across Europe, Americas
The new study comes amid an ongoing outbreak of avian influenza in North and South America and Europe which began in 2021 and has been described as "the largest-ever" outbreak on both continents.
The outbreak has been widely affecting both birds and mammals. In the US alone, over 58 million poultry have been affected and 6,715 infected wild birds have been found in almost every state. In Europe, thousands of wild and domestic birds were found to be infected in over 24 countries, with many sea birds affected.
The virus has been reported in Israel as well, with the last case reported in a seagull on April 9 at Habonim, north of Zichron Ya'akov, over two months after the last recorded case, according to the Agriculture Ministry. Additional cases of the H5N1 strain were reported in January, December and November in various locations throughout Israel. The first outbreak of the season was reported at a turkey slaughterhouse in Kibbutz Shluhot in northern Israel in November.
A number of human cases have been reported among the outbreaks around the world as well, with the most recent H5N1 case in humans reported in Chile. Earlier this month, the US Centers for Disease Control and Prevention (CDC) reported that two mutations associated with adaption to mammals were found in the PB2 gene of the virus in a sample collected from a patient in Chile. The mutations have been previously detected in samples of the H7N9 subtype of avian influenza. The CDC added that these mutations are not typical of other samples of the virus circulating in birds in Chile, "strongly suggesting" that the mutations were acquired in the patient during the course of the illness.
The CDC stressed that the overall risk to human health from H5 avian influenza outbreaks remains low.
In a risk assessment published on April 24, the World Health Organization (WHO) stated that the likelihood of sustained human-to-human transmission of avian influenza remains low, although sporadic human infections in places where the virus is spreading among animals are possible.
Earlier this week, Nicola Lewis, director of the World Influenza Centre at the Francis Crick Institute, noted to The BMJ that viruses such as H5N1 could "mutate into something that then has the capability to infect an even wider host range or potentially to start to manage to sustain transmission in the mammalian host."
"I certainly think, I’m afraid to say, that future pandemics are likely inevitable," added Lewis. “I’m very concerned that we are missing the opportunity. We cannot not take this opportunity to learn what we can from the covid pandemic to make sure that we are better prepared next time. Because there will be a next time.