How Ferrets Are Helping Researchers Battle Covid-19

They are adorable animals with little furry faces, and they’re playful and cuddly. But ferrets can catch and spread disease to humans, which is one reason many jurisdictions in the U.S. have banned them as pets.

In an infectious disease lab, however, that same viral vulnerability can make the common ferret an asset — perhaps now more than ever. In the worldwide race to develop treatments and vaccines for Covid-19, researchers need animals in which to observe the illness and challenge it with interventions. And it turns out that ferrets are vulnerable to the same respiratory infections that impact humans — including SARS-CoV-2, the virus that causes Covid-19. A study published earlier this month concluded that ferrets can carry and pass on the disease, and get sick with it as well, developing fevers and losing their appetites.

“They are a great animal model for human respiratory viruses,” said Alyson Kelvin, assistant professor in the division of infectious diseases in the department of pediatrics at Dalhousie University in Halifax, Nova Scotia.

This now has ferrets at the center of lab work around the globe. The animals are being used, for example, in two pre-clinical trials run by the Commonwealth Scientific and Industrial Research Organization (CSIRO) in Australia, the group that first identified ferrets as able to contract and be sickened by the novel coronavirus back in February. A $2.4 million project to develop ferrets as a model for studying Ebola, funded by the Food and Drug Administration and outsourced to Public Health England, has also been recently updated to look at ferrets and this novel coronavirus, for an additional $250,000.

Of course, some researchers are testing potential vaccines directly in humans, though that’s not the norm. “You need to have an animal model to test your hypothesis,” Kelvin said.

That obligation often goes to mice — the most familiar and widely used animal in research — and they are fundamental to coronavirus research, too, though they must first be genetically modified to be susceptible to Covid-19. (Research has also shown that cats can be susceptible to this novel coronavirus, and other studies have identified monkeys and hamsters as potentially useful models, too.)

For all the utility of mice, however, ferrets also have a long and often overlooked history as a research animal, and it’s little wonder that the creatures are now being drafted to help combat SARS-CoV-2. Volker Gerdts, director and CEO of the Vaccine and Infectious Disease Organization — International Vaccine Center (VIDO-InterVac) lab at the University of Saskatchewan, noted that as soon as the first genetic sequence for the virus was released back in January, it looked like ferrets would serve as an apt model. “The receptor that is used for the virus to enter the cells in ferrets,” Gerdts said, it is “closely related to humans.”

Working alongside Kelvin and others, Gerdts and his team have some 260 ferrets in the Saskatchewan lab, where they are being used to test two potential vaccines and to track levels of viral shedding, among other studies. Kelvin is heading up a study to understand why some ferrets — and by extrapolation, some people — get severely ill with Covid-19, while for others it remains relatively mild, or even asymptomatic. She also expects to look at the virus’ impact on ferrets of different ages soon. “We are doing a lot of work with them,” says Gerdts.

Ferrets have been on the radar as an animal model for nearly a hundred years, when researchers first discovered that they can get the flu, and pass it on to other ferrets. A study published in the July 8, 1933 edition of The Lancet followed up on that year’s influenza epidemic, giving the illness on to two ferrets using “throat washings” from people. They observed that the animals got sick on the third day and could pass it on to other ferrets by direct contact or nasal washings given from a sick animal to an uninfected one. “The ferret disease is characterized by a two-day incubation period, a diphasic temperature response, symptoms of nasal catarrh [discharge], and variable systemic disturbances,” study authors wrote. The ferrets developed temperatures, seemed lethargic, lost their appetites, and wheezed. After getting the flu, they showed immunity to getting the same strain again.

Thus, an animal model was born. Ferrets were used in influenza studies throughout the following several decades. In particular, they were used during the SARS outbreak, starting in 2002, to hunt for treatments and a vaccine. And in recent years they’ve been used to continue to study influenza, particularly H5N1 and H1N1, but also Ebola.

Related

Pain in Lab Animals: How Much Is Too Much?

Ferrets are also used to study cystic fibrosis and lung cancer, because their respiratory tracts resemble those of humans, and as an animal model for heart disease and spinal cord injuries. They serve as a good model for understand drug validation and toxicity as well. Ferrets share many neurological similarities with humans, so they’re used to study brain conditions, including strokes and epilepsy. In fact, researchers have created transgenic ferrets, which means they’ve altered some of their genes, to study neurological conditions.

Respiratory illnesses in ferrets resemble those in humans because they have a similarly proportioned respiratory tract, with relatively large lungs compared to the rest of their body. (Mice, for instance, don’t: They have tiny lungs in a short torso.) Kelvin says that like humans, they have five lung lobes and branched-out airways in their lungs, and a comparable distribution of receptors that viruses bind to in their upper and lower respiratory tracts. They cough and sneeze and pass on their respiratory illnesses to nearby ferrets, mimicking human modes of transmission.

Importantly, their immune systems have similarities to ours, and they offer a good model for studying vaccines. Kelvin was a co-author on a 2013 study, for instance, that detailed how ferrets become infected with influenza. Research conducted by a graduate student under Bianca Mothé, a professor of biological sciences at California State University San Marcos, has looked at ferrets’ major histocompatibility complex (MHC) genes, which help the immune system recognize foreign invaders, and found they have a predictable response to respiratory pathogens. (The research has not yet been published.)

Gerdts says ferrets are cheaper and easier to work with than nonhuman primates, and researchers can test their full arsenal of potential treatments on them. “They’re the only model that allow you to stream many different candidates, whether it’s antivirals, therapeutics, or vaccines.” Because they live to be as old as eight in a lab setting, meanwhile, Kelvin has been able to develop age models for influenza and ferrets, to understand how it affects babies up to seniors, and expects to transfer this approach to SARS-CoV-2.

Like every animal model, ferrets have limitations. Thomas Geisbert, a professor of microbiology and immunology at the University of Texas Medical Branch at Galveston, who’s worked with ferrets to study illnesses such as the Ebola virus, says, “They can be difficult to work with because you don’t have as many reagents as you do for mice or monkeys.” Reagents are lab substances that help scientists detect biomarkers.

Kelvin often makes her own reagents. That’s time-consuming, as are other tasks related to working with ferrets: They’re bigger than mice and hamsters, so it’s more expensive to buy and care for them. Mothé says keeping ferrets healthy in an infectious disease lab poses a challenge. “These animals tend to be social and want to burrow,” she said. “Yet, for these studies, they need to be isolated and not close to each other to not infect each other.” A study published in ILAR Journal states it plainly: “Ferrets should be housed in groups or in pairs, and solitary housing should be avoided.”

Thoughts or questions on Covid-19? See our full coverage, or email us at [email protected].

Gerdts says his lab may look at working with cats soon — they use them for other illnesses. A Clinical Infectious Disease study from late March highlights the value of hamsters for researching SARS-CoV-2. They become unwell and it affects their airways. Geisbert suspects using hamsters in large numbers could help, for instance, to quickly identify the most effective antibodies derived from the blood plasma of people who have recovered from Covid-19. “You could screen through hundreds of these things and figure out which are the best ones before you start putting them in monkeys,” he says.

Geisbert calls nonhuman primates such as monkeys the “gold standard” for this kind of research. But Gerdts and Kelvin also think ferrets might offer researchers enough information to be able to skip monkey studies and move directly to human testing by the fall.

“I don’t want to say they’re perfect,” Kelvin said of ferrets. “But they’re the best model that we have.”