200530 covid research

The virus detectives: ferrets help in a pandemic

About an hour southwest of Melbourne on the Geelong waterfront sits a CSIRO facility that houses one of only a few Physical Containment Level 4 (PC4) labs in the world, and the only one in the Southern Hemisphere.

This is the Australian Centre for Disease Preparedness (ACDP). It’s where some of the most dangerous infectious agents on the planet are studied.

And to do that, says the centre’s director, Trevor Drew, you often need ferrets.

It happens that ferrets are susceptible to a wide range of RNA viruses that are also harmful to humans, including influenza, Nipah, Ebola and SARS. Now, one more could be added to that list. From the moment the first genome sequence was released, it was clear that SARS-CoV-2 had a lot in common with the original SARS virus, including the tools it uses to enter human cells.

Trevor Drew

From research on SARS, says Drew, “we knew which receptor it needed in order to gain access to cells”. The little protein stalks sticking out of it, called spike proteins, “actually attach onto a cellular receptor called ACE2. [The virus] then uses that as a sort of a key to unlock the cell membrane and get into the cell.”

SARS-CoV-2 has the same spike protein and, like SARS, it goes straight for ACE2 receptors found on many cells in the human body, including cells lining the respiratory system. In fact, it binds much more tightly than the SARS version did, which makes it more infectious.

Ferrets, it turns out, also have the ACE2 receptor on their cells, and it’s remarkably similar to the human version. The CSIRO team was the first in the world to demonstrate that ferrets could be infected with SARS-CoV-2, but don’t get severe COVID-19 – just a slight rise in body temperature and a bit of sneezing. “They recover quite quickly,” says Drew.

Nevertheless, for a few days the ferrets excrete the virus, so it’s clearly replicating in their systems.

“The first thing to do is to thoroughly define that course of infection in fine detail and also understand something of how the ferret responds,” says Drew. “What is the first reaction to the infection? What parts of the immune system respond and in what way? And how, ultimately, does the ferret, in this case, get rid of the virus?”

Once upon a time you needed a virus sample before vaccine development could begin, Drew explains. “Nowadays we don’t even need the virus, we just need to know what its genomic sequence is.”

What is the first reaction to the infection? What parts of the immune system respond and in what way? 

The moment the first SARS-CoV-2 genome sequence was published, numerous vaccine development projects were launched around the world. That’s a good thing, as long as it’s well coordinated. This, says Drew, is where the Coalition for Epidemic Preparedness Innovations (CEPI) has been valuable.

A partnership of public, private and philanthropic organisations – drawing funding from the Bill and Melinda Gates Foundation, Wellcome, and various international governments, private businesses and individuals – CEPI’s goal is to accelerate the development of vaccines against emerging infectious diseases, including the so-called “big one”.

“We called it Disease X at the time,” says Drew, because when CEPI was launched in 2017, no-one really knew what the next pandemic pathogen would be. Regardless, it would certainly require a coordinated response at well-known points along the vaccine development pathway: from design and testing, all the way to clinical trials, large-scale manufacture, and distribution.

In a move that Drew calls “prescient”, CEPI has been funding facilities around the world to make ready these capabilities. When SARS-CoV-2 showed up, things were able to move quickly. Vaccine experts at CEPI and WHO analysed numerous vaccine development projects and chose several of the most promising to pursue. These included projects at Oxford University and the University of Queensland, and those at a handful of biotech companies.

ACDP was given the task of running pre-clinical trials on vaccine candidates from two of them. Normally the preclinical phase entirely precedes clinical trials, but these are unusual times. Both the Oxford and Inovio vaccines have simultaneously entered Phase 1 human trials elsewhere to test for tolerability in humans while preclinical work continues at ACDP.

“I would say almost without a doubt it’s the most heavily studied virus at the molecular level in the history of science,” says Drew. “It’s been a phenomenal example of international collaboration.”

This is an extract from The Virus Detectives, the cover story in the upcoming issue of Cosmos magazine, out on 4 June 2020. It is one of two major features looking at the massive international effort to understand and thwart the spread of COVID-19. You can subscribe to Cosmos online here.

The Australian Centre for Disease Preparedness in Geelong. Credit: CSIRO

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