Rapid response

As most of us were blithely welcoming the new year of 2020, word was just starting to get out in medical and scientific circles. A virus that had never been seen before in humans was making an alarming number of people in Wuhan, China, desperately ill with pneumonia.

Soon the worst was confirmed: the new virus was exceptionally virulent and contagious, spreading quickly within China, then to other countries. Nowhere was safe.

Within weeks, the genome of the SARS-CoV-2 virus, which causes COVID‑19, had been sequenced and shared online, launching an unprecedented worldwide co-operative effort among scientists, public health officials and health-care workers, all focused on stopping the virus's deadly progress.

At the U of A's Li Ka Shing Institute of Virology, researchers were paying attention. They had been preparing for this moment.

Ready to pivot

The Li Ka Shing Institute was formed in 2010, bringing together top researchers to tackle the world's deadliest scourges: infectious diseases like hepatitis, human immunodeficiency virus, Ebola and coronaviruses. They knew the next one could be the big one - a pandemic that would bring the world to a halt.

But they had never seen anything quite so vicious as COVID‑19.

When virologist Michael Houghton first heard about COVID‑19, he thought it might be like the SARS epidemic of 2003. "You know, SARS was a major problem but it went away quite quickly," he says. "Of course, I and everyone else soon realized this is much worse than SARS."

Which is why, once the genome was public, Houghton and many others at the Li Ka Shing Institute jumped straight to work brainstorming new ideas and re-examining old ones, pivoting to focus their expertise and laboratories on the novel coronavirus. Over the course of a weekend, federal officials reviewed research proposals - record time in the world of scientific funding - and in early March, five U of A projects received federal dollars and the green light. Before the end of the month, 11 U of A projects were awarded a total of $5.8 million by the Canadian government's rapid response fund for COVID‑19 research, the highest number of funded projects at a Canadian institution. Philanthropists saw the need, too: soon after the pandemic began, one anonymous donor stepped forward with a $100,000 investment in promising COVID‑19 research across the university.

Across faculties and disciplines, researchers and others have responded, ready to apply their expertise in any way they can.

Among them are some of the world's foremost experts, who are hunting for three important weapons against COVID‑19: tests, treatment and, of course, the Holy Grail - a targeted vaccine.

Quest for a vaccine

Here is the traditional approach to making a vaccine. First, grow the virus in a cell culture. Next, purify it, then chemically inactivate it and, finally, inoculate people. Those people will now produce antibodies that, when exposed to the active virus, help shut down any potential infection and prevent disease. The downside? This approach requires a very large biohazard manufacturing facility, which we don't have in Canada.

Another common method involves weakening the virus before inoculation. This is the type of vaccine given routinely to Canadian children to prevent diseases such as measles, mumps and chicken pox. But it can take a long time to develop a safe version - a big risk when there is no approved treatment for COVID‑19.

And time is something we don't have.

That's why many of the COVID‑19 vaccine projects underway around the world are taking new tacks to produce effective antibodies. Some will isolate and inject a nucleic acid (DNA or RNA) from the virus in order to trick the body into mounting an immune response even though the whole virus isn't present. Others will use a harmless, defective "vector virus" that acts as a delivery vehicle for the surface spike protein of the coronavirus - again tricking the body into creating antibodies against just part of the virus.

Houghton is taking his own approach, which his many years of experience tell him is the best way to produce viral antibodies. And he knows a thing or two about infectious diseases. He is the co‑discoverer of the hepatitis C virus. In collaboration with Lorne Tyrrell, '64 BSc, '68 MD, founding director of the Li Ka Shing Institute, Houghton developed a hepatitis C vaccine that is headed for clinical trials next year.

"We can save time by transferring the technology we developed for the hepatitis C vaccine into the COVID research," Houghton says.

Their approach is to make the sticky spike proteins themselves. These are the "awesome-looking mushrooms" on the virus's surface, Houghton says, as seen in many illustrations of COVID‑19. When viewed on an electron micrograph, they look like a halo or "corona" around the virus, hence the name "coronavirus."

Houghton used the same "subunit protein" method to find a prototype vaccine during the SARS epidemic, when he was working for a pharmaceutical company in the United States. The vaccine was shown to produce protective antibodies to the SARS virus, which would have prevented infection.

While a SARS vaccine wouldn't have been a perfect fit against COVID‑19, Houghton believes there are enough similarities between the two viruses that it would have at least slowed the current pandemic down. But when SARS faded thanks to public health measures, the $150 million needed to develop a new vaccine just wasn't worth it with only private sector funding, he says.

The good news is that the previous research is providing a foundation for the work today - work that could help the world rein in COVID‑19.

Promising results for treatment

It could take anywhere from six months to two years to create, test, make and begin to distribute vaccines against SARS-CoV-2, and that's if we can find one. So researchers are searching for treatments to help reduce the impact of the virus in those who get sick.

It may seem strange, but some of the most promising weapons against the new virus are drugs that were developed to bring down past scourges. One of these is a drug called remdesivir, which you've likely heard about in the news. Made by the U.S. pharmaceutical giant Gilead, the drug was first tested to treat Ebola, a virus that causes a horrifying death by internal bleeding in up to 50 per cent of patients. During the most recent Ebola outbreak in 2019, remdesivir proved to be less effective than two other treatments.

But when COVID‑19 emerged, a research team at the U of A that was already studying how remdesivir worked wondered whether it had potential against SARS-CoV-2. The fact that remdesivir has already been used in humans gives it a huge advantage over anything that might be developed from scratch during the pressure-cooker time frame of a pandemic.

Matthias Götte, chair of the U of A's Department of Medical Microbiology and Immunology and an expert in HIV and hepatitis C, retooled his lab a couple of years ago to study the World Health Organization's list of top pathogens likely to cause severe outbreaks, including coronaviruses.

Götte's lab is focused on viral polymerases, which are key enzymes involved in the replication mechanism of viruses. Polymerases are kind of like the engines of a virus: if they're not in working order or given the right fuel, the virus can't go anywhere in the body.

The lab last year showed how remdesivir, a polymerase inhibitor, works on Ebola. A fast-tracked paper in late February then showed how the drug works against SARS and MERS. By April, after COVID‑19 reared its head, the team had shown remdesivir also works against SARS-CoV-2.

Remdesivir shows enough promise as a treatment that clinical trials are already underway around the world. One randomized trial has announced the drug reduced recovery time from 15 to 11 days. Based on this data, the U.S. Food and Drug Administration (FDA) gave emergency use authorization in May, making remdesivir the first treatment to be made available, even though it's not officially approved.

And that means that Götte's work on remdesivir is done. He is what's known as a bench scientist - a researcher who works in the lab - so while others take up the torch on remdesivir and clinical trials, he is back at the lab bench, starting to test other potential antiviral agents.

One of the reasons research like Götte's could move so quickly is that he started the groundwork years ago. That's the thing about research: a success in the lab is anything that can be proven or recreated, no matter how seemingly small to the layperson. Results don't necessarily mean cures for disease, but every confirmation or discovery adds up - and it often lays the path toward something else. The work happening now on COVID‑19 wouldn't be possible without all the work that went before.

Building on past research

Other U of A researchers are also dusting off and revisiting past work in the hunt for a treatment.

Biochemist Joanne Lemieux, who usually works on proteases involved in diseases such as Parkinson's and urinary tract infections, is building on research first done at the U of A during the 2003 SARS epidemic. A team of researchers studied a mechanism that stopped the virus from replicating, using compounds known as protease inhibitors. The approach was never developed into a drug, but veterinary scientists have since used it to treat and cure a virus that causes fatal peritonitis in cats.

Like polymerases, proteases are involved in the replication of a virus when it infects a body, in this case helping to cut the viral proteins into pieces so they can reproduce, kind of like scissors. Proteases are key to many body functions and are common targets for drugs to treat everything from high blood pressure to cancer and HIV.

Lemieux, Tyrrell and chemist John Vederas combined their labs' efforts to test the SARS protease inhibitor against the COVID‑19 virus. Within a couple of months, they discovered the feline drug does inhibit the SARS-CoV-2 virus from replicating in cells. They hope to take the drug to clinical trials as soon as possible.

"Our lab worked as fast as we could to get our results out," says Lemieux. "We did not take weekends. The days of the week blurred."

The non-stop work can take its toll, but Lemieux says it's worth it. Despite the impediments of physical distancing on her lab's day-to-day work - cumbersome personal protective equipment and staggered shifts - and the fact that she leaves her scientist husband behind to work from home and home-school their three children, Lemieux says she's proud to add her expertise to the anti-COVID‑19 effort.

"My kids are excited about it, too. They say 'Go to work, Mom, we want you to get this done.' "

Advising the community

Lynora Saxinger finds herself checking the online editions of medical journals before she goes to bed each night, just to be sure she hasn't missed anything new. The associate professor of infectious diseases has become an almost-nightly feature on CBC News and other media ever since COVID‑19 restrictions began, doing her best to explain the latest developments in layperson's terms. She is the epitome of calm, clear authority in the face of constantly shifting science.

Saxinger acknowledges it can be frustrating and confusing for the public to try to keep up with changing messages from health officials. "That's why I decided when this thing started that I was going to be accessible to answer questions, as we need to work together and trust each other right now," she says. "That puts me in the uncomfortable position of looking like I want to be a TV doctor, which I don't - I can't even watch myself!"

The audience responds to Saxinger's quiet assurance, and so do the public health experts who are shaping Alberta's response to the pandemic. Saxinger was tapped to co‑chair Alberta Health Services' Scientific Advisory Group on COVID‑19, which reviews and assesses the new medical information coming in daily from around the world.

The science of COVID‑19 is a moving target, which is why the public sometimes hears new directions from health officials or sees very different takes on the same topic, and why Saxinger will continue to explain the nuances of COVID‑19 rather than making definitive statements. "The biggest red flag for me is when someone says something that is certain with COVID." Saxinger laughs. "I'm like, 'OK, I don't trust you now.' You just can't say anything with certainty when it comes to this virus."

Many U of A experts are applying their knowledge to help deploy health-care resources, even as that knowledge changes daily.

Stephanie Smith is ensuring that health-care workers know how to protect themselves and their patients from the virus. In normal times, Smith - as director of infection prevention and control for the University of Alberta Hospital and Mazankowski Heart Institute in Edmonton - devotes about 30 per cent of her time to infection control. "Now I'm pretty much doing infection control 120 per cent of the time," says Smith, who is also an associate professor of medicine at the U of A. All the while, she continues to see patients remotely and to conduct research. "The attention to detail that is necessary in this situation, where we have no immunity, is unprecedented," says Smith.

Like Saxinger, Smith advises public health officials daily - in her case, the Public Health Agency of Canada - interpreting the latest knowledge about how the virus is spread and the most appropriate protective gear and systems to prevent it. She also oversees local patients enrolled in the worldwide clinical trials for treatments. She knows hopes are high for all the trials but cautions we must be careful as studies come out fast and furious from all over the world. "The methodology in some is not quite as rigorous as we would like, so we have to be really careful about drawing definitive conclusions based on these studies."

What's next?

As we contemplate the reopening of business and society - and possibly a new round of restrictions - so many questions linger about the virus and how it will behave. For the foreseeable future, public health officials will continue to hold the key to where we can go, whom we can spend time with, how we behave. We're told that life will never be the same post-COVID‑19. It's certain to change in ways we can't even anticipate.

Helping us navigate this future will be a host of U of A researchers and experts, who will continue to seek and share knowledge, comment, guide and participate in the public discussion about how to move forward in a safe, fair and humane manner.

Perhaps near the top of that list will be Carole Estabrooks, '87 MN, '97 PhD, a U of A nursing professor whose work will help us understand why the pandemic took hold so fiercely in Canada's long-term care homes, where nearly 80 per cent of all deaths have occurred.

Estabrooks, the Canada Research Chair in Knowledge Translation, is calling for co-ordinated national and provincial reviews of nursing homes. She's asking for facility upgrades, better training and equipment, more support for families, and improved working conditions for nursing home staff, who are at the bottom of the ladder in terms of pay, benefits and status within the health-care system. She wants nursing homes to be places where quality of life is primary. "[The elderly] have no voice, they're frail, they have dementia," she says. "But these people built this country, so it seems to me that since we're all going to be there [one day], we might want to think differently and use this tragic pandemic to make fundamental and lasting changes."

The forward-looking research taking place now is broad and deep. Across the U of A, scholars are digging into topics like how being stuck at home is affecting the movement of toddlers and preschoolers, how to combat misinformation around the origins and treatments of the virus, the impact of COVID‑19 on pregnant women, and the stigmatizing of people of East Asian descent.

As for Houghton, he's hopeful the world will be much better prepared next time a virus runs rampant. And that we will learn from what we did - or didn't do - after past major virus infections.

It was the work of Houghton and his colleagues, remember, that back in 2003 found a vaccine shown to produce protective antibodies to the SARS virus. But when the SARS threat faded, so did the will to fund development of a vaccine.

This time, it has to be different.

"[In 2003] the governments of the world should have said, 'We will fund you to make a stockpile,' " Houghton says. "Not enough to give to everyone in every country, but enough so that if a related virus outbreak occurs, we'd have enough stockpiled to give it to the first responders, the vulnerable elderly in long-term care homes, the relatives of those infected to stop familial transmission and so on."

He predicts this isn't the last time we'll have to respond to the threat of a pandemic.

"When you look back at infectious disease over the past 30, 40 years, it's apparent that every few years we will be under major threat from virus infection. Thanks to the hard lessons learned from COVID‑19, we will be able to respond faster and better."

Götte agrees. He revels in the remarkable co-operation that COVID‑19 has created among scientists and public health officials around the world, and he's hopeful it will continue. "It is a highly collaborative international scientific environment right now and that's a good thing," he says. "It helps to explain the incredible pace of research.

"It's very clear that there will be a lot of support to cross the finish line to find treatments and vaccines this time."

 - with files from Michael Brown