2 years into the pandemic, burning questions remain about COVID-19 and how we fight it

In early 2020, as Dr. Samira Mubareka was following global updates on a strange new virus first reported in China, people with pneumonia-like symptoms started showing up in her hospital in Toronto.

One of the patients that came to Sunnybrook Health Sciences Centre wasa man who'd travelled back from Wuhan. He was quite sick more so than others who'd proven to be false alarms, Mubareka thought.

Inside Sunnybrook a stately, sprawling hospital campus in one of Toronto's toniest neighbourhoods a newly developed diagnostic test confirmed what she and others suspected: the man had Canada's first official case of what's now known as COVID-19.

"The fact that it came as early as January, it lit a fire," Mubareka later recalled.

While dressed in full protective gear, the microbiologist and infectious diseases specialist took samples from the patient's isolation room. Her team was then able to culture the virus from several specimens inside a Level 3 containment facility just one piece of the global effort to better understand SARS-CoV-2.

Not long after, on March 11, 2020, the World Health Organization declared a global pandemic. One day later, Mubareka's team officially announced they'd isolated the virus behind it, joining other global scientists in offering hope that the world would be able to develop vaccines and treatments.

"Since then, we've just been following the virus around, whether it's been variants of concern that have emerged in fairly rapid sequence, and finally following it into animals," Mubareka said.

Two years into a pandemic that's still raging around much of the globe, scientists like her are striving to unpack what makes this mysterious pathogen tick. Leading vaccines have proven remarkably effective at keeping severe disease at bay, yet SARS-CoV-2 remains a formidable foe a mutating shapeshifter that's evading our defencesand capable of spreading at rapid rates rarely seen among other viruses.

Despite a surge in research, leading Canadian virologistsand front-line physicianssay burning questions remain over how the coronavirus operates and where this pandemic is heading.

Why are certain people so susceptible to infection, or serious illness? How will this virus continue to evolve? Which vaccines, drugsand public health strategies will protect our population from future variants? And where will SARS-CoV-2 show up next?

"There are just so many things we have to stay on top of," Mubareka said.

Why does SARS-CoV-2 cause such a range of health impacts?

Two years' worth of research into SARS-CoV-2 has painted an alarming picture of its uncanny ability to impact whole-body health. Studies have linked infections to a host of multi-organ issues, impacting everything from the brain to the gut to the heart, along with the entire circulatory system that pumps blood through your body.

Amid all the dire possible impacts, questions remain over why some people wind up with barely a sniffle, while others are ravaged by COVID-19.

Dr. Srinivas Murthy, a researcher on childhood infections and an associate professor in the University of British Columbia's faculty of medicine, said that aside from whether someone is vaccinated or not, being elderly remains the clearest predictor of someone's potential for severe COVID.

"Nothing impacts how you do with this virus more than age," he said. "That's corrected for how sick you are, how many comorbidities you have, and so on."

But it's not yet clear why this trend is seen at a staggering level beyond other viruses, which typically impact very young children to the same degree, he noted.

There are early signals that genetic differences might help explain why some people get hit so much harder than others, with one recent paper finding more than a dozen markers in those who developed severe COVID-19 paving the way, potentially, for targeted treatments.

Then there's long COVID cases where people get over their initial infection but suffer lasting post-viral impacts, from cognitive difficulties to extreme fatigue. Those reactions seem to strike people more broadly, yet the condition remains little understood, with no known cure.

What's the future for COVID-19 vaccines and treatments?

Humanity's ability to ward off the worst outcomes from COVID has improved over the last two years, with a slate of vaccines, personal protections, medications and an ever-evolving treatment plan all playing a role.

But while vaccinations in particular have changed the course of the pandemic offering high levels of protection against severe disease what form they'll take in the future isn't set in stone, said Dr. Alexander Wong, an infectious disease physician and clinician-researcher with the Saskatchewan Health Authority.

Some researchers are developing shots that could potentially target a variety of coronaviruses, not just SARS-CoV-2; other teams are exploring vaccines inhaled through the nose in hopes of curbing infections at the source by targeting the virus's respiratory entry points.

There are also questions over whether vaccines will be tailored to emerging variants, and how often booster shots might be needed to prevent immunity from waning over time.

Which treatments will become standard going forward is also shifting, with antivirals increasingly part of the equation as research teams race to develop new and better drugs to ward off serious health impacts.

"There arejust so many unknowns about what this is going to look like," Wong said.

Which public health measures work best?

Multiple experts also stressed the importance of figuring out which public health measures worked best and which ones were a flop so governments can put in place the best plans to live with this virus in the long term.

That could be particularly crucial given the looming threat of future variants that may be more contagious, more pathogenicor more capable of evading our current vaccines.

"What actually worked to help the bottom line, which was to prevent deaths and hospitalizations? I don't think we have a good answer to that," said Dr. Sumon Chakrabarti, an infectious diseases specialist at Trillium Health Partners in Mississauga, Ont.

He said there's "no doubt" vaccines are important, butthat more evidence is needed to understand what role mask-wearing played particularly since mask mandates across much of the country did little to stop the unprecedented infection rates seen in the Omicron-driven wave.

WATCH | Experts warn about returning to 'normal' too soon:

Experts warn about returning to normal too soon

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Various countries have started removing all COVID-19 public health restrictions and some provinces are preparing to do the same, but experts say a rushed return to normal could backfire.

Society-wide lockdowns, several experts agreed, were a last-ditch option in the early pandemic that proved not to be a sustainable or successful approach for curbing virus transmission long-term.

"Even if restrictions worked, it protected the laptop class," said Chakrabarti, who often treated essential workers from local big box stores or factories who were battling COVID.

"If you look at the death rates, during lockdowns, people still died. And the people who died were people who couldn't work from home or isolate," said Murthy. "Lockdowns were a public health failure, but we used them as a last resort, because we couldn't respond in any other way."

A better approach for the future, he stressed, is a shift in how society strives to curb virus transmission more broadly, by focusing on measures like improving ventilation throughout indoor settings.

"In the 1800s, we sanitized water. In the 1900s, we sanitized streets," he said. "In the 21st century, are we going to sanitize our air?"

How will health-care systems grapple with COVID-19 going forward?

A burning question for Jason Kindrachuk, a microbiologist with the University of Manitoba, is how health-care systems will function if seasonal waves of COVID wind up layering on top of other respiratory illnesses.

"It's not like COVID replaced influenza. It did for the last two years, because we were able to keep influenza at bay. But without restrictions, we don't know the toll on an annual basis," he said.

"How much of that can we continue to add up before the health-care system can't care for the people that we've traditionally been able to?"

How COVID competes with flu is one thing, and there'salso a pre-existing issue in health care: even before the pandemic hit, hospitals faced a capacity crunch while grappling with high levels of patients, including those who fill beds simply because they're waiting for spots in retirement homes or long-term care facilities.

"It's all an interlocking system," said Chakrabarti. "If one aspect has stress on it, it's going to affect the whole system."

WATCH |How Canadian researchers are preparing for the next pandemic:

How Canadian researchers are preparing for the next pandemic

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As the world fights the latest phase of the COVID-19 pandemic, Canadian researchers are analyzing hundreds of bat specimens in order to identify new viruses and get a head start on future vaccines.

How is this virus transmitting between species?

While many scientists are striving to understand the pandemic's future impact on humans,Sunnybrook's Mubareka is keeping her focus on animals, since our health is ultimately connected.

A crucial question going forward, she said, is which animals are susceptible to SARS-CoV-2 infections, and how various species that are already getting infected like white-tailed deer are being exposed to the virus.

As part of a team of Canadian scientists, Mubareka recently helped produce preliminary research that outlined the discovery of a heavily mutated lineage of SARS-CoV-2 within Canadian deer populations, and an apparent instance of deer-to-human virus transmission.

But that paper is just the tip of the iceberg, with so much still unknown about how this virus is spreading throughout the animal kingdom.

"We need to understand where coronaviruses are in nature and what the behaviours are that we undertake with zoonotic pathogens that lead to spillover events," said Kindrachuk. "It's something we understand somewhat, but we don't fully know how to mitigate those risks."

Angela Rasmussen, a virologist and researcher with the University of Saskatchewan's Vaccine and Infectious Disease Organization, said more research is underway in Canada to answer key questions about this virus's evolution within animal hosts.

"Are those variants a threat to the human population? We don't know. Are there threats to animal populations? I mean, that's something that has huge implications for food security, for the economy, for animal welfare, for the ecology," she warned.

"So I think that a better understanding of ... which animals may actually have SARS-CoV-2 circulating in them already is going to be really crucial going forward for our long-term prospects of controlling [this virus]."