(Left to right): Michael Norris, Samira Mubareka, Sharon Walmsley, Vanessa Allen and Beate Sander

January 30, 2025

By Sunitha Chari

The University of Toronto’s Emerging & Pandemic Infections Consortium (EPIC) has launched a Rapid Research Response to address the public health risk posed by highly pathogenic avian influenza (HPAI).

Leveraging the multidisciplinary EPIC research community, the response will support projects that aim to understand the fundamental biology of these viruses and their potential for human transmission and to develop new methods for detecting viral infections and outbreak management.

The EPIC response coincides with action at the national level by the Canadian Institute of Health Research (CIHR) which launched a funding program for HPAI research that integrates One Health approaches — assessing animal, human and environmental risks — to help Canada prepare for and respond to outbreaks.

HPAI viruses typically infect birds, but since 2022, there have been increasing reports of virus spillover to mammals, leading to mass die-offs in both bird and mammal species. In early 2024, widespread detection of HPAI in commercial dairy cows in the United States was confirmed along with infection of people working on affected farms. Since then, the US reported its first death of an infected person and a teen in British Columbia became critically ill with HPAI— the first human case in Canada.

The evolution and spread of HPAI between species and growing reports of infections in humans have raised concerns of a potential outbreak in human populations, which could have devastating effects.

Using biology to inform vaccines

“We want to understand what is fundamentally different about HPAI that allows it to infect such a broad range of host species and why it’s so severe in some hosts but not others,” says Michael Norris, assistant professor of biochemistry at U of T’s Temerty Faculty of Medicine.

To understand how HPAI viruses can infect so many different hosts, Norris and his group will look for naturally occurring mutations in a virus gene that codes for a surface protein known as hemagglutinin (HA). HA binds receptors on host cells initiating virus entry to these cells. The findings from this study will determine which natural mutations in HA allow these viruses to enter a wide range of host species, including humans. “Once we understand the mechanisms of viral entry, we can develop methods to block it,” says Norris.

Because HA is essential for initiating influenza virus infection, it is also a major target for vaccine development. Understanding what parts of the HA protein elicit the best antibody responses will help inform better vaccine design.

To identify these ideal antibody targets, Norris’ team will use a method known as electron cryomicroscopy (Cryo-EM) to compare how antibodies from animals and birds previously infected with HPAI target the HA protein. “It’s all about figuring out what the immune system needs to see to guide the development of the most effective antibody response,” says Norris.

Understanding risk

The ability of HPAI viruses to jump between species greatly increases the risk of their transmission to humans. “Understanding the differences between these viruses will inform their risk of transmission to human populations,” says Samira Mubareka, an infectious diseases physician, medical microbiologist and scientist at Sunnybrook Research Institute.

As part of the EPIC HPAI Rapid Research Response, Mubareka’s group will characterize different HPAI viruses in the Toronto High Containment Facility (THCF), the only research-dedicated containment level 3 facility in the Greater Toronto Area.

“One of the advantages of the EPIC HPAI project is the access to the high containment facility needed to work with these viruses, which require a highly specialized and secure work environment,” says Mubareka, who is also an associate professor of laboratory medicine and pathobiology at Temerty Medicine, and a CIHR-Public Health Agency of Canada Applied Public Health Chair in One Health.

While H5N1 is the dominant strain associated with HPAI, other subtypes collectively known as H5Nx have also emerged as pathogens of concern because of their ability to cause infections in multiple host species. The H5N1 strain has also reassorted by exchanging genetic information among the subtypes, increasing the odds that a strain will emerge that can infect and transmit between humans.

“There are at least 50 genotypes of H5N1, and we need to figure out which ones to worry about,” says Mubareka. Her group’s work in the THCF is crucial to understanding the differences between these viruses and the risks they pose for a widespread human outbreak.

Researchers can also work with at-risk populations to understand the dynamics of transmission to humans. Currently, the greatest risk is for individuals who come in proximity with infected birds and animals, such as wildlife and livestock workers, but it remains unclear what proportion of exposed individuals show symptoms of infection.

As part of the EPIC HPAI Rapid Research Response, Sharon Walmsley, a clinician scientist at University Health Network (UHN) and professor of medicine at Temerty Medicine, will screen individuals at high risk of exposure and test them for evidence of HPAI infection. The data will inform public health agencies of the prevalence of symptomatic and asymptomatic HPAI infections in this high-risk population.

Developing pandemic preparedness

Monitoring infection levels in the population is a critical component of any public health response to an outbreak. But when the outbreak involves a novel pathogen, we may not have the sensitive and accurate tests needed to detect these infections with confidence.

“Serological assays help us figure out how many people in a population are exposed to the virus and existing levels of population immunity,” says Vanessa Allen, a medical microbiologist and infectious diseases physician at Sinai Health and UHN.

Allen and her team will adapt the Plaque Reduction Neutralization Test (PRNT or “print”) to detect HPAI-specific antibodies and measure how effective those antibodies are at stopping viral infection. By validating these tests early on, this project strengthens pandemic readiness by developing a tool to track infections in the population, identify at-risk groups and inform management strategies.

“Developing a serological test for a new pathogen requires coordinated efforts, bringing together people with different expertise and providing them access to the high containment facility,” says Allen, who is also an associate professor of laboratory medicine and pathobiology at Temerty Medicine, and has served as the medical director of Ontario’s Provincial Diagnostic Network since March 2020. “EPIC can rally people and bring them together to address these challenging questions.”

To further bolster our ability to respond to a potential HPAI outbreak, Beate Sander, a senior scientist at UHN, and her team will develop computer models to predict how an HPAI outbreak might affect healthcare systems and resources. Their project builds on the team’s previous work developing models during the H1N1 and the COVID-19 pandemics.

“We will look at surveillance data, health administrative records of patients admitted to hospitals, pandemic literature on disease history from all over the world and come up with different scenarios of how an influenza pandemic could play out,” says Sander, who is also a professor at the Institute of Health Policy, Management and Evaluation at the Dalla Lana School of Public Health. “We can then simulate individual patients’ flow through a hospital and estimate the resources they may need.”

The information will be used to predict resource demands — including medications, vaccinations, ICU capacity, hospital beds and ventilators — likely to be placed on healthcare systems coping with an HPAI outbreak. These predictions can then be implemented into public health approaches, creating more resilient hospital- and community-based pandemic preparedness.

“EPIC’s unique ecosystem, comprising members with diverse expertise and perspectives, means that we are able to leverage talent quickly and prioritize work that will address the most complex and urgent infectious disease-related challenges,” says Scott Gray-Owen, EPIC’s academic director and professor of molecular genetics in Temerty Medicine.

“Our Rapid Research Response program provides the capacity for investigators to establish critical capacities and provide key data that can be used to prepare for emerging threats rather than scrambling to catch up once they arrive. This way, the work being done can be most impactful and our experts can be best equipped to lead a response that will protect Canadians and the global community.”