Research shows how boosting immune memory could help develop improved flu vaccine

Karen Yeung is no stranger to outbreaks of respiratory infections. As a child growing up in Hong Kong, she lived through the first SARS outbreak in 2003 and witnessed the city dealing with repeated threats of bird flu in the years that followed.

Twenty years later, in the midst of a global pandemic caused by SARS-CoV-2, the fourth-year PhD student in the department of immunology at the University of Toronto's Temerty Faculty of Medicine is leading critical research to understand how our immune systems respond to influenza infection – and how we might be able to leverage that knowledge to create a long-lasting, universal flu vaccine.

Yeung is one of 31 recipients of the inaugural Emerging and Pandemic Infections Consortium (EPIC) Doctoral Awards, which supports outstanding students pursuing infectious disease research.

“Current flu vaccines work by inducing an antibody response against a specific component of the influenza virus, but this viral component mutates very quickly every year. This means that the antibodies that you make against this year’s flu vaccine likely won’t match the strain of flu that we’ll see next season,” says Yeung, who is supervised by Tania Watts, a professor of immunology at U of T who holds the Canada Research Chair in anti-viral immunity.

Immune cells called memory CD8+ T cells might hold the key to unlocking broad protection against multiple flu strains. These immune cells retain a memory of a pathogen long after the initial infection, which allows the body to quickly mount a powerful immune response the next time it encounters that pathogen. And unlike the antibodies generated from a flu vaccine, memory T cells recognize parts of the influenza virus that are more likely to remain unchanged between strains and from one year to another.

Previous work from Watts’ lab was the first to show that a protein receptor on CD8+ T cells called 4-1BB is an important player in the formation of memory T cells after a flu infection. 4-1BB is part of a communications cascade that relays cues to regulate the immune system. Yeung’s doctoral research aims to uncover how this pathway is turned on to produce memory CD8+ T cells.

“We’re really interested in how cells can communicate to each other through the language of receptors like 4-1BB and signaling,” Yeung says.

“When you have a lung infection due to flu, what kinds of signals are the CD8+ T cells receiving in the lungs that are helping them transition to memory T cells? How can we manipulate these mechanisms to form more of these memory cells?”

So far Yeung’s work points to monocytes – a type of immune cell that is recruited to the lungs early on during an infection – as providing the activating signal to allow more CD8+ T cells to become memory cells. Next, she’ll be looking at what happens during a secondary flu infection if 4-1BB signaling is disrupted and there are fewer protective memory T cells.

By deepening the understanding of how immune memory develops, Yeung’s research – which is funded by the Canadian Institutes for Health Research – is laying the groundwork for new approaches that could complement existing flu vaccine strategies to elicit a broader and longer-lasting immune response.

“It takes us closer towards a universal flu vaccine strategy, where one shot will be enough to protect against seasonal influenza and future influenza pandemics as well.”