Stimulating long-term memory T cells to fight coronavirus

In the search for an effective vaccine against coronavirus, antibodies grab much of the attention. But there is more to the immune response than antibodies, and Prof Kingston Mills and colleagues at Trinity College Dublin are digging deeper into the body's defence system to see how we could build up a long-term memory of the virus in the body.

Their approach focuses on T-cells, white blood cells that carry out a range of important functions in immunity. They include cytotoxic T-cells, which kill hapless cells in our body that that have been infected with viruses; helper T-cells that signal to other cells of the immune system to make antibodies and long-term memory T cells that can potentially stick around for years in the body – like a dog sleeping with an ear out for potential intruders.

The current focus internationally for developing a Covid-19 vaccine is mostly on generating antibodies against the SARS-CoV-2 virus, says Mills, who is professor of experimental immunology and co-director of a strategic research partnership funded by Science Foundation Ireland and AIB to focus on Covid-19.

“Most of the vaccines currently being developed and tested focus on using the spike protein of the SARS-CoV-2 virus. They use this to encourage the body to make antibodies that can stop the virus infecting cells. If you have these antibodies, that would mean when you are exposed to the virus you don’t get the disease,” he explains. “But we know from experience with other viruses that sometimes a vaccine that stimulates the body to make antibodies is just not enough to be effective.”

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Another approach

Taking another approach, Mills is looking at how to encourage T-cells to train their sights on the SARS-CoV-2 virus. He has form in this area – long before this pandemic, he and colleagues had been working on a way to develop a T-cell response to the bacterium that causes whooping cough.

“My group is particularly interested in making vaccines that encourage the immune system to have a long-term memory of a disease,” he says. “In the case of the whooping cough, we focused on ‘tissue-resident memory T-cells’ that would remain in the lung and be specifically primed to recognise and respond to whooping cough bacteria if they showed up there. Now, we are looking at how to do that for SARS-CoV-2, and because of the previous research on whooping cough, we have been able to hit the ground running.”

The current research at Trinity is looking at ways to deliver vaccines that stimulate these long-term memory cells. That includes using adjuvants or carriers in the vaccine to bring about a T-cell response and ensuring that the vaccine and responses to it land where they are needed.

“We think local immunity will be important for tackling SARS-CoV-2, and as the airways are a big point of entry for this virus, we are looking at delivering the vaccine in through the nose,” says Mills. “Another advantage is that you can deliver a powdered vaccine into the airways, and this vaccine would be relatively stable and easy to transport and store in different climates and parts of the world.”

Candidate vaccines

However, Mills stresses this research is still very much lab-based, and he sees their work on T-cells as part of the longer-term control of Covid-19.

“On a global front, there are around 150 candidate vaccines in various stages of testing, and if any of them work I think we are looking at the middle of next year at least until we have a vaccine in wider use,” he says.

“That initial antibody-stimulating vaccine could be a short-term solution, and it would be good to have it. Where our research would feed in would be later generations of vaccines where you can potentially use T-cells to achieve more sustained immunity and longer-term memory against this disease,” Kingston points out.