How To Create Long-Lasting Immune Cells For Stronger Vaccines

Scientists at the University of Wisconsin School of Veterinary Medicine have identified a potential approach to develop longer-lasting vaccines for respiratory viruses such as influenza and the coronavirus that causes COVID-19.

The study, published in the journal Cell Reports, focuses on T cells, a type of immune cell that helps control infections by destroying virus-infected cells.

T cells identify more stable parts of viruses, providing a route to more comprehensive protection, in contrast to antibodies, the foundation of most existing vaccinations. These can lose efficacy as viruses mutate.

However, the limited lifespan of T cells poses a challenge for vaccine development. The latest research reveals a startling potential workaround.

We have discovered essentially a mechanism which we can target – a new clue to generating long-lived T cells.

M. Suresh, Professor, Department of Pathobiological Sciences, University of Wisconsin–Madison

Rethinking How Vaccines Trigger Immunity

Most vaccines are developed to stimulate antibodies that prevent infection. This approach is effective against many infectious diseases, but it can be less effective against rapidly evolving viruses.

“So, what do we do? We need a plan B,” says Suresh.

For viruses such as SARS-CoV-2 and seasonal influenza, the approach has involved regularly updating vaccines to target newer viral variants and encouraging the public to receive the latest flu and COVID shots each year. However, this strategy has its limitations.

“With the pandemic we went through, people are just tired of getting vaccinated,” Suresh says. Vaccination rates in the United States have been declining for years.

The ability to harness T cells could provide a potentially more effective alternative strategy. Instead of preventing infection outright, T cells help reduce disease severity and support early recovery by identifying and eliminating infected cells.

“They go and hunt one infected cell at a time and eliminate them,” Suresh says.

Because T cells recognize internal viral proteins that change very little over time, they can remain effective even as viruses mutate.

A major challenge, however, is the persistence of T-cell protection, particularly in the lungs, where respiratory infections take hold.

This lab focuses on tissue-resident memory T cells, a subset of immune cells that stay in the lungs and airways as a first line of defense. When infected, these cells can react swiftly.

But the problem is they don’t stay very long. They die off, and we still don’t know why.

M. Suresh, Professor, Department of Pathobiological Sciences, University of Wisconsin–Madison

A Different Early Signal, A Different Immune Outcome

This research examined what occurs in the initial hours following vaccination, when the body's innate immune system is engaged.

Various pathogens induce distinct early inflammatory signals that “program” memory T cells to identify and target infected cells. Suresh's group questioned whether altering such signals may alter the way T cells develop.

The researchers evaluated two kinds of early immunological signals, one that resembles a bacterial response and the other that mimics a viral infection, using an experimental vaccination technique in mice.

When we had a virus-like inflammation, the memory T cells dropped off, and we quickly lost protection. But when we created a bacterial-like inflammation, the mice developed a different kind of memory T cell, which actually persisted longer and protected longer.

M. Suresh, Professor, Department of Pathobiological Sciences, University of Wisconsin–Madison

Stem-Like Cells That Adapt When Needed

According to Suresh, the longer-lasting cells shared traits with stem cells, including being able to endure and proliferate.

The fact that those cells could adapt in the face of a virus was even more unexpected. The T cells changed into a more usual virus-fighting state when the researchers infected the vaccinated mice.

“They just flipped,” Suresh says.

That flexibility indicated that T cells can balance durability with the ability to successfully fight off a viral infection.

Toward Longer-Lasting, Broader Vaccines

The results point to a possible route toward vaccines that provide greater protection across variants and require fewer booster shots.

“The duration of immunity is really, really important,” Suresh says. “Can we vaccinate fewer times, and can shots protect against new strains?”

The study also emphasizes the importance of providing immunity in areas where infections occur. This may entail creating vaccinations for respiratory illnesses that act via the nose and lungs instead of an injection.

“The best way to immunize against all our respiratory infections is to give through the normal route of infection,” Suresh says.

What Comes Next

The current research was carried out in mice. The group intends to test the strategy in models that more accurately represent the variety of human immune systems as well as in nonhuman primates.

Future research will also look for ways to direct immune cells to the lungs following conventional vaccination, a tactic that could increase protection without the need for novel delivery systems.