New vaccine strategy could help extend immunity against evolving viruses

UW-Madison research identifies a way to program longer-lasting T cells, a potential step toward broader, more durable protection against infections like the flu and COVID-19.

Researchers at the University of Wisconsin School of Veterinary Medicine have identified a possible way to make longer lasting vaccines for respiratory viruses like influenza and the coronavirus that causes COVID-19.

The work, published March 25 in in the journal Cell Reports, focuses on T cells, a type of immune cell that helps control infections by killing virus-infected cells. Unlike antibodies - the basis of most current vaccines, which can lose effectiveness as viruses mutate - T cells recognize more stable parts of viruses, offering a path to broader protection.

A problem with designing vaccines around T cells, though, is their relatively short lifespan. The new research sheds light on a surprising potential workaround.

"We have discovered essentially a mechanism which we can target - a new clue to generating long-lived T cells," says M. Suresh, a professor in the Department of Pathobiological Sciences who led the study.

Rethinking how vaccines trigger immunity

Most vaccines are designed to stimulate antibodies that block infection. That approach works well for many infectious diseases, but it can fall short against viruses that evolve quickly.

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

For viruses like SARS-CoV-2 and seasonal influenza, that plan B has meant regularly updating vaccines to target newer virus variants and encouraging the public to get the latest flu and COVID shots each year. But that strategy has its pitfalls.

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

The ability to harness T cells could offer a potentially more effective plan B. Rather than preventing infection outright, T cells help limit disease severity and promote early recovery by identifying and destroying 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 don't change much over time, they can remain effective even as viruses mutate.

A key challenge, however, is the durability of protection offered by T cells, especially in the lungs, where respiratory infections take hold.

Suresh's lab studies a specialized group of immune cells known as tissue-resident memory T cells, which remain in the lungs and airways as a first line of defense. These cells can respond quickly to infection.

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

A different early signal, a different immune outcome

In the new study, which was funded by the National Institutes of Health, Suresh and his colleagues looked at what happens in the first hours after vaccination, when the body's innate immune system is activated.

Different types of pathogens trigger different early inflammatory signals that "program" memory T cells to recognize and go after infected cells. Suresh's team asked whether changing those signals could reshape how T cells develop.

Using an experimental vaccine approach in mice, the researchers compared two types of early immune signals: one that mimics a viral infection and another that resembles a bacterial response. The difference was striking.

"When we had a virus-like inflammation, the memory T cells dropped off and we quickly lost protection," Suresh says. "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."

Stem-like cells that adapt when needed

The longer-lasting cells had characteristics similar to stem cells, Suresh says, including the ability to persist and regenerate.

Even more surprising, those cells were able to adapt when confronted with a virus. When the researchers exposed vaccinated mice to infection, the T cells shifted into a more typical virus-fighting mode.

"They just flipped," Suresh says.

That flexibility suggests the T cells could combine durability with the ability to effectively combat a viral infection.

Toward longer-lasting, broader vaccines

The findings offer a potential path toward vaccines that require fewer boosters and provide broader protection across variants.

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

The research also highlights the importance of delivering immunity where infections occur. For respiratory diseases, that may mean developing vaccines that work in the nose and lungs rather than through 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 study was conducted in mice. The team plans to test the approach in nonhuman primates and in models that better reflect the diversity of human immune systems.

Future work will also explore ways to guide immune cells to the lungs after traditional vaccination - a strategy that could improve protection without requiring new delivery methods.

This research received funding from the National Institutes of Health ( U01 AI124299 and R21 AI149793).