The mystery surrounding a key immune defense is behind much of the uncertainty around who should get a second Covid-19 booster and when.

People 50 years and older can now get the additional booster at least four months after their first. The Centers for Disease Control and Prevention isn’t pushing those eligible to get the shots, however, and many vaccine experts say healthy people under 65 years old can wait.

A big reason: researchers’ limited understanding of the molecular soldiers known as T cells that help mount the immune defense against Covid-19.

Researchers and U.S. health officials measuring whether Covid-19 vaccines work have largely focused on the body’s first-line defense, called antibodies. The Food and Drug Administration recently cleared a second booster shot partly based on real-world research out of Israel showing the extra dose restored antibody levels that had waned and reduced risk of infections.

But when deciding whether to get boosters, people should also factor in the role that other parts of the immune system play in protecting against Covid-19, vaccine experts say.

An immunocompromised resident received a second booster shot to protect against Covid-19 in Waterford, Mich., this month.

Photo: EMILY ELCONIN/REUTERS

“You have T cells that are not waning to the same degree and are likely a big part of what’s going to keep you out of the hospital,” said John Wherry, director of the Institute for Immunology at the University of Pennsylvania.

An FDA spokeswoman said an analysis of emerging data indicated a second booster dose of either the Covid-19 vaccines from Pfizer Inc. and partner BioNTech SE or from Moderna Inc. “could help increase protection levels” for higher-risk individuals. The CDC declined to comment. 

Antibodies are the immune system’s quick-strike force, on high alert after Covid-19 vaccination and spurred into action to neutralize the virus before it attacks cells.

T cells, and another molecular soldier known as memory B cells, are also mobilized by Covid-19 vaccines to protect against the new coronavirus. T cells and B cells play a longer game than antibodies, however. Antibody levels jump after each Covid-19 shot but fall back weeks or months later, as they do with other vaccines. The T cells and memory B cells stick around, researchers have found, an army waiting for when the body becomes infected.

T cells kill cells infected with the virus and help direct the body’s overall immune response, including assisting with what types of antibodies are made. B cells, another important component of the body’s immune defenses, make antibodies.

“In a matter of a few days, the B cell memory and T cell memory gets reactivated and can deal with the infection,” said Alessandro Sette, an immunologist at La Jolla Institute for Immunology in California. “So you might have an infection, but the symptomatic disease or certainly the more severe disease, is prevented.”

The presence of T cells, vaccine experts say, might explain why many vaccinated people who tested positive for Covid-19 several months after their inoculations managed to avoid severe cases.

The T cells continue to work against the virus, according to the experts and studies, after antibodies have waned or lost effectiveness because of a variant. 

Some studies have found that T cells from Covid-19 shots persist for at least half a year after initial series of vaccination. A study by researchers at La Jolla Institute and published in the journal Cell in March found that the T cells lasted six months and were about 80% as effective against Omicron as other variants.

Lingering T cells might reduce the need for many healthy people to get a second booster dose within months of their first, some vaccine experts say. In fact, there might be diminishing returns from getting boosters over time if T-cell levels eventually plateau or slowly drop over time as people get more shots, researchers say.

There is limited evidence to go on, however. T-cell analysis is more time-consuming and expensive than performing antibody tests, according to researchers. T-cell research, largely performed by a handful of academic labs on specialized equipment, can take several days. Antibody research, by contrast, can yield results in hours.

Some research suggests that an initial booster modestly increases the body’s supply of Covid-fighting T cells, which could help them stay longer to ward off the virus, though researchers say more study is needed.

Due to the limited time that Covid-19 vaccines and boosters have been in use, it isn’t known when the T cells decline to the point where they are no longer effective against the virus.

Some researchers express hope the T cells will stick around for a long time, because T cells generated by yellow fever, smallpox and other vaccines last decades. 

Dr. Wherry said his lab expects to publish data soon showing that T cells after the initial series of vaccines remain in the body for at least nine to 12 months. 

“We are building the plane as we’re flying,” Dr. Wherry said. 

Write to Jared S. Hopkins at jared.hopkins@wsj.com