By Carrie Arnold

Winter break had arrived in Stockholm in late February, and Soo Aleman watched as her fellow Swedes departed the capital city for ski vacations across Europe. Aleman’s colleagues at the Karolinska University Hospital, where she works as a researcher and physician, returned relaxed and invigorated, with stories to tell about their days on the slopes. But a few of the city’s residents also brought back a most unwelcome souvenir: the SARS-CoV-2 coronavirus.

Like much of the rest of the world, Sweden soon found itself in the grips of an outbreak. As Aleman pivoted from her work on the hepatitis B and C viruses to study COVID-19, she began screening patients for the novel infection and for signs of the body’s immune response. And that’s when things got weird.

The body should produce both protective antibodies, which keep the virus from invading, and killer T cells, which tell virus-infected human cells to destroy themselves to keep the virus from spreading. Normally, these immune responses appear in tandem. But in a subset of those who tested positive for COVID-19, Aleman found T cells but no antibodies.

Other scientists around the world also had similar findings. Much of this work is still preliminary, and scientists don’t know what it means in terms of assessing how well a vaccine will work or how well people are protected from severe forms of the disease. But one thing is becoming clear: antibodies might not be telling the whole story when it comes to COVID-19 immunity. “We shouldn’t just look blindly at antibody tests,” Aleman says.

“I don’t know another virus like this,” adds Rory de Vries, a virologist at the Erasmus Medical Center in the Netherlands. “We are living in special times with a special virus.”

The Bs and Ts of immune cells

Wellness gurus may exhort us to treat our bodies like temples, but when it comes to fighting off pathogens, the body is more like a castle under siege. Like any fortress, the body has several lines of defenses to protect it from infectious microbes.

The innate immune system is the first line, and it sets out to discourage any potential intruder by making the body as inhospitable for them as possible by raising the body’s temperature with a fever and assaulting pathogens with toxic chemicals. It acts like an overzealous security guard and reacts against any sign that a cell or protein is not the body’s own.

Even these security forces can be overwhelmed and outmaneuvered by pathogens that have evolved stealth to evade the immune system and counter inflammatory responses dedicated to stopping germs. When that happens, the adaptive immune system kicks in—and that’s when we see things like antibodies and T cells. These defenses emerge after a pathogen has invaded, and the body has learned the type of threat it poses.

B cells produce antibodies, small proteins that recognize certain pieces of a pathogen known as epitopes. If enough antibodies bind to a virus, it can’t enter the body’s cells to make copies of itself, and thus cannot make you sick. Likewise, killer T cells recognize epitopes displayed by virus-infected cells and tell the cells to self-destruct.

It's a process that has evolved over hundreds of millions of years, and all the different arms of the immune system generally work together seamlessly.

When the body is actively fighting off a pathogen, it mobilizes large numbers of antibodies and T cells. In the following weeks and months, those numbers can slowly decline. That’s normal and even beneficial, said Nicolas Vabret, an immunologist at the Mount Sinai School of Medicine in New York.

“If antibodies didn’t decline, over time, there would only be antibodies in the blood with no room for anything else,” he says.

But the defenses haven’t completely evaporated after this initial siege. A portion of the B cells and T cells form memories of past invaders, while a low level of antibodies keep circulating in the blood. For months or even years, these forces continue to patrol the bloodstream, the spleen, bone marrow, and lymph nodes embedded in various organs long after the infection is over, so if the body ever sees the same pathogen again, it can respond faster.

Sometimes, a reinfected person won’t even have symptoms. Other times, the disease may be very mild. The amount and type of antibodies and T cells present after an infection can tell scientists how well a vaccine might protect people.

More than waning antibodies

Historically during epidemics, scientists have focused on antibody responses rather than T cells, because antibodies are easier to measure in the lab. Antibodies can be detected directly from a blood sample, explains Daniela Weiskopf, an immunologist at the La Jolla Institute for Immunology in California.

When Weiskopf wants to spot a T cell response, however, she has to reenact the series of steps the T cells use to identify a pathogen. First, she synthesizes a library of all the possible tiny epitopes the T cells can recognize. Then she needs to isolate the T cells from the blood and test them against all the different protein epitopes, to see which ones interact with the cells.

For most viruses, antibody and T cell responses usually match up in terms of timing and strength of response, so scientists generally rely on antibody tests alone because they are quicker, cheaper, and easier to administer. Some antibody test kits can provide results in minutes to hours, whereas T cell tests need to be sent to a specialized lab.

“It’s just not practical to test for T cell response in large samples,” says Weiskopf.

But when Aleman and other virologists and immunologists began turning their attention to COVID-19, a different story started emerging. Aleman and her colleagues began to study how immunity developed in people who had tested positive for SARS-CoV-2, as well as their close contacts, some of whom were presumably exposed to the virus, even if they didn’t get sick. As expected, hospitalized individuals developed strong antibody and T cell responses to SARS-CoV-2. But two-thirds of the close contacts who were asymptomatic showed a subsequent T cell response, even though tests didn’t detect any antibodies.

“It was very strange and very surprising,” Aleman says. The study results, released June 29 without peer review via the medical pre-print service medRxiv, didn’t reveal whether these individuals never developed antibodies or whether they rapidly declined to undetectable levels. Regardless, the report immediately raised concerns about a vaccine, since stimulating antibody production is a key strategy by which immunizations protect against disease.

This apparent decline in antibodies was reported again on July 21, in 34 individuals with mild COVID-19 infections. If some people infected with SARS-CoV-2 don’t produce antibodies, it could mean they might not respond to a vaccine.

T cells to the rescue?

Immunologist Adrian Hayday at King’s College London is less worried. Even though T cells are harder to measure and may not prevent a second infection, they play a major role in the body’s ability to remember past infections and protect someone from severe disease.

“It kind of looks like T cells could be really useful to you in this infection,” Hayday says, pointing to several new papers on SARS-CoV-2 and other coronaviruses as proof.

SARS-CoV-2 is one of seven known coronaviruses that can infect humans. The original SARS virus vanished after creating large outbreaks in 2003, and the Middle Eastern Respiratory Syndrome (MERS) virus has only infected a small number of people in the Middle East and North Africa. Four other coronaviruses circulate widely and cause the common cold.

Immunity to the common cold coronaviruses only lasts a year or two, which is why sniffles and stuffiness remain a pervasive part of life. However, patients infected with the original SARS virus still possessed memory T cells that responded to the virus’ proteins 17 years later, immunologist Antonio Bertoletti at Duke-NUS Medical School in Singapore recently reported in Nature. These same memory T cells also reacted to SARS-CoV-2. It’s something Bertoletti says bodes well for COVID-19.

“Even if the T cells don’t prevent a second infection, you might not get as sick,” he says.

Likewise, Leif Erik Sander, an infectious disease physician at Charité University Hospital in Berlin, found that 83 percent of 25 COVID-19 patients in Germany produced helper T cells, a cousin of the killer variety so named for their ability to help stimulate antibody production. These cells were able to mount a response to the spike protein that coats SARS-CoV-2. Sander and colleagues also found that a third of the 68 people who had never been exposed to the novel coronavirus also had these helper T cells. Although Sander can’t yet say for sure, he suspects that these T cells were originally produced to protect against a common cold coronavirus.

A Science paper published August 4 by Weiskopf and colleagues supports this hypothesis and hints that preexisting immunity to these common cold coronaviruses may help explain why some people have no symptoms. Since COVID-19 has some similarity to these viruses, some T cells may respond to both pathogens. However, it’s still early days for this idea.

“We really don’t know how T cells relate to disease severity,” he says.

Weiskopf, fellow La Jolla Institute immunologist Alessandro Sette, and de Vries also conducted an in-depth analysis of the immune response from 20 adults who had recovered from COVID-19. They found that although antibodies developed primarily to the spike protein that coated the virus, T cells could respond to epitopes from inside and outside of the virus. Their results were published in Cell.

That’s good news for a vaccine, de Vries says, because it means that even if the outer spike proteins mutate over time, T cells will still be able to provide some protection, since they recognize other parts of the virus that are less prone to change.

What no one can say yet is what these T cell responses mean in terms of preventing and infection, or how long they might last. Potential preexisting T cell responses may yet affect how well a vaccine protects people, Sander says.

“We’ve been dealing with this virus for six months,” Weiskopf says, “so we cannot know about what might happen 12 months out.”