To reverse COVID-19, we will need more than antibodies

Winter stop had arrived in Stockholm at the end of February, and Soo Aleman was watching as her fellow Swedes left the capital for ski holidays in Europe. Aleman’s colleagues at Karolinska University Hospital, where she works as a researcher and doctor, came back relaxed and strengthened, with stories to tell about their days on the slopes. But some of the city’s residents also returned a very unusual souvenir: the SARS-CoV-2 coronavirus.

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

The body must produce both protective antibodies, which do not enter the virus, and killer T cells, which tell us that virus-infected human cells destroy themselves in order not to spread the virus. 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 do not know what it means in terms of assessing how well a vaccine will work or how well people are protected against severe forms of the disease. But one thing becomes clear: antibodies may not tell the whole story when it comes to immunity to COVID-19. “We should not just blindly look at antibody tests,” Aleman says.

“I do not know of any other virus like this,” adds Rory de Vries, a virologist at the Erasmus Medical Center in the Netherlands. “We live in special times with a special virus.”

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

The innate immune system is the first line, and it aims to discourage all possible invaders by making the body so unsafe for them by raising the body temperature with fever and attacking pathogens with toxic chemicals. It acts as an over-the-counter protector and reacts against any sign that a cell or protein is not its own body.

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

B cells produce antibodies, small proteins that recognize certain pieces of a pathogen called epitopes. If enough antibodies bind to a virus, it can not enter the body’s cells to make copies of itself, and therefore cannot make you sick. Similarly, killer T cells recognize epitopes displayed by virus-infected cells and tell the cells to self-destroy.

It is 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 a pathogen, it mobilizes large numbers of antibodies and T cells. In the following weeks and months, those numbers may gradually decrease. That is normal and even beneficial, said Nicolas Vabret, an immunologist at the Mount Sinai School of Medicine in New York.

“If antibodies did not decrease over time, there would be only antibodies in the blood, with no room for anything else,” he says.

But the defenses were not completely evaporated after this first siege. Some of the B cells and T cells form memories of invaders of the past, while a low level of antibodies circulates in the blood. For months or even years, these forces continue to embed the bloodstream, spleen, bone marrow, and lymph nodes in various organs long after the infection is over, so if the body ever sees the same pathogen again, it can react more quickly.

Sometimes a re-infected person has no symptoms. Other times the disease can be very mild. The amount and type of antibodies and T cells present after an infection can tell scientists how well a vaccine can protect humans.

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

However, if Weiskopf wants to detect a T-cell response, it must record the series of steps that the T-cells use to identify a pathogen. First, it synthesizes a library of all possible thin epitopes that the T cells can recognize. Then she has to isolate the T cells from the blood and test them against all the different protein epitopes, to see what interactions are with the cells.

For most viruses, antibody and T cell responses are usually similar in terms of timing and strength of response, so scientists generally rely only on antibody tests because they are faster, cheaper, and easier to manage. . Some anti-antibody test kits can deliver results in minutes to hours, while T-cell tests need to be sent to a specialized lab.

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

But as Aleman and other virologists and immunologists began to turn their attention to COVID-19, a different story began to emerge. Aleman and her colleagues began studying how immunity developed in people who tested positive for SARS-CoV-2, as well as their close contacts, some of whom were likely exposed to the virus, even when they were not ill. As expected, hospital subjects developed strong antibody and T cell responses to SARS-CoV-2. But two-thirds of the close contacts that were asymptomatic showed a subsequent T cell response, even though tests did not detect any antibodies.

“It was very strange and very surprising,” Aleman says. The research results, released June 29 without peer review via the medical pre-print service medRxiv, did not show whether these individuals never developed antibodies or if they relapsed to undetective levels. However, the report immediately raised concerns about a vaccine, as stimulating antibody production is an important strategy that protects immunizations 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 do not produce antibodies, it may mean that they may not respond to a vaccine.

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 do play an important role in the body’s ability to remember past infections and protect someone from serious illness.

“It seems that T cells may be useful to you in this infection,” says Hayday, pointing to several new papers on SARS-CoV-2 and other coronaviruses as evidence.

SARS-CoV-2 is one of seven known coronaviruses that can infect humans. The original SARS virus disappeared after major outbreaks in 2003, and the Middle East MERS virus has infected only a small number of people in the Middle East and North Africa. Four other coronaviruses circulate widely and cause fever.

Immunity to common cold coronaviruses lasts only a year or two, which is why sniffles and drowsiness remain an ongoing part of life. However, patients infected with the original SARS virus still have memory T cells that responded to the virus’ proteins 17 years later, immunologist Antonio Bertoletti told Duke-NUS Medical School in Singapore recently. Nature. These same memory T cells also respond to SARS-CoV-2. It’s what Bertoletti says is good for COVID-19.

“Even if the T cells do not prevent a second infection, you might not get so sick,” he says.

Similarly, Leif Erik Sander, an infectious disease doctor at the 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 calculate a response to the spike protein that covers SARS-CoV-2. Sander and colleagues also found that a third of the 68 people who were never exposed to the novel coronavirus also had these helper T cells. Although Sander can not yet say for sure, he suspects that these T cells were originally produced to protect against a common cold coronavirus.

IN Science paper published August 4 by Weiskopf and colleagues supports this hypothesis and hints that prior immunity to these common cold coronaviruses may help explain why some people have no symptoms. Since COVID-19 is somewhat similar to these viruses, some T cells may respond to both pathogens. However, it is still early days for this idea.

“We really do not know how T cells relate to the severity of diseases,” he says.

Weiskopf, colleague La Jolla Institute immunologist Alessandro Sette, and de Vries also conducted an in-depth analysis of the immune response of 20 adults who received COVID-19. They found that although antibodies primarily develop against the spike protein that covers the virus, T cells could respond to epitopes inside and outside the virus. Their results were published in Sel.

This is good news for a vaccine, says de Vries, because it means that even if the outer spike proteins mutate over time, T cells can still provide some protection because they recognize other parts of the virus that are less are envious of change.

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

“We have six months to deal with this virus,” says Weiskopf, “so we can not know what could happen in 12 months.”