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New type of test could better discern coronavirus immunity

A new type of test may better detect a person’s immune response to coronavirus than a widely used antibody test, according to a study published Tuesday.

The test, if cleared by the Food and Drug Administration, would be the first commercial product to detect the response of a T cell – a type of immune cell – to the virus. Antibodies have dominated the conversation about immunity since the start of the pandemic, but scientists believe T cells may be just as important in preventing reinfection.

The test was developed by Adaptive Biotechnologies, a Seattle-based company. The company used small blood samples from 1,000 people in 25 metropolitan areas across the United States as well as 3,500 other participants in Europe to create the test, which can detect recent or past infection with the coronavirus.

The company’s data has yet to be reviewed for publication in a scientific journal, but experts say the work shows promise in assessing the role of T cells in disease caused by the coronavirus.

Exposure to a pathogen awakens multiple arms of the immune system: antibodies, but also immune cells that can mobilize the fight against the intruder.

“What we’re developing is basically a way to look at this cellular part of immunity,” said Dr Lance Baldo, chief medical officer of Adaptive Biotechnologies.

So far, antibodies have monopolized much of the attention – mainly because their detection is quick and easy. But antibody levels tend to decline after active disease resolves and may be undetectable within months.

Several studies have suggested that T cells that remember the virus persist for at least six months. “There is a growing realization that T cells are important and may even be a better indicator of clinical outcomes” than antibodies, said Alessandro Sette, an immunologist at the La Jolla Institute of Immunology in California.

But isolating T cells is a complex and expensive process, severely limiting information about their role.

Each of the trillions of T cells present at birth carries a unique receptor on its surface that can spot a different molecule, or antigen, from potential invaders. This enormous diversity among T cell receptors allows the human body to recognize virtually any new pathogen it may encounter (although a large majority may never encounter their match.) But it also makes it extremely difficult for scientists to ‘identify the 20 or 30 T cells among the trillions that can recognize fragments of a specific pathogen like the coronavirus.

“One of the brutal things about immunology is that all white blood cells are the same,” said Shane Crotty, a virologist at the La Jolla Institute of Immunology. “You can’t even tell B cells from T cells, let alone virus specific T cells.”

To find the specific T cells for a virus, researchers must first separate most of the immune cells from a few milliliters of blood, which takes time. Then they wash and count the cells and stimulate them with pieces of virus to identify the tiny pool of responding T cells. Activated cells release a molecule called gamma interferon which serves as a signal for their activity.

“The better the test, the more complicated it is,” said Dr Crotty. “You get more and more information, but it gets more and more complicated.”

A single researcher cannot process more than five blood samples in a day and a half.

“This is pretty much the reason why with every article done on T cells, the number of subjects studied never exceeds 100,” said Dr Antonio Bertoletti, virologist at Duke NUS Medical School in Singapore. “There has also never been a significant demand for delving into the intricacies of T cell testing.”

Adaptive Biotechnologies takes a completely different approach: instead of looking at cells, the company has focused on sequencing proteins on the cell surfaces.

Each person has a different repertoire of trillions of T cell receptors, called TCRs. But at least some of these TCRs are the same as other people’s. “We call these public sequences T-cell receptors because theoretically many people in the population will elicit these responses,” Dr Baldo said.

When the pandemic began, Adaptive Technologies had already worked with Microsoft to design a TCR-based diagnostic test for Lyme disease, a project made possible by the advent of fast and inexpensive sequencing technologies.

Pivoting towards the coronavirus, the team has identified 135,000 public TCRs that recognize 545 fragments of the virus. About 11 of those 545 antigens elicit the largest immune response, the researchers reported in September. (Only one of these antigens, the spike protein, is used to develop vaccines.)

In the new work, the team analyzed samples from 2,200 people in Vo, Italy, who tested for the presence of the coronavirus on 2,900 of its residents in March, as cases soared there. The researchers’ test, called T-Detect, correctly identified 97% of those with a confirmed diagnosis, compared to 77% of a commercial antibody test called DiaSorin. The results are available for free in a database called ImmuneCode.

The company is in the process of creating a point-of-care test for the general public that can diagnose previous infection, as well as a sophisticated version for vaccine manufacturers interested in tracking T-cell responses to their candidates.

Experts not involved in the work praised the company’s innovative approach, but said they wanted to see evidence that the test was specific for coronavirus.

“There is no consensus out there now that you can take one person’s TCRs that are specific for a given person and say that another person is infected with the virus in a consistent way,” said said Dr Crotty. “If they found a way to do it, that’s great, but it’s pretty new.”

A commercial test would also not offer information to people beyond proof of a past infection, warned Akiko Iwasaki, an immunologist at Yale. But if the test is specific to the novel coronavirus, she said, “it will give us a much more sensitive way of measuring whether a person has been exposed.”

The test may also offer information about Covid-19. And about 5 percent of critically ill patients show a “huge drop” in their T-cell response, Dr Baldo said. But in a large majority of people, the T cell response seems to peak around day 10 and persists for many months, he said, adding, “We are seeing an earlier, more robust and even more durable as opposed to the antibody response. “