NEW YORK – While much of the discussion around immunity to SARS-CoV-2 has focused on antibodies, a growing body of research indicates other components of the immune system may play a significant role in combating COVID-19, the disease caused by the coronavirus.
Specifically, the T cell-mediated immune response has become an area of interest with a number of groups exploring its role and several parties developing tests to assess T-cell response for research and vaccine development and perhaps ultimately in the clinic.
Serology tests measuring antibodies produced in response to COVID-19 infection have been widely used since the spring to assess whether people have been exposed to the virus and to determine how widely the virus has spread throughout populations. A number of reports have observed, though, that in many people this antibody response wanes relatively quickly after their recovery, suggesting that serology testing could miss people who were infected but whose anti-SARS-CoV-2 antibodies have since dropped below detectable levels.
At the same time, the T-cell response to the virus appears to be more enduring, which suggests that assays for measuring that response could detect cases missed by molecular or antibody testing.
"You missed the window for PCR, and you missed the window for antibodies, but we know that T cells to coronavirus can be detected 18, 20 years after exposure, so it's a kind of permanent footprint of the virus having been there," said Daniel Altmann, professor of immunology at Imperial College London.
What exactly that means for immunity to the virus is yet to be worked out, Altmann noted. "The jury is still out on that. There's no data yet."
Antonio Bertoletti, a professor of infectious disease at Duke-NUS Medical School in Singapore, is working with colleagues to develop a test to measure patient T-cell response to SARS-CoV-2 that he said he plans to offer for clinical use.
In a study published last month in Nature, a team led by Bertoletti looked at SARS-CoV-2-specific T-cell responses to several peptides from the virus in subjects with COVID-19, SARS, and uninfected controls, finding T-cell reactivity both among patients who had been infected by SARS-CoV-2 and SARS as well as in some patients who had not been infected or exposed to either virus.
Bertoletti said that while unexposed subjects do show some T-cell reactivity, he and his colleagues have found that they had T cells against, at most, one or two SARS-CoV-2 proteins. On the other hand, patients who were infected and recovered from the virus have showed reactivity against at least three to four virus proteins, he said.
Bertoletti said he believed a test assessing the breadth of a person's T-cell response could prove useful for determining their susceptibility to the disease.
"I'm convinced that to have an idea of whether we can control the [virus] through our immune system, we should test not only antibodies, but interrogate both arms of adaptive immunity," he said. "Only an analysis of the presence of antibodies and T cells in large patient populations can reveal what are the real correlates of protection."
One challenge, he noted, is determining what SARS-CoV-2 proteins to test against.
"It might be that T cells specific for different SARS-CoV-2 proteins have similar protective effects," he said. "Or maybe one can be more important than others. We still don't know."
SARS-CoV-2 has a relatively large proteome, making it impractical to test for reactivity against all the virus' proteins. Bertoletti said he and his colleagues are building an assay that will test three to four structural proteins from the virus that they believe are likely important in generating a T-cell response.
He said the assay they were working on differed from the traditional Elispot approach used to study T-cell response in that they performed it in whole blood as opposed to isolated peripheral blood mononuclear cells. This, he noted, allows them to skip the PBMC isolation step, making for a higher-throughput assay.
"Our idea is to make a test that is quick, that can be run in eight to 12 hours," he said. "A single operator should be able to run around 100 samples a day. It won't be as easy as classic serological tests for antibody detection, but it will be less complicated than the [T-cell] assays that are used at the moment in research labs."
Bertoletti added that he and his colleagues are forming a company to commercialize the test and are exploring possible collaborations with diagnostic firms but did not provide further details.
Other parties are also working to bring T cell tests to market. During PerkinElmer's Q2 earnings call last month, President and CEO Prahlad Singh said that the company has "several assays in development" that "will aid researchers and clinicians in understanding how the broader immune system may help for protection, including a patient's T cell response, cytokine levels, or cellular damage."
He added that while it was not yet clear what role assays for T cell response might play in the clinic or clinical research, "immune insights are going to be important, and that’s where sort of we are trying to focus on as to what aspects and what avenues do we need to look at.
The company declined to provide further information about its work in this area.
Deepak Nath, president of laboratory diagnostics at Siemens Healthineers, said that his company is also exploring testing for T cell response to SARS-CoV-2, though he noted that the firm "was not in a position to say that we have a path forward or anything like that at this point."
In July, Cardiff, Wales-based immunodiagnostics firm Indoor Biotechnologies said it had received £50,000 ($65,000) in funding from Innovate UK to support develop a T-cell response test in collaboration with researchers at the School of Medicine, Cardiff University.
Also in the UK, diagnostics firm Oxford Immunotec launched in May a T-cell response test based on its T-Spot platform. Called the T-Spot Discovery SARS-CoV-2 test kit, the assay is intended for research use but could ultimately find a place in the clinic said CEO Peter Wrighton-Smith. The company currently offers clinical T-cell immunity tests for identifying tuberculosis and cytomegalovirus based on the T-Spot platform.
"I think we can hypothesize a few potential [clinical] use cases that might emerge," he said. "The first is, if we really want to be sure about diagnosing someone, recognizing that both PCR and antibodies can be negative, we might want to throw T cells into the mix in certain situations."
He added that such a test could prove useful for assessing the true extent of exposure in populations, particularly given observations that antibody levels can wane several months after infection.
Measuring exposure could also be important for vaccine development and clinical trials, Wrighton-Smith noted. "Vaccine companies are going to need to know if the people they enroll into their [clinical trial] cohorts, have they had it or not. Because if they have had it, they might have some preexisting immunity … and if companies are only using antibody testing, they are going to miss some people."
For now, Wrighton-Smith said, the research-use version of the test is drawing customers from three main areas — academic groups doing basic research into immunity and COVID-19; government programs exploring T-cell testing as a possible addition to serology for understanding disease spread; and vaccine development.
"We've seen a significant increase in interest for our test on the back of the scientific and general community starting to realize the importance of T cells," he said.