Much of the research on the immune response in patients with COVID-19 has focused on the humoral antibody response.

• The FDA has authorized 37 antibody tests to determine if patients have been previously exposed to SARS-CoV-2, the novel coronavirus that causes COVID-19.
• Antibodies, including the coveted neutralizing variety, are being used as early measurements of efficacy for COVID-19 vaccines.
• Antibodies are even being used to treat patients, including antibodies isolated from plasma donated by patients who have recovered as well as manufactured antibody treatments from companies such as Tarrytown, N.Y.-based Regeneron Pharmaceuticals Inc. and Incheon, South Korea-based Celltrion Inc.

Adaptive Biotechnologies Corp., on the other hand, has focused on cellular immunity to measure the T-cell response to infection with SARS-CoV-2. The cellular response has gained more interest as research has found that sicker patients have a "very blunted T-cell response," Lance Baldo, Adaptive's chief medical officer, explained, noting that it still isn't clear if the depletion of T cells is a cause or an effect of becoming sicker.

The company easily pivoted into studying COVID-19 because it was already studying T cells through a partnership with Redmond, Wash.-based Microsoft Corp. that was announced in early 2018. The deal was designed to sequence T-cell receptors (TCR) and then use Microsoft's machine learning to map antigens from infectious diseases that are bound by the TCRs. The companies had made some early progress with Lyme disease and had started a clinical program.

Then the COVID-19 pandemic hit.

It was easy to get Microsoft to sign on to the new project focused on mapping areas on SARS-CoV-2 that T-cell receptors use to identify cells infected with the virus. "It took one phone call to their head of research," Baldo told BioWorld.

The companies also signed on San Diego-based Illumina Inc. for sequencing support, health care partners to gather patient blood samples and Laboratory Corp. of America Holdings, of Burlington N.C., to help with mobile laboratories and assays.

The prospective ImmuneRACE (Immune Response Action to COVID-19 Events) study was launched in early June, and the companies have already released initial findings from ImmuneCODE, which includes data from roughly 1,000 patients enrolled in ImmuneRACE plus 4,000 additional patients from around the world.

The study found two types of TCRs in patients who were infected with SARS-CoV-2. "Private" TCRs appear to be specific to individual patients, while "public" TCRs are found in multiple patients, suggesting those antigens are more effective at activating and expanding T cells with those TCRs.

Adaptive then went into the wet lab to determine what antigens from SARS-CoV-2 bind to the TCRs in a project it's calling Immunoseq T-Map. About 545 multiplexed putative peptide antigens were incubated with T cells that have the identified TCRs to measure which antigens were able to activate which T cells.

"There are hundreds of these T-cell receptor sequences that map to important parts of the proteome," Baldo explained. While some of the hotspots fall in the spike protein on the coronavirus that most COVID-19 vaccine makers are using to elicit immunity to SARS-CoV-2, other parts of the virus also elicited strong immune responses. "This could absolutely inform the next generation – or even, frankly, the current generation – of therapeutics or the next-generation of vaccines," Baldo said.

As Adaptive and its partners continue to study the data, they plan to link the TCR responses to the outcomes of the patients to see if the development of certain TCRs result in milder symptoms or faster recovery times.

Diagnostic test

Using the common "public" TCRs, Adaptive is developing Immunoseq Dx, a blood-based test to determine if a patient has developed a T-cell response to SARS-CoV-2.

Testing for T cells could have a temporal advantage over currently available tests, potentially acting as a test for both current and past infections. About 60% to 70% of patients have a T-cell response in the first couple of days after infection and data from ImmuneCODE showed that the response persists beyond 90 days in almost all patients. By contrast, current molecular and antigen diagnostic tests only work while the virus is present. And, while tests for antibodies are designed to diagnose past infection, they'll only detect prior exposure for as long as the humoral antibody response persists, which doesn't appear to last as long as a T-cell response.

Immunoseq Dx could also offer an advantage simply by looking at a different kind of immune response. "It seems like many more subjects are having a cellular immune response vs. a humoral – or antibody – immune response, so it's possible that we'll be able to pick up additional patients that actually had the infection as compared to antibody serology," Baldo noted.

Adaptive is in talks with the FDA about the necessary steps to gain emergency use authorization for Immunoseq Dx with plans to hopefully launch the test this fall.