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T cell tests aim for broader picture of COVID-19 immunity

T cell tests could uncover COVID-19 patients and biology missed by other assays

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While the COVID-19 testing conversation has centered on assays for antiviral antibodies or the virus itself, at least two companies think T cell tests could catch patients the other methods miss. T cell tests could also guide vaccine design, predict patient outcomes and inform the ongoing debate about the role of the cells in SARS-CoV-2 immunity.

The world of COVID-19 tests is largely carved up into polymerase chain reaction (PCR) assays that diagnose active infections by detecting viral genomes, and serological immunoassays that flag past viral exposure by detecting host antibodies against the virus. Other molecular diagnostics that detect the novel coronavirus -- using probes, CRISPR, tool antibodies or genomic sequencing -- have also come onto the market via FDA Emergency Use Authorization (EUA) (see “COVID-19 Diagnostic Tech Tableau”).

Now, an emerging class of tests that measure host T cell responses against SARS-CoV-2 stands to fill gaps left by viral and antibody assays by catching patients who have cleared the virus without forming antibody responses.

Adaptive Biotechnologies Corp. (NASDAQ:ADPT) and Oxford Immunotec Global plc (NASDAQ:OXFD) have each announced they are developing T cell-based COVID-19 tests, with the eventual goal of seeking EUA. The former launched a prospective study on May 5 to determine the predictive power of its TCR sequencing platform, while the latter released its live cell cytokine production test on May 19 for research use; both have marketed tests for other indications that use similar underlying technologies.

The companies believe antibody tests are under-counting past SARS-CoV-2 exposure. T cell responses offer a more complete signal because they generally arise independently of and earlier than antibodies, said Oxford Immunotec CEO Peter Wrighton-Smith.

“There’s a very credible belief that we’ll need to add some knowledge of T cells to heighten our understanding of who is immune.”

Peter Wrighton-Smith, Oxford Immunotec

“Evidence is rapidly emerging that not everybody develops antibodies,” he said. “There is the hope that T cells will detect additional people who have been exposed, but were missed by serology tests."

Adaptive CSO Harlan Robins told BioCentury that because antiviral T cell responses emerge within days of exposure and persist for weeks, the company’s technology, which captures circulating TCR repertoires, could play the role of both molecular diagnostic and serological test by simultaneously scanning for TCR signatures associated with active and past infections. “The test should straddle both.”

The companies think their quantitative T cell tests could help determine whether a patient is having an effective vaccine response. Vaccine developers have primarily reported clinical and preclinical efficacy signals in terms of neutralizing antibody titers, but there are concerns that these values only tell part of the story.

“There’s a very credible belief that we’ll need to add some knowledge of T cells to heighten our understanding of who is immune,” Wrighton-Smith said.

Because severe COVID-19 is driven by aberrant immune responses, the companies believe T cell signatures could be predictive of disease severity.

And since both companies’ technologies involve linking T cell responses to SARS-CoV-2 antigens, the tests could shed light on which antigens could make the best vaccines. On June 11, Adaptive released the first set of data from its ImmuneCODE database, which contains de-identified data capturing how TCRs from over a thousand COVID-19 patient blood samples reacted to SARS-CoV-2 antigens in the company’s lab.

“What we just released shows the exact parts of the virus the immune system is seeing. Those are the pieces that will be relevant for creating a vaccine,” said Robins.

Live signal

Oxford Immunotec’s testing platform is based on the industrialization of a long-used functional test known as an ELISPOT (enzyme-linked immune absorbent spot) assay.

ELISPOTs detect active effector T cells in patient samples by counting the number of cells that secrete IFNγ when exposed to antigenic peptides.

The major challenge for live, functional clinical assays is keeping the functions of the cells intact during sample shipping and processing, and avoiding artifacts introduced by freezing and thawing the cells.

Oxford Immunotec overcame those hurdles by discovering they could preserve T cell function at room temperature for 54 hours after sample collection by removing granulocytes, which secrete factors that inhibits T cell function. The company has automated the assay for high-throughput use.

The technology has been applied to the company’s tuberculosis (TB) diagnostic, and to its test for assessing immune responses to cytomegalovirus (CMV) in transplant patients.

Oxford Immunotec’s COVID-19 test measures T cell responses to pools of SARS-CoV-2 antigens. Wrighton-Smith said the company has data in hand showing the test detects T cell responses in patients exposed to the novel coronavirus, without high background signals in the general population.

The company is in collaboration discussions with undisclosed groups.

Pattern detection

Adaptive believes that by studying the array of TCR sequences in thousands of patients’ blood, it can identify patterns in TCR specificity and frequency corresponding to different disease states, including pre-symptomatic cancers, infections and autoimmune diseases (see “Adaptive Betting on Immune System”).

The company markets a diagnostic for minimal residual disease (MRD) in B cell cancers, and is developing a test for Lyme disease.

To broaden the scope of its test, Adaptive has partnered with Microsoft Corp. (NASDAQ:MSFT) to create a map that connects TCR sequences to the antigens they recognize using a combination of wet lab screening and machine learning. That mapping allows it to identify which TCRs are relevant for which types of disease; in turn, it points out which disease antigens are driving T cell responses.

Through its ImmuneCODE database, Adaptive is sharing information on interactions between patient TCRs and SARS-CoV-2 antigens, which the company believes could help researchers understand the biology of COVID-19, including the most immunogenic T cell antigens. The company has made a point of including geographically and ethnically diverse samples.

Adaptive is also conducting a prospective study, dubbed ImmuneRACE (Immune Response Action to COVID-19 Events), to determine whether TCR signatures can be used to identify patients with active and past infections.

The study has three cohorts: one of convalescent patients, another of acutely infected patients, and a third of individuals who have been exposed to the virus but not diagnosed. Robins told BioCentury the third group is designed to enrich for asymptomatic patients, which have been the most challenging to study.

Adaptive also plans to longitudinally monitor patients’ TCR sequences in tandem with their antibody signatures and clinical outcomes, with the goal of identifying signals that predict outcomes like protection from reinfection, or admission to the ICU.

“Everyone is getting more or less the same virus," Robins said. "Why do some people end up in the ICU and some people not, it's almost for sure related to how your immune system is handling the virus.”

Targets

IFNγ - Interferon γ

TCR - T cell receptor

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