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The changing landscape of COVID-19 testing – the potential of T-cell response monitoring

COVID-19 is here to stay

The efforts to manage the pandemic have led to an unprecedented technological development culminating in the largest vaccination campaign in history.1 The World Health Organization (WHO) has granted emergency use listing for 11 vaccines2 and over 13 billion doses have been administered globally.3 In its first year, the vaccination campaign was estimated to have saved around 20 million lives.4 Furthermore, hundreds of diagnostic tests, including antibody, antigen and polymerase chain reaction (PCR) tests, were developed in record time.5  

While it is generally believed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)  will become endemic and vaccines will provide protection from severe disease and death, a lot of uncertainty remains. First, predicting the evolutionary course of SARS-CoV-2 variants is exceedingly difficult due to the overlayed complexity of pre-existing immunity.6 Second, our understanding of the innate and adaptive immunologic mechanisms associated with coronavirus disease 2019 (COVID-19) is still incomplete.7,8 COVID-19 is here to stay, and there will still be an ongoing need for new treatments and diagnostics.

Patient-centricity – a hallmark of COVID-19 management in the future

 

Understanding of the immunologic responses in these populations at risk for severe COVID-19 is central to making better informed decisions on COVID-19 management, in the context of regular clinical care and could be ascertained by development of new testing strategies. 

As the COVID-19 pandemic transitions to endemicity, understanding of the immunologic mechanisms underlying SARS-CoV-2 immunity in patients at high risk of severe COVID-19 becomes increasingly important (data as of February 17, 2023).1,3‑5,9‑11

A holistic understanding of immunity against COVID-19 is key

 

The immune system provides protection from countless pathogens that are constantly evolving. B and T lymphocytes are the two major pillars of the adaptive immune response [Video].

The role of the adaptive immune system

Although vaccination reduces SARS-CoV-2 infection-related morbidity and mortality, emerging variants may have decreased susceptibility to antibody-mediated neutralization.13,14 As SARS-CoV-2 is likely to continue evolving, we must use every tool at our disposal to enable normal social functioning while protecting individuals from severe disease and death. To accomplish this goal, a comprehensive understanding of the adaptive immune response to SARS-CoV-2 is needed.13 This understanding could be facilitated by development of new COVID-19 diagnostic tools for routine use (Figure 1). 

Figure 1. COVID-19 unmet diagnostic needs: an assay that determines protection from infection following vaccination or re-infection after past infection13,15-21

figure 1.1

Binding antibody assays generally cannot differentiate between neutralizing and other antibodies, yet may show a good correlation depending on assay design15

figure 1.2

Decrease in IgG levels and nAbs has been observed in recovered individuals at different extent and speed, possibly depending on the assay employed and intrinsic patient differences16–18

figure 1.3

There is limited knowledge on how SARS-CoV-2-specific humoral or cellular immunity mediates durable protection19

nAb antibody titers are highly predictive of immune protection from symptomatic SARS-CoV-2 infection20

Fail

Some patients fail to develop high titers of nAbs after COVID-19 infection21

antibody-response

T-cell reactivity is therefore very important for individuals who are not able to mount a sufficiently strong antibody response13

A better understanding of cellular immunity is urgently needed to better predict disease outcome and determine whether patients develop long-lasting immunity

Abbreviations: COVID-19, coronavirus disease 2019; IgG, immunoglobulin G; nAbs, neutralizing antibodies; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 

During COVID-19 vaccine development the role of neutralising antibodies (nAbs) has been a major focus and less emphasis has been applied on understanding the role of T cells, memory B cells, and non-nAbs that may confer protection.13 As both humoral and cellular immunity collaborate for pathogen control, the development of a holistic understanding of the host response to pathogens like SARS-CoV-2 requires assessment of both antibodies and T cells.13

T-cell responses are less likely to be affected by virus variants. T-cell epitopes are derived from many viral antigens, including those that are under less selection pressure, while nAbs are predominantly targeting the spike protein. The spike protein shows a high number of mutations in emerging variants. T-cell responses are not only directed against spike but also the membrane, nucleocapsid, as well as non-structural proteins. In fact, >90% of CD4 + and CD8 + epitopes are 100% conserved across variants (including Omicron), and T cells of exposed donors or vaccinees effectively recognize SARS-CoV-2 variants (including Omicron).22-25

 

The Elecsys® IGRA SARS‑CoV‑2 assay for measurement of the T cell response complements Roche’s broad portfolio of COVID‑19 diagnostics

 

Elecsys® IGRA SARS-CoV-2 is an immunoassay for the qualitative detection of the T cell-mediated immune response to SARS-CoV-2. The assay is based on the ability of antigen-specific T cells to produce the pro-inflammatory cytokine IFN‑γ after encountering the antigen, which is a well-established marker of T-cell activation.13 IFN‑γ release assays (IGRA) employing similar principles have proven useful in tuberculosis where the Mycobacterium tuberculosis–specific IGRA test has replaced the previously used tuberculin skin test.13 The Elecsys® IGRA SARS-CoV-2 assay is intended as an aid in identifying individuals with an adaptive T cell response to SARS‑CoV‑2, indicative of past exposure to the virus or COVID-19 vaccination. It provides valuable information on the T cell responses of the patient, enabling the healthcare provider to make better informed decisions for patient care.

The assay uses a two-phased method to determine T cell immune response to SARS‑CoV‑2.

Elecsys® IGRA SARS-CoV-2
Tube

In vitro T cell stimulation using SARS-CoV-2-specific antigens in the cobas® IGRA SARS-CoV-2 Tubes: a fresh whole blood sample containing living T cells is incubated for 16–24 hours in the cobas® IGRA SARS-CoV-2 Tubes. Per patient sample, three different tube types are used: a Positive Control (PC) tube to determine the maximum T cell stimulation potential as a validation of sample quality; a Negative Control (NC) tube to determine the baseline IFN-γ level; and the specially coated Antigen tube to determine the IFN-γ released upon stimulation with SARS-CoV-2 peptides. The coating consists of 189 different peptides (the antigens) representing the SARS-CoV-2 membrane, nucleocapsid, spike, and non-structural proteins, providing a broad coverage of the SARS-CoV-2 genome. This peptide mix is designed to provide a substantial coverage (98%) of commonly occurring HLA subtypes to ensure that the response of both CD4+ and CD8+ T cells is captured. During the incubation, the stimulated SARS-CoV-2-specific T cells release IFN-γ, which is measured in the second phase.

Tube

IFN-y read-out using an automated electrochemiluminescence immunoassay (ECLIA): IFN-y released as a result of the T cell stimulation step is measured with the Elecsys® IGRA SARS-CoV-2 assay in plasma generated from the incubated blood samples. The numerical results from the NC tube, PC tube, and Antigen tube are evaluated in combination to derive the final qualitative result (T cell response detected or not detected).

The Elecsys® IGRA SARS-CoV-2 assay simplifies the determination of the cellular immune response to SARS-CoV-2 by automating a crucial part of the testing workflow.

 

It provides the physician with valuable information on the T-cell responses of their patients and can help inform clinical decisions in the next phase of the COVID-19 era. A better understanding of the holistic adaptive immune response in SARS-CoV-2-infected or -vaccinated individuals, and particularly the role played by T cells, will help future-proof our strategies against COVID-19. However, definitive verification for the protective role of T cells requires further research.13

Roche’s comprehensive response to the COVID-19 pandemic 

Figure 2. Roche’s extensive portfolio covers COVID-19 diagnostics across the disease continuum

Figure 3

Abbreviations: COVID-19, coronavirus disease 2019; POC, point-of-care; RAT, rapid antigen test; RT-PCR, reverse transcription-polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; * Available in the US only, under an EUA

Example

Elecsys® IGRA SARS-CoV-2

Learn more about how the Elecsys® IGRA SARS-CoV-2 assay can help to improve the understanding of the cellular immune response against SARS-CoV-2

References

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Video 1 references:

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