Viewpoint explains how T cell testing can help research on population-level SARS-CoV-2 adaptive immunity and inform public health policies

A recent viewpoint published in the journal Science Immunology illustrated that evaluating T cell responses to coronavirus disease 2019 (COVID-19) is essential to inform public health initiatives.

Study: Understanding T-cell responses to COVID-19 is essential for informing public health strategies. Image Credit: ESB Professional/Shutterstock
Study: Understanding T-cell responses to COVID-19 is essential for informing public health strategies. Image Credit: ESB Professional/Shutterstock

Background

COVID-19 vaccinations have significantly lowered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and infection-linked morbidity and death worldwide. Nevertheless, the emergence of SARS-CoV-2 variants resistant to neutralizing antibodies (nAbs) has posed a substantial threat to public health.

Hospitals in the United States (US) have been inundated with new SARS-CoV-2 patients, and death rates have risen as a result of the SARS-CoV-2 Delta variant surge. The advent of the Omicron variant indicated that even in nations with robust population immunity owing to earlier infection and immunization, waves of SARS-CoV-2 reinfection might occur. These data depict that SARS-CoV-2 will continue to mutate, becoming more resistant to host immunity.

To promote societal movement and freedom while still safeguarding people from severe COVID-19 and associated mortality, deployment of every available instrument is necessary. In the present work, the researchers evaluated the importance of T cell immune responses in COVID-19.

T cells identify a wide spectrum of SARS-CoV-2 antigens following COVID-19 vaccination or incidence

T-cells may react better to SARS-CoV-2 infection with emerging viral variants than antibodies because they recognize a wider variety of viral epitopes. T cells can identify linear determinants of proteins such as spike (S), including segments of the protein immune to antibody escape induced by viral mutations. Furthermore, nAbs can only target proteins on the viral surface, such as the S protein targeted by the contemporary COVID-19 vaccines. However, T-cell epitopes were derived from both the surface and structural proteins. Unlike other CoVs, where the S protein was targeted by more than 50% of T-cell recognition, the antigen hierarchy in the SARS-CoV-2 proteome was more evenly distributed.

The SARS-CoV-2 variants share T cell epitopes. S-derived epitopes conserved at 100% amino acid sequence identity accounted for 95.3% and 84.5% of the total CD8+ and CD4+ T cell epitopes, respectively. The CD8+ and CD4+ T cell responses to SARS-CoV-2 ancestral and Delta S were similar. On the contrary, SARS-CoV-2 variants of concern (VOCs) induced partial evasion of humoral immune responses with diminished vaccination- or infection-generated nAb activity.  

Vaccine effectiveness in preventing severe COVID-19, hospital admission, and mortality has been moderately or minimally impacted, regardless of the known loss of neutralizing ability against the Omicron, Delta, and other SARS-CoV-2 VOCs. This observation implies that long-term cellular immune memory plays a role in safeguarding against SARS-CoV-2 variants. Further, supporting these findings, Omicron mutations do not alter 70-80% of CD8+ and CD4+ T-cell epitopes in the S protein, and T-cell responses appear to be mostly intact.

T cells might defend against SARS-CoV-2 reinfection and offer long-term immunologic memory

Studies indicated that following SARS-CoV-2 vaccination or exposure, cellular and humoral immunity was maintained. The link between mild illness and optimum T cell responses after primary infection was backed by more recent studies demonstrating protection imparted by COVID-19-specific memory T cells on the second incidence of SARS-CoV-2. Those who failed to seroconvert after mild or asymptomatic SARS-CoV-2 infection exhibited T cell responses.

Patients undergoing B cell-depleting treatment had a lower antibody response despite maintaining a similar T cell response to healthy controls after COVID-19 vaccination. CD8+ T cell responses were linked with COVID-19 severity and death among hematologic malignancy patients exhibiting impaired humoral immunity. Although the T-cell response's longevity is still being studied, substantial COVID-19-specific CD8+ and CD4+ T cell responses were observed up to one year of SARS-CoV-2 infection and around six months after vaccination. Of note, memory T cells to SARS-CoV-1 have been found 17 years after exposure, indicating that T cells may impart long-term protection against severe SARS-CoV-2 illness.

T cell responses might indicate expected disease severity in COVID-19

Early activation of SARS-CoV-2-specific interferon-γ (IFN-γ)–secreting T cells were linked to a milder illness and faster viral clearance. Limited sequencing of SARS-CoV-2 epitopes targeted by CD8+ and CD4+ T cells demonstrated that some viral proteins consist of dominant epitopes shared by several people. The identification of decreased or increased SARS-CoV-2 risk in populations with certain human leukocyte antigen (HLA) polymorphisms might be aided by identifying these frequently shared epitopes in the setting of peptide presentation by HLA alleles.

A comprehensive study of T- and B-cell populations in SARS-CoV-2 patients revealed that more severe illness was linked with lower frequencies of CD4+ and CD8+ T cells. In less severe COVID-19, CD8+ T cells were reduced more than CD4+ T cells. In one study, T cells specific to certain SARS-CoV-2 peptides were elevated in people with severe COVID-19, suggesting that the immune reaction to some epitopes may have a role in disease severity. Moreover, T cells with specific morphologic characteristics and overactive T-cell responses have been associated with negative consequences.

Implications of progress in T cell activation quantifications in public health

T-cell detection methods, which can be separated into molecular and cellular tests, have their own set of benefits and drawbacks. The availability of equipment, reagents, data analysis experience, and the scope of the inquiry, among other criteria, may influence the choice of a specific test to investigate T-cell responses.

Assays assessing cytokine production upon antigen stimulation, like the enzyme-linked immunosorbent spot (ELISpot) analysis and the activation-induced marker (AIM) assay or intracellular cytokine staining (ICS), can be used to assess antigen-specific T-cell responses. ELISpot has previously been used to estimate the duration of SARS-CoV-2-induced persistent T-cell responses. AIM and ICS combined with flow cytometry have been employed to profile activated cells, enabling the analysis of severe SARS-CoV-2-linked immunophenotypes.

Direct ex vivo evaluation of SARS-CoV-2-specific T cells has been possible because of the use of tetramers. A high-throughput test that uses next-generation sequencing to characterize and detect COVID-19–specific T cell receptors (TCRs) was also granted Emergency Use Authorization (EUA) by the Food and Drug Administration (FDA) for prior COVID-19 incidence detection.

A more precise assessment of COVID-19 prevalence and population immunity may be obtained by combining T-cell measurements and seroprevalence. A better knowledge of SARS-CoV-2's adaptive immune response might help to improve public health policy and targeted treatments to protect susceptible populations. Furthermore, a thorough examination of vaccine-induced immunity will enable to combat the vaccine misinformation that emerged due to the absence of T-cell measurements.

Conclusions

The viewpoint implied that long-lasting T-cell responses to SARS-CoV-2 antigens promote immune-facilitated viral clearance following COVID-19 or its vaccination. Population-based COVID-19 adaptive immunity assessments so far have primarily evaluated IgG antibodies that neutralize SARS-CoV-2 or engage with its S protein. However, the current viewpoint demonstrated that employing existing techniques for quantifying T-cell immunity might offer a much fuller view of the immunological state following SARS-CoV-2 vaccination or infection. Furthermore, this could influence public health policies and treatments against COVID-19.

Journal reference:
Shanet Susan Alex

Written by

Shanet Susan Alex

Shanet Susan Alex, a medical writer, based in Kerala, India, is a Doctor of Pharmacy graduate from Kerala University of Health Sciences. Her academic background is in clinical pharmacy and research, and she is passionate about medical writing. Shanet has published papers in the International Journal of Medical Science and Current Research (IJMSCR), the International Journal of Pharmacy (IJP), and the International Journal of Medical Science and Applied Research (IJMSAR). Apart from work, she enjoys listening to music and watching movies.

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