Abstract
SARS-CoV-2 infection takes a mild or clinically inapparent course in the majority of humans who contract this virus. After such individuals have cleared the virus, only the detection of SARS-CoV-2-specific immunological memory can reveal the exposure, and hopefully the establishment of immune protection. With most viral infections, the presence of specific serum antibodies has provided a reliable biomarker for the exposure to the virus of interest. SARS-CoV-2 infection, however, does not reliably induce a durable antibody response, especially in sub-clinically infected individuals. Consequently, it is plausible for a recently infected individual to yield a false negative result within only a few months after exposure. Immunodiagnostic attention has therefore shifted to studies of specific T cell memory to SARS-CoV-2. Most reports published so far agree that a T cell response is engaged during SARS-CoV-2 infection, but they also state that in 20-81% of SARS-CoV-2-unexposed individuals, T cells respond to SARS-CoV-2 antigens (mega peptide pools), allegedly due to T cell cross-reactivity with Common Cold coronaviruses (CCC), or other antigens. Here we show that, by introducing irrelevant mega peptide pools as negative controls to account for chance cross-reactivity, and by establishing the antigen dose-response characteristic of the T cells, one can clearly discern between cognate T cell memory induced by SARS-CoV-2 infection vs. cross-reactive T cell responses in individuals who have not been infected with SARS-CoV-2.
Highlights
The assessment of immune memory has relied upon measurements of serum antibodies without queries of the T cell compartment
The Rationale for Selecting IFN-g ELISPOT for Detecting SARS-CoV-2-Specific Memory T cells T cell immune monitoring aims at detecting in vivo expanded and differentiated antigen-specific T cell populations directly ex vivo, either in freshly isolated peripheral blood mononuclear cells (PBMC), or in PBMC that have been cryopreserved following protocols that maintain full T cell functionality upon thawing the cells [50]
The overall question that we addressed was whether test conditions can be established that permit to clearly identify SARS-CoV-2specific T cell memory engaged in individuals who underwent a mild infection vs. humans who have not been infected with this virus
Summary
The assessment of immune memory has relied upon measurements of serum antibodies without queries of the T cell compartment. While the majority of SARS-CoV-2-infected individuals initially develop an antibody response to this virus, false negative results are a concern because not all infected individuals attain high levels of serum antibody reactivity acutely after infection [1,2,3], and those who do develop detectable antibody reactivity might decline to the limit of detection within a few months [4] In such cases, the detection of T cell memory might be the only evidence of such infection, and is a surrogate of acquired immune protection from SARS-CoV-2 reinfection. Progress with settling the issue of T cell cross-reactivity in SARS-CoV-2 antigen recognition, and identifying suitable test systems, will decide whether T cell diagnostics can reliably detect specific immune memory to SARS-CoV-2 infection/exposure, and possibly identify the immune protected status of those subjects
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