Whole-Blood Cellular Responses: A Promising Indicator of SARS-CoV-2 Immunity Compared to Serology

<b>Background:</b> Currently available immunological tests for SARS-CoV-2 assess only antibody responses. Despite the growing evidence that T cells play a crucial role in protection, especially against emerging viral variants, no routine test is available to determine T cell immunity. The prognostic value of SARS-CoV-2-specific antibodies for determining whether individuals are immune and protected against disease remains uncertain. This is in part due to the following: (a) specificity and limitations such as the sensitivity of antibody tests, and (b) the lack of correlation between antibody titers (quantity) and the antiviral function of antibodies (quality). Approximately a quarter of SARS-CoV-2-infected patients with symptoms fail to show seroconversion in serological assays. <b>Methods</b>: The current report describes the development and application of a whole-blood-based assay to detect previous exposure to SARS-CoV-2. Whole blood is stimulated with SARS-CoV-2-derived peptides identified during assay development and stimulation-induced cytokines quantified using a multiplex testing platform. The resulting cytokine profiles are generated using computational tools to identify previous exposure to the virus. <b>Results</b>: The application of the assay revealed a lack of self-awareness of individuals' COVID-19 infection history and demonstrated the value of this new assay to assess the prevalence of SARS-CoV-2 exposure history and immunity in populations. <b>Conclusions</b>: Positive responses in this assay can facilitate the identification of underlying causes of unexplained symptoms and provide clinically actionable insights for healthcare applications, including in the continued conundrum of post-acute sequela of SARS-CoV-2 infection (PASC or "long COVID"), for which both diagnosis and management remain challenging.