T-cell receptor sequencing identifies prior SARS-CoV-2 infection and correlates with neutralizing antibody titers and disease severity

Abstract

Measuring the adaptive immune response to SARS-CoV-2 can enable the assessment of past infection as well as protective immunity and the risk of reinfection. While neutralizing antibody (nAb) titers are one measure of protection, such assays are challenging to perform at a large scale and the longevity of the SARS-CoV-2 nAb response is not fully understood. Here, we apply a T-cell receptor (TCR) sequencing assay that can be performed on a small volume standard blood sample to assess the adaptive T-cell response to SARS-CoV-2 infection. Samples were collected from a cohort of 302 individuals recovered from COVID-19 up to 6 months after infection. Previously published findings in this cohort showed that two commercially available SARS-CoV-2 serologic assays correlate well with nAb testing. We demonstrate that the magnitude of the SARS-CoV-2-specific T-cell response strongly correlates with nAb titer, as well as clinical indicators of disease severity including hospitalization, fever, or difficulty breathing. While the depth and breadth of the T-cell response declines during convalescence, the T-cell signal remains well above background with high sensitivity up to at least 6 months following initial infection. Compared to serology tests detecting binding antibodies to SARS-CoV-2 spike and nucleoprotein, the overall sensitivity of the TCR-based assay across the entire cohort and all timepoints was approximately 5% greater for identifying prior SARS-CoV-2 infection. Notably, the improved performance of T-cell testing compared to serology was most apparent in recovered individuals who were not hospitalized and were sampled beyond 150 days of their initial illness, suggesting that antibody testing may have reduced sensitivity in individuals who experienced less severe COVID-19 illness and at later timepoints. Finally, T-cell testing was able to identify SARS-CoV-2 infection in 68% (55/81) of convalescent samples having nAb titers below the lower limit of detection, as well as 37% (13/35) of samples testing negative by all three antibody assays. These results demonstrate the utility of a TCR-based assay as a scalable, reliable measure of past SARS-CoV-2 infection across a spectrum of disease severity. Additionally, the TCR repertoire may be useful as a surrogate for protective immunity with additive clinical value beyond serologic or nAb testing methods.

Vaccine Considerations for Multiple Sclerosis in the COVID-19 Era

“…When thinking about the potential impact of MS DMTs on vaccine efficacy, the role of specific immune cell populations may be considered. For example, T cell signatures may be a more sensitive measure of past SARS-CoV-2 infection than antibody assays, as individuals with symptomatic infections or who required hospitalization had higher T cell responses [ 176 ]. This suggests that disease-specific memory T cells, in addition to antibody titers, may be measurable and reliable correlates of protection [ 176 ].…”

“…For example, T cell signatures may be a more sensitive measure of past SARS-CoV-2 infection than antibody assays, as individuals with symptomatic infections or who required hospitalization had higher T cell responses [ 176 ]. This suggests that disease-specific memory T cells, in addition to antibody titers, may be measurable and reliable correlates of protection [ 176 ]. However, SARS-CoV-2-reactive CD4 + T cells have been reported in 35–60% of unexposed individuals, suggesting possible cross-reactive T cell recognition between other coronaviruses (e.g., common cold viruses) and COVID-19 [ 177 – 179 ]; the protective effect of such cross-reactive T cells is unclear.…”

“…Coronavirus-specific T cells from Middle Eastern respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) have been shown to have long-term persistence and contribute to protection [ 176 , 180 , 181 ]. Hence, DMTs that deplete or significantly impact T cells may affect the efficacy of potential COVID-19 vaccines.…”

Immunosequencing of the T-cell receptor repertoire reveals signatures specific for diagnosis and characterization of early Lyme disease

“…CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) previous observations characterizing the T-cell response in patients infected with SARS-CoV-2 (46). Median model scores decreased from 6.1 to 2.5, and model sensitivity decreased from 56% (91/161) at enrollment to 32% (51/161) 6 months posttreatment.…”

“…We have previously shown that classifiers based on quantification of disease-associated public TCR sequences can be used for sensitive identification of past infection with CMV (43) or SARS-CoV-2 (44). Such classifiers leverage the relative frequency of disease-associated sequences within the repertoire, measures that have been shown to be associated with disease severity in the setting of SARS-CoV-2 (45,46). Clinical validation of a T-cell assay for SARS-CoV-2 utilizing a similar methodology demonstrated high positive percent agreement (>94.5%) and negative percent agreement (~100%) with reverse transcriptase PCR (RT-PCR) for detection of past SARS-CoV-2 infection (46,47).…”