Magnitude and Dynamics of the T-Cell Response to SARS-CoV-2 Infection at Both Individual and Population Levels

Abstract

T cells are involved in the early identification and clearance of viral infections and also support the development of antibodies by B cells. This central role for T cells makes them a desirable target for assessing the immune response to SARS-CoV-2 infection. Here, we combined two high-throughput immune profiling methods to create a quantitative picture of the T-cell response to SARS-CoV-2. First, at the individual level, we deeply characterized 3 acutely infected and 58 recovered COVID-19 subjects by experimentally mapping their CD8 T-cell response through antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I presented viral peptides (class II data in a forthcoming study). Then, at the population level, we performed T-cell repertoire sequencing on 1,015 samples (from 827 COVID-19 subjects) as well as 3,500 controls to identify shared "public" T-cell receptors (TCRs) associated with SARS-CoV-2 infection from both CD8 and CD4 T cells. Collectively, our data reveal that CD8 T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the T-cell response to SARS-CoV-2 peaks about one to two weeks after infection and is detectable for several months after recovery. As an application of these data, we trained a classifier to diagnose SARS-CoV-2 infection based solely on TCR sequencing from blood samples, and observed, at 99.8% specificity, high early sensitivity soon after diagnosis (Day 3-7 = 83.8% [95% CI = 77.6-89.4]; Day 8-14 = 92.4% [87.6-96.6]) as well as lasting sensitivity after recovery (Day 29+/convalescent = 96.7% [93.0-99.2]). These results demonstrate an approach to reliably assess the adaptive immune response both soon after viral antigenic exposure (before antibodies are typically detectable) as well as at later time points. This blood-based molecular approach to characterizing the cellular immune response has applications in vaccine development as well as clinical diagnostics and monitoring.

CD8+ T cell responses in convalescent COVID-19 individuals target epitopes from the entire SARS-CoV-2 proteome and show kinetics of early differentiation

“…In addition to the detection of epitopes previously described by others, over a third (i.e. 35%) of the antigen-specific T cells identified here have not been previously reported (Table S6), thereby highlighting the sensitivity of the adopted screening approach 8,9,22–27 . However, given the low frequencies of many of these CD8 T+ cells, it is possible that these were below the detection threshold since T cell counts are very low in acutely infected patient samples 28 .…”

An Effective COVID-19 Vaccine Needs to Engage T Cells

“…Indeed, several recent studies reported initial results from profiling B cell receptor (BCR) and TCR repertoires in COVID-19 patients (27,45,67,68). Consistent with the data from other virus infections, they report convergent B cell clonotypic responses closely associated with SARS-CoV-2 AB.…”

“…Additional recent studies have decoded blood T cell clonotypes and recognized antigen epitopes restricted by HLA class I or II in mostly convalescent COVID-19 patients and controls (19,32,38,40,67,69,70). Taken together, the studies show that anti-SARS-CoV-2 T cell responses target immunodominant epitopes broadly spread across the viral proteome mostly beyond the S protein, involve convergent and shared T cell clonotypes among patients and persist for several months post-recovery.…”

“…The precise impact of virus reactive T cell clonotypes and their epitope specificity and phenotype on disease course, and their prognostic relevance remain to be elucidated. Pointing to the latter, profiling a subject's TCR repertoire worked as a diagnostic for past or current COVID-19 even in absence of virus-specific AB (67).…”

The bumpy road to achieve herd immunity in COVID-19

“…This data aids the route toward effective vaccine development. [25] More data will emerge in the post-pandemic period when the duration of effective immunity will be challenged. If the specific immunity is transient, the virus will lead to biennial/annual outbreaks entering a five years cycle.…”