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Peptide Libraries Probe SARS-CoV-2 Crossreactive T Cell Memory

How is the immune response to SARS-CoV-2 influenced by previous infections with other coronaviruses? This is a question currently puzzling investigators, following the discovery of substantial T cell responses to SARS-CoV-2 proteins in patients with no history of COVID-19. These patients, commonly referred to as "unexposed", may have however plenty of history with coronavirus exposure in the form of HCoVs infections or "common colds". Investigators are keen on understanding the factors underscoring this T cell crossreactivity, which may be present in as many as 40-60% of "unexposed" individuals (Grifoni et al. 2020). Whether this newly uncovered T cell crossreactivity is beneficial for COVID-19 resolution or for immunization outcomes, remains to be determined.

In order to identify viral protein epitopes stimulating T cell crossreactivity, multiple groups have developed overlapping peptide libraries from SARS-CoV-2 sequences for ex vivo testing (Grifoni et al. 2020, Le Bert et al. 2020, Mateus et al. 2020). Using this approach, investigators have interrogated both CD4+ and CD8+ T cell responses to key SARS-CoV-2 derived peptides, by stimulating peripheral blood mononuclear cells (PBMCs) from various donor groups including: "unexposed", defined as individuals with no SARS or SARS-CoV-2 exposure, and COVID-19 convalescents.

T Cell Responses to SARS-CoV-2 from the "Unexposed"

In a recent Science article, investigators used a peptide megapool approach for T cell stimulation, which allowed them to screen over 400 peptides derived from SARS-CoV-2 spike and other viral protein sequences. A total of 142 SARS-CoV-2 epitopes were identified, which stimulated CD4+ T cells in "unexposed" samples. Interestingly, while spike derived epitopes activated T cells more frequently, this effect was predominantly associated with non-RBD spike regions. This finding may have important implications for ongoing vaccine clinical trials, which use immunogens derived from RBD sequences alone (e.g., Pfizer's BNT162b1, consisting of a lipid nanoparticle-formulated nucleoside-modified mRNA encoding the RBD trimer of SARS-CoV-2 spike protein).

Homology between SARS-CoV-2 and HCoV epitopes May Underscore T Cell Crossreactivity

To further understand the basis for SARS-CoV-2 T cell cross-reactivity in the "unexposed", investigators generated peptide pools from HCoV sequences. HCoV sequences were selected based on their homology to previously identified SARS-CoV-2 epitopes, corresponding to spike and other viral sequences, shown to induce T cell crossreactivity. Stimulation of "unexposed" samples with homologous HCoV derived peptides induced CD4+ T cell reactivity, supporting that T cell crossreactivity to SARS-CoV-2 may be linked to previous exposure to common cold viruses. Finally, CD4+ T cells activated by homologous SARS-CoV-2 and HCoV derived epitopes, were confirmed to have phenotypes consistent with that of effector and central memory T cells.

Similar T cell crossreactivity has been found by stimulating PBMCs from SARS-CoV donors with SARS-CoV-2 derived peptides. In a recent Nature article, peptides derived from SARS-CoV-2 nucleocapsid (N) protein sequences, re-activated T cells from SARS survivors. Overall, peptide library based screening of immune reactivity, may provide the foundation for identifying critical coronavirus epitopes to enable long lasting protection through immunization. Additionally, these findings further provide hope that certain vaccine candidates may offer broad protection to past, current and future unforeseeable coronavirus types.


1. Grifoni, A. et al. Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell (2020) doi:10.1016/j.cell.2020.05.015.

2. Le Bert, N. et al. SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature (2020) doi:10.1038/s41586-020-2550-z.

3. Mateus, J. et al. Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans. Science (80-. ). (2020) doi:10.1126/science.abd3871.

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