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Research Article: Promiscuous class II-binding SARS-CoV-2-nuc derived vaccine-peptide induced extensive conventional, innate and unconventional T cell responses

Date Published: 2025-11-11

Abstract:
We describe the T-cell response of two healthy SARS-CoV-2-unexposed volunteers to a SARS-CoV-2 nucleoprotein-derived vaccine peptide predicted to promiscuously bind multiple HLA-DR allotypes. NGS-based bulk TCR-repertoire analysis of peptide-specific T-cell responses 4 (D2) and 27 (D1) weeks after vaccination identified CDR3 regions of TCR?, -?, -? and -? chains in T cells responding ex-vivo to the vaccine peptide LLLLDRLLNQLESKMS with IFN? + -secretion. Adaptive repertoires were unique. Donors shared 15 TCR? and 9 TCR? clonotypes, all public, showing no conserved motifs but TdT-independent “neonatal” CDR3 regions close to the germline. Half the wtSARS-CoV-2 nucleocapsid-reactive adaptive clonotypes show preferential V-segment usage (6/64 V? and 4-8/45 V? chains), and all share/show a N-nucleotide-encoded hydrophobicity in their CDR3 region. V?C? rearrangements (20.4% and 15.3% of the TCR?-repertoires, respectively), V?1C? ??-clonotypes homologous to public CD1-restricted V?1 + ??TCRs, and the induction of “adaptive” V?2V?9 negative T cells support the role of innate T cells in the immune response.

Introduction:
SARS-CoV-2, the causative agent of coronavirus disease 19 (COVID-19), has caused devastating global morbidity and mortality ( 1 ) particularly in the elderly ( 2 ), people with chronic diseases ( 3 ), and co-morbidities such as cancer ( 4 ). Globally licensed COVID-19 vaccines focus on humoral immune responses as protective immune mediators ( 5 ). However, short duration and limited neutralizing effect against certain virus variants provide only temporary protection and require repeated vaccine boosters. T-cell…

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