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Cell
. 2025 Jul 30:S0092-8674(25)00804-9.
doi: 10.1016/j.cell.2025.07.015. Online ahead of print. Highly conserved Betacoronavirus sequences are broadly recognized by human T cells
Tertuliano Alves Pereira Neto 1 , Christian Zmasek 2 , Liliana Avalos 1 , John Sidney 1 , Raphael Trevizani 1 , Elizabeth Phillips 3 , Simon Mallal 3 , April Frazier 1 , Gene S Tan 4 , Richard H Scheuermann 5 , Alessandro Sette 6 , Alba Grifoni 7
Affiliations
The COVID-19 pandemic highlighted the critical need for vaccine strategies capable of addressing emerging viral threats. Betacoronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome (MERS), and SARS-CoV-2, present significant pandemic risks due to their zoonotic potential and genetic diversity. T cell-mediated immunity has demonstrated durable responses and strong cross-reactivity, offering a promising avenue for achieving broad immunity within a viral family. In this study, we combined comprehensive epitope mapping with sequence conservation analyses to identify conserved T cell epitope regions (CTERs), which constitute 12% of the complete SARS-CoV-2 proteome. We showed that SARS-CoV-2 CTER-specific T cells cross-reactively recognize sequences from multiple Betacoronavirus subgenera. Importantly, incorporating CTERs from non-spike proteins significantly enhanced T cell cross-reactivity potential and human leukocyte antigen (HLA) coverage compared with T cells targeting only spike proteins. Our findings lay the groundwork for a multi-antigen vaccine strategy that includes non-spike proteins to expand cross-reactive immunity across a broader spectrum of Betacoronaviruses.
Keywords: Betacoronavirus; SARS-CoV-2; T cells; epitopes; immunogenic regions; pandemic preparedness; sequence conservation; vaccine.
. 2025 Jul 30:S0092-8674(25)00804-9.
doi: 10.1016/j.cell.2025.07.015. Online ahead of print. Highly conserved Betacoronavirus sequences are broadly recognized by human T cells
Tertuliano Alves Pereira Neto 1 , Christian Zmasek 2 , Liliana Avalos 1 , John Sidney 1 , Raphael Trevizani 1 , Elizabeth Phillips 3 , Simon Mallal 3 , April Frazier 1 , Gene S Tan 4 , Richard H Scheuermann 5 , Alessandro Sette 6 , Alba Grifoni 7
Affiliations
- PMID: 40774254
- DOI: 10.1016/j.cell.2025.07.015
The COVID-19 pandemic highlighted the critical need for vaccine strategies capable of addressing emerging viral threats. Betacoronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome (MERS), and SARS-CoV-2, present significant pandemic risks due to their zoonotic potential and genetic diversity. T cell-mediated immunity has demonstrated durable responses and strong cross-reactivity, offering a promising avenue for achieving broad immunity within a viral family. In this study, we combined comprehensive epitope mapping with sequence conservation analyses to identify conserved T cell epitope regions (CTERs), which constitute 12% of the complete SARS-CoV-2 proteome. We showed that SARS-CoV-2 CTER-specific T cells cross-reactively recognize sequences from multiple Betacoronavirus subgenera. Importantly, incorporating CTERs from non-spike proteins significantly enhanced T cell cross-reactivity potential and human leukocyte antigen (HLA) coverage compared with T cells targeting only spike proteins. Our findings lay the groundwork for a multi-antigen vaccine strategy that includes non-spike proteins to expand cross-reactive immunity across a broader spectrum of Betacoronaviruses.
Keywords: Betacoronavirus; SARS-CoV-2; T cells; epitopes; immunogenic regions; pandemic preparedness; sequence conservation; vaccine.