Defects in T cell immunity to SARS-CoV-2 have been linked to an increased risk of severe COVID-19 disease (even after vaccination), persistent viral shedding and the emergence of more virulent viral variants. To address this T cell deficit, we sought to prepare and cryopreserve banks of virus-specific T cells (VSTs), which would be available as a partially HLAmatched off-the-shelf product for immediate therapeutic use. By interrogating the peripheral blood of healthy convalescent donors, we identified immunodominant and protective T cell target antigens, and generated and characterized polyclonal VST lines with activity against multiple clinically important SARS-CoV-2 variants (including ‘delta’ and ‘omicron’). The feasibility of making and safely utilizing such VSTs clinically was assessed by administering partially HLAmatched, third-party, cryopreserved SARS-CoV-2-specific T cells (ALVR109) in combination with other antiviral agents to 4 individuals who were hospitalized with COVID-19. In conclusion, this study establishes the feasibility of preparing and delivering off-the-shelf SARS-CoV-2-directed VSTs to patients with COVID-19 and supports the clinical use of VSTs outside of the profoundly immune compromised setting (ClinicalTrials.gov number, NCT04401410).
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