据推测,含有破伤风-白喉抗原的疫苗可诱导对严重急性呼吸道综合症冠状病毒2(SARS-CoV-2)的交叉反应性免疫,可以预防冠状病毒病(COVID-19)。在这项工作中,我们研究了破伤风白喉(Td)疫苗引发SARS-CoV-2现有T细胞免疫的能力。为此,我们首先收集了已知的SARS-CoV-2特异性CD8+T细胞表位,这些表位在SARS-CoV-2感染人类过程中被靶向,并鉴定为与破伤风-白喉疫苗抗原具有相似性的Td疫苗潜在交叉反应,根据Levenshtein编辑距离判断(每个表位序列编辑率≤20%)。因此,我们选择了25个具有高群体覆盖率的潜在交叉反应性SARS-CoV-2特异性CD8+T细胞表位,这些表位被组装成合成肽池(TDX池).使用外周血单核细胞,我们首先通过细胞内IFNγ染色测定确定现有的CD8+T细胞对TDX池和其他肽池的回忆反应,包括覆盖SARS-CoV-2尖峰蛋白和核衣壳磷蛋白(NP)的重叠肽库。在研究的科目中,CD8+T细胞对Spike和TDX肽库的回忆反应是显性的和可比较的,而对NP肽库的回忆反应频率较低且较弱。随后,我们使用Td疫苗体外引发/刺激的无抗原经验的幼稚T细胞研究了对相同肽的反应。通过在Td疫苗存在下将幼稚T细胞与自体辐照的外周单核细胞共培养来进行引发刺激,IL-2、IL-7和IL-15。有趣的是,用Td疫苗刺激/引发的幼稚CD8+T细胞对TDX池反应强烈且特异性,不是其他SARS-CoV-2肽池。最后,我们显示C57BL/6J小鼠的Td免疫引起T细胞与TDX池交叉反应。总的来说,我们的研究结果支持破伤风-白喉疫苗可以引发SARS-CoV-2交叉反应性T细胞,并可能有助于塑造T细胞对病毒的反应.
Vaccines containing tetanus-diphtheria antigens have been postulated to induce cross-reactive immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which could protect against coronavirus disease (COVID-19). In this work, we investigated the capacity of Tetanus-diphtheria (Td) vaccine to prime existing T cell immunity to SARS-CoV-2. To that end, we first collected known SARS-CoV-2 specific CD8+ T cell epitopes targeted during the course of SARS-CoV-2 infection in humans and identified as potentially cross-reactive with Td vaccine those sharing similarity with tetanus-diphtheria vaccine antigens, as judged by Levenshtein edit distances (≤ 20% edits per epitope sequence). As a result, we selected 25 potentially cross-reactive SARS-CoV-2 specific CD8+ T cell epitopes with high population coverage that were assembled into a synthetic peptide pool (TDX pool). Using peripheral blood mononuclear cells, we first determined by intracellular IFNγ staining assays existing CD8+ T cell recall responses to the TDX pool and to other peptide pools, including overlapping peptide pools covering SARS-CoV-2 Spike protein and Nucleocapsid phosphoprotein (NP). In the studied subjects, CD8+ T cell recall responses to Spike and TDX peptide pools were dominant and comparable, while recall responses to NP peptide pool were less frequent and weaker. Subsequently, we studied responses to the same peptides using antigen-inexperienced naive T cells primed/stimulated in vitro with Td vaccine. Priming stimulations were carried out by co-culturing naive T cells with autologous irradiated peripheral mononuclear cells in the presence of Td vaccine, IL-2, IL-7 and IL-15. Interestingly, naive CD8+ T cells stimulated/primed with Td vaccine responded strongly and specifically to the TDX pool, not to other SARS-CoV-2 peptide pools. Finally, we show that Td-immunization of C57BL/6J mice elicited T cells cross-reactive with the TDX pool. Collectively, our findings support that tetanus-diphtheria vaccines can prime SARS-CoV-2 cross-reactive T cells and likely contribute to shape the T cell responses to the virus.