模块化纳米壳疫苗技术诱导多价和平衡T细胞反应

Pinghan Huang, Hsiao-Han Tsai, Vivian Y Tat, Jason C. Hsu, Drelich Aleksandra, Hui-Wen Chen, C. J. Hu, C. Tseng
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摘要

在COVID-19爆发后,细胞免疫已被证明可以提供保护,特别是在突破性感染和B细胞缺陷患者中。此外,持久的细胞免疫靶向SARS-CoV-2变体或不同冠状病毒中的保守表位,从而激发了一种有吸引力的疫苗开发策略。然而,如何同时诱导针对多个表位的平衡T细胞应答仍有待阐明。在这项研究中,我们试图设计一种基于T细胞的疫苗,可以针对不同的T细胞表位调整价。我们选择了7种SARS-CoV-2特异性短肽作为抗原,包括I-Ab/H-2Kb/H-2Db限制性表位。此外,我们使用PLGA纳米颗粒作为疫苗平台,实现了指定肽的精确加载。用不同的多肽组合免疫小鼠,并使用脾细胞获得表位特异性ifn γ表达CD8+或CD4+ T细胞反应。首先,我们证实了每个肽的强大免疫原性。然后我们结合了等量的指示表位肽,并在组合中获得了每个表位的免疫原性。结果表明,无论MHC等位基因和MHC类别如何,多肽相互竞争诱导T细胞反应。此外,显性表位显著抑制亚显性表位的免疫原性。最后,通过优化抗原剂量,纳米颗粒疫苗诱导了针对所有7个表位的更平衡的T反应。利用纳米颗粒的优势,我们的研究结果揭示了一种诱导多价T细胞反应的可行策略。进一步说明T细胞表位的竞争是控制细胞免疫的因素之一。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Induction of multivalent and balanced T cell responses by modular nanoshell vaccine technology
After the outbreak of COVID-19, cellular immunity has been shown to provide protection especially in breakthrough infection and B cell-deficient patients. Furthermore, durable cellular immunity targets conserved epitopes among SARS-CoV-2 variants or different coronavirus then inspiring an attractive strategy for vaccine development. However, how to simultaneously induce balanced T cell responses against multiple epitopes still needs to be elucidated. In this study, we sought to design a T cell-based vaccine that can adjust valency against different T cell epitopes. We selected seven SARS-CoV-2 specific short peptides as antigens, including I-Ab/H-2Kb/H-2Db restricted epitopes. Furthermore, we used PLGA nanoparticle as vaccine platform to achieve the precise loading of the indicated peptides. Mice were immunized with different combinations of peptides and splenocytes were used to access epitope specific-IFN gamma expressing CD8+ or CD4+ T cell responses. First, we confirmed the robust immunogenicity of each peptide. We then combined an equal amount of indicated epitope peptides and accessed the immunogenicity of each epitope in the combination. The results showed peptides compete with each other to induce T cell responses regardless of MHC allele and MHC class. In addition, dominant epitopes significantly suppressed the immunogenicity of the subdominant epitopes. Finally, by optimizing the antigen dose, nanoparticle vaccine induced more balanced T responses against all seven epitopes. Taking advantage of nanoparticle, our results reveal a viable strategy to induce multivalent T cell response. Furthermore, the result suggests that competition of T cell epitopes is one of the factors controlling cellular immunity.
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