Lin Guibin, Yan Huan, Sun Jing, Zhao Jincun, Zhang Yuan
The Second Affiliated Hospital, School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou, Guangdong 511442, China.
National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, Guangdong 510006, China.
Mol Ther Nucleic Acids. 2023 Jun 13;32:650-666. doi: 10.1016/j.omtn.2023.04.021. Epub 2023 Apr 23.
The creation of safe and effective vaccines that induce potent cellular and humoral immune responses against SARS-CoV-2 is urgently needed to end the global COVID-19 epidemic. Here, we developed an alphavirus-derived self-replicating RNA (repRNA)-based vaccine platform encoding the receptor-binding domain (RBD) of SARS-CoV-2 spike glycoprotein. The repRNA triggers prolonged antigen expression compared with conventional mRNA due to the replication machinery of repRNA. To improve the delivery and vaccine efficacy of repRNA, we developed a self-assembling liposome-protamine-RNA (LPR) nanoparticle with highly efficient encapsulation and transfection of repRNA. LPR-repRNA vaccines substantially activated type I interferon response and innate immune signaling pathways. Subcutaneous immunization of LPR-repRNA-RBD led to prolonged antigen expression, stimulation of innate immune cells, and induction of germinal center response in draining lymph nodes. LPR-repRNA-RBD induced antigen-specific T cell responses and skewed cellular immunity toward an effector memory CD8 T cell response. Immunizations with LPR-repRNA-RBD triggered the production of anti-RBD IgG antibodies and induced neutralizing antibody response against SARS-CoV-2 pseudovirus. LPR-repRNA-RBD vaccines reduced SARS-CoV-2 infection and lung inflammation in mice. Altogether, these data suggest that the LPR-repRNA platform can be a promising avenue for COVID-19 vaccine development.
为终结全球新冠疫情，迫切需要研发出能诱导针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）产生强大细胞免疫和体液免疫反应的安全有效的疫苗。在此，我们开发了一种基于甲病毒衍生的自我复制RNA（repRNA）的疫苗平台，该平台编码SARS-CoV-2刺突糖蛋白的受体结合域（RBD）。由于repRNA的复制机制，与传统mRNA相比，repRNA能触发更长时间的抗原表达。为提高repRNA的递送效率和疫苗效力，我们开发了一种自组装脂质体-鱼精蛋白-RNA（LPR）纳米颗粒，其对repRNA具有高效封装和转染能力。LPR-repRNA疫苗能显著激活I型干扰素反应和先天免疫信号通路。皮下注射LPR-repRNA-RBD可导致抗原表达延长、刺激先天免疫细胞，并在引流淋巴结中诱导生发中心反应。LPR-repRNA-RBD诱导抗原特异性T细胞反应，并使细胞免疫偏向效应记忆CD8 T细胞反应。用LPR-repRNA-RBD进行免疫接种可触发抗RBD IgG抗体的产生，并诱导针对SARS-CoV-2假病毒的中和抗体反应。LPR-repRNA-RBD疫苗可减少小鼠体内的SARS-CoV-2感染和肺部炎症。总之，这些数据表明LPR-repRNA平台可能是新冠疫苗开发的一条有前景的途径。
