State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China.
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China; Key Laboratory of Biopharmaceutical Preparation and Delivery, Chinese Academy of Sciences, Beijing 100190, China.
J Control Release. 2024 Apr;368:275-289. doi: 10.1016/j.jconrel.2024.02.027. Epub 2024 Mar 4.
Virus like particles (VLPs) have been well recognized as one of the most important vaccine platforms due to their structural similarity to natural viruses to induce effective humoral and cellular immune responses. Nevertheless, lack of viral nucleic acids in VLPs usually leads the vaccine candidates less efficient in provoking innate immune against viral infection. Here, we constructed a biomimetic dual antigen hybrid influenza nanovaccines THM-HA@Mn with robust immunogenicity via in situ synthesizing a stimulator of interferon genes (STING) agonist MnO inside the cavity of a recombinant Hepatitis B core antigen VLP (HBc VLP) having fused SpyTag and influenza M2e antigen peptides (Tag-HBc-M2e, THM for short), followed by conjugating a recombinant hemagglutinin (rHA) antigen on the surface of the nanoparticles through SpyTag/SpyCatcher ligating. Such inside MnO immunostimulator-outside rHA antigen design, together with the chimeric M2e antigen on the HBc skeleton, enabled the synthesized hybrid nanovaccines THM-HA@Mn to well imitate the spatial distribution of M2e/HA antigens and immunostimulant in natural influenza virus. In vitro cellular experiments indicated that compared with the THM-HA antigen without MnO and a mixture vaccine consisting of THM-HA + MnOx, the THM-HA@Mn hybrid nanovaccines showed the highest efficacies in dendritic cells uptake and in promoting BMDC maturation, as well as inducing expression of TNF-α and type I interferon IFN-β. The THM-HA@Mn also displayed the most sustained antigen release at the injection site, the highest efficacies in promoting the DC maturation in lymph nodes and germinal center B cells activation in the spleen of the immunized mice. The co-delivery of immunostimulant and antigens enabled the THM-HA@Mn nanovaccines to induce the highest systemic antigen-specific antibody responses and cellular immunogenicity in mice. Together with the excellent colloid dispersion stability, low cytotoxicity, as well as good biosafety, the synthetic hybrid nanovaccines presented in this study offers a promising strategy to design VLP-based vaccine with robust natural and adaptive immunogenicity against emerging viral pathogens.
病毒样颗粒(VLPs)由于其结构与天然病毒相似,能够诱导有效的体液和细胞免疫反应,因此被广泛认为是最重要的疫苗平台之一。然而,VLPs 中缺乏病毒核酸通常导致疫苗候选物在引发针对病毒感染的先天免疫方面效率较低。在这里,我们通过在融合了 SpyTag 和流感 M2e 抗原肽的乙型肝炎核心抗原 VLP(Tag-HBc-M2e,简称 THM)的空腔内原位合成干扰素基因刺激物(STING)激动剂 MnO ,构建了一种具有强大免疫原性的仿生双抗原流感纳米疫苗 THM-HA@Mn。随后,通过 SpyTag/SpyCatcher 连接将重组血凝素(rHA)抗原连接到纳米颗粒的表面。这种内部 MnO 免疫刺激剂-外部 rHA 抗原设计,再加上 HBc 骨架上的嵌合 M2e 抗原,使合成的杂交纳米疫苗 THM-HA@Mn 能够很好地模拟天然流感病毒中 M2e/HA 抗原和免疫刺激剂的空间分布。体外细胞实验表明,与没有 MnO 的 THM-HA 抗原和由 THM-HA+MnO 组成的混合疫苗相比,THM-HA@Mn 杂交纳米疫苗在树突状细胞摄取和促进 BMDC 成熟方面具有最高的功效,以及诱导 TNF-α和 I 型干扰素 IFN-β的表达。THM-HA@Mn 还在注射部位表现出最持续的抗原释放,在促进免疫小鼠淋巴结中 DC 成熟和生发中心 B 细胞激活方面具有最高的功效。免疫刺激剂和抗原的共递送使 THM-HA@Mn 纳米疫苗能够在小鼠中诱导最高的系统抗原特异性抗体反应和细胞免疫原性。结合出色的胶体分散稳定性、低细胞毒性以及良好的生物安全性,本研究中提出的合成杂交纳米疫苗为设计具有针对新兴病毒病原体的强大天然和适应性免疫原性的 VLP 疫苗提供了一种有前途的策略。
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