Amsterdam UMC, location University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Laboratory of Experimental Virology, Amsterdam, The Netherlands.
Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, The Netherlands.
Nat Commun. 2022 Nov 25;13(1):7271. doi: 10.1038/s41467-022-34961-8.
Hepatitis C virus (HCV) infection affects approximately 58 million people and causes ~300,000 deaths yearly. The only target for HCV neutralizing antibodies is the highly sequence diverse E1E2 glycoprotein. Eliciting broadly neutralizing antibodies that recognize conserved cross-neutralizing epitopes is important for an effective HCV vaccine. However, most recombinant HCV glycoprotein vaccines, which usually include only E2, induce only weak neutralizing antibody responses. Here, we describe recombinant soluble E1E2 immunogens that were generated by permutation of the E1 and E2 subunits. We displayed the E2E1 immunogens on two-component nanoparticles and these nanoparticles induce significantly more potent neutralizing antibody responses than E2. Next, we generated mosaic nanoparticles co-displaying six different E2E1 immunogens. These mosaic E2E1 nanoparticles elicit significantly improved neutralization compared to monovalent E2E1 nanoparticles. These results provide a roadmap for the generation of an HCV vaccine that induces potent and broad neutralization.
丙型肝炎病毒 (HCV) 感染影响约 5800 万人，并导致每年约 30 万人死亡。HCV 中和抗体的唯一靶标是高度序列多样的 E1E2 糖蛋白。产生识别保守交叉中和表位的广泛中和抗体对于有效的 HCV 疫苗至关重要。然而，大多数仅包含 E2 的重组 HCV 糖蛋白疫苗仅诱导较弱的中和抗体反应。在这里，我们描述了通过 E1 和 E2 亚基的排列产生的重组可溶性 E1E2 免疫原。我们将 E2E1 免疫原展示在双组分纳米颗粒上，这些纳米颗粒诱导的中和抗体反应比 E2 强得多。接下来，我们生成了共展示六种不同 E2E1 免疫原的嵌合纳米颗粒。与单价 E2E1 纳米颗粒相比，这些嵌合 E2E1 纳米颗粒引起的中和作用明显改善。这些结果为产生诱导强大和广泛中和的 HCV 疫苗提供了路线图。
