Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Cell Chem Biol. 2022 May 19;29(5):811-823.e7. doi: 10.1016/j.chembiol.2022.02.004. Epub 2022 Feb 28.
Zika virus (ZIKV) is a flavivirus that can cause severe disease, but there are no approved treatments or vaccines. A complication for flavivirus vaccine development is the potential of immunogens to enhance infection via antibody-dependent enhancement (ADE), a process mediated by poorly neutralizing and cross-reactive antibodies. Thus, there is a great need to develop immunogens that minimize the potential to elicit enhancing antibodies. Here we utilized structure-based protein engineering to develop "resurfaced" (rs) ZIKV immunogens based on E glycoprotein domain III (ZDIIIs), in which epitopes bound by variably neutralizing antibodies were masked by combinatorial mutagenesis. We identified one resurfaced ZDIII immunogen (rsZDIII-2.39) that elicited a protective but immune-focused response. Compared to wild type ZDIII, immunization with resurfaced rsZDIII-2.39 protein nanoparticles produced fewer numbers of ZIKV EDIII antigen-reactive B cells and elicited serum that had a lower magnitude of induced ADE against dengue virus serotype 1 (DENV1) Our findings enhance our understanding of the structural and functional determinants of antibody protection against ZIKV.
Zika 病毒（ZIKV）是一种黄病毒，可导致严重疾病，但目前尚无批准的治疗方法或疫苗。黄病毒疫苗开发的一个并发症是免疫原有可能通过抗体依赖性增强（ADE）增强感染，这是由中和能力差和交叉反应性抗体介导的过程。因此，非常有必要开发出能最大程度减少产生增强抗体潜力的免疫原。在这里，我们利用基于结构的蛋白质工程，基于 E 糖蛋白结构域 III（ZDIII）开发了“重新表面化”（rs）ZIKV 免疫原，其中通过组合诱变使可变中和抗体结合的表位被掩盖。我们鉴定出一种重新表面化的 ZDIII 免疫原（rsZDIII-2.39），它可引发保护性但免疫聚焦的反应。与野生型 ZDIII 相比，用重新表面化的 rsZDIII-2.39 蛋白纳米颗粒免疫产生的 ZIKV EDIII 抗原反应性 B 细胞数量较少，并诱导出针对登革热病毒血清型 1（DENV1）的诱导 ADE 幅度较低的血清。我们的研究结果增强了我们对抗体保护 ZIKV 的结构和功能决定因素的理解。
