State Key Laboratory of Respiratory Disease, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Nat Commun. 2024 Oct 16;15(1):8932. doi: 10.1038/s41467-024-53242-0.
Antibody-dependent enhancement (ADE) is a potential concern for the development of Zika virus (ZIKV) vaccines. Cross-reactive but poorly neutralizing antibodies, usually targeting viral pre-membrane or envelope (E) proteins, can potentially enhance dengue virus (DENV) infection. Although E domain III (EDIII) contains ZIKV-specific epitopes, its immunogenicity is poor. Here, we show that dimeric EDIII, fused to human IgG1 Fc fragment (EDIII-Fc) and encoded by circular RNA (circRNA), induces better germinal center reactions and higher neutralizing antibodies compared to circRNAs encoding monomeric or trimeric EDIII. Two doses of circRNAs encoding EDIII-Fc and ZIKV nonstructural protein NS1, another protective antigen, prevent lethal ZIKV infection in neonates born to immunized C57BL/6 mice and in interferon-α/β receptor knockout adult C57BL/6 mice. Importantly, a single-dose optimized circRNA vaccine with improved antigen expression confers potent and durable protection without inducing obvious DENV ADE in mice, laying the groundwork for developing flavivirus vaccines based on circRNAs encoding EDIII-Fc and NS1.
抗体依赖的增强作用（ADE）是寨卡病毒（ZIKV）疫苗开发的一个潜在关注点。通常针对病毒前膜或包膜（E）蛋白的具有交叉反应性但中和能力差的抗体，可能会增强登革热病毒（DENV）感染。尽管 E 结构域 III（EDIII）包含 ZIKV 特异性表位，但它的免疫原性很差。在这里，我们表明，与编码单体或三聚体 EDIII 的 circRNA 相比，融合到人 IgG1 Fc 片段（EDIII-Fc）并由环状 RNA（circRNA）编码的二聚体 EDIII 诱导更好的生发中心反应和更高的中和抗体。两剂circRNA 编码 EDIII-Fc 和 ZIKV 非结构蛋白 NS1（另一种保护性抗原）可预防免疫接种的 C57BL/6 小鼠所生新生儿和干扰素-α/β受体敲除成年 C57BL/6 小鼠的致命性 ZIKV 感染。重要的是，具有改进的抗原表达的单剂量优化的 circRNA 疫苗在小鼠中没有引起明显的 DENV ADE，可提供强大而持久的保护作用，为基于编码 EDIII-Fc 和 NS1 的环状 RNA 的黄病毒疫苗的开发奠定了基础。
