School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China.
School of Life Sciences, Tsinghua University, Beijing, China.
Front Immunol. 2023 Dec 11;14:1259386. doi: 10.3389/fimmu.2023.1259386. eCollection 2023.
Since the outbreak of SARS-CoV-2, vaccines have demonstrated their effectiveness in resisting virus infection, reducing severity, and lowering the mortality rate in infected individuals. However, due to the rapid and ongoing mutations of SARS-CoV-2, the protective ability of many available vaccines has been challenged. Therefore, there is an urgent need for vaccines capable of eliciting potent broadly neutralizing antibodies against various SARS-CoV-2 variants.
In this study, we developed a novel subunit vaccine candidate for SARS-CoV-2 by introducing a series of shielding glycans to the Fc-fused receptor-binding domain (RBD) of the prototypic spike protein. This approach aims to mask non-neutralizing epitopes and focus the immune response on crucial neutralizing epitopes.
All modified sites were confirmed to be highly glycosylated through mass spectrometry analysis. The binding affinity of the glycan-shielded RBD (gsRBD) to the human ACE2 receptor was comparable to that of the wildtype RBD (wtRBD). Immunizing mice with gsRBD when combined with either Freund's adjuvant or aluminum adjuvant demonstrated that the introduction of the glycan shield did not compromise the antibody-inducing ability of RBD. Importantly, the gsRBD significantly enhanced the generation of neutralizing antibodies against SARS-CoV-2 pseudoviruses compared to the wtRBD. Notably, it exhibited remarkable protective activity against Beta (B.1.351), Delta (B.1.617.2), and Omicron (B.1.1.529), approximately 3-fold, 7- fold, and 17-fold higher than wtRBD, respectively.
Our data proved this multiple-epitope masking strategy as an effective approach for highly active vaccine production.
自 SARS-CoV-2 爆发以来，疫苗已证明其在抵抗病毒感染、降低严重程度和降低感染个体死亡率方面的有效性。然而，由于 SARS-CoV-2 的快速和持续突变，许多现有疫苗的保护能力受到了挑战。因此，迫切需要能够引发针对各种 SARS-CoV-2 变体的强效广泛中和抗体的疫苗。
在这项研究中，我们通过向原型刺突蛋白的 Fc 融合受体结合域（RBD）引入一系列屏蔽糖基，开发了一种新型 SARS-CoV-2 亚单位疫苗候选物。这种方法旨在掩盖非中和表位，并将免疫反应集中在关键的中和表位上。
通过质谱分析证实所有修饰的位点均高度糖基化。糖基化屏蔽的 RBD（gsRBD）与人 ACE2 受体的结合亲和力与野生型 RBD（wtRBD）相当。当与弗氏佐剂或铝佐剂联合免疫小鼠时，gsRBD 表明糖基屏蔽的引入并未损害 RBD 诱导抗体的能力。重要的是，与 wtRBD 相比，gsRBD 显著增强了针对 SARS-CoV-2 假病毒的中和抗体的产生。值得注意的是，它对 Beta（B.1.351）、Delta（B.1.617.2）和奥密克戎（B.1.1.529）的保护活性分别显著提高了约 3 倍、7 倍和 17 倍。
我们的数据证明了这种多表位掩蔽策略是一种生产高活性疫苗的有效方法。
