State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Research Unit of Frontier Technology of Structural Vaccinology of the Chinese Academy of Medical Sciences, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361005, China; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Cell Rep Med. 2023 Nov 21;4(11):101296. doi: 10.1016/j.xcrm.2023.101296.
Epstein-Barr virus (EBV) is closely associated with cancer, multiple sclerosis, and post-acute coronavirus disease 2019 (COVID-19) sequelae. There are currently no approved therapeutics or vaccines against EBV. It is noteworthy that combining multiple EBV glycoproteins can elicit potent neutralizing antibodies (nAbs) against viral infection, suggesting possible synergistic effects. Here, we characterize three nAbs (anti-gp42 5E3, anti-gHgL 6H2, and anti-gHgL 10E4) targeting different glycoproteins of the gHgL-gp42 complex. Two antibody cocktails synergistically neutralize infection in B cells (5E3+6H2+10E4) and epithelial cells (6H2+10E4) in vitro. Moreover, 5E3 alone and the 5E3+6H2+10E4 cocktail confer potent in vivo protection against lethal EBV challenge in humanized mice. The cryo-EM structure of a heptatomic gHgL-gp42 immune complex reveals non-overlapping epitopes of 5E3, 6H2, and 10E4 on the gHgL-gp42 complex. Structural and functional analyses highlight different neutralization mechanisms for each of the three nAbs. In summary, our results provide insight for the rational design of therapeutics or vaccines against EBV infection.
爱泼斯坦-巴尔病毒（EBV）与癌症、多发性硬化症和急性冠状病毒病 2019（COVID-19）后遗留问题密切相关。目前尚无针对 EBV 的批准治疗方法或疫苗。值得注意的是，结合多种 EBV 糖蛋白可以引发针对病毒感染的强大中和抗体（nAbs），表明可能存在协同作用。在这里，我们描述了三种针对 gHgL-gp42 复合物中不同糖蛋白的 nAb（抗-gp42 5E3、抗-gHgL 6H2 和抗-gHgL 10E4）。两种抗体鸡尾酒在体外协同中和 B 细胞（5E3+6H2+10E4）和上皮细胞（6H2+10E4）的感染。此外，5E3 单独和 5E3+6H2+10E4 鸡尾酒在人源化小鼠中对致死性 EBV 挑战具有强大的体内保护作用。一个七原子 gHgL-gp42 免疫复合物的冷冻电镜结构揭示了 5E3、6H2 和 10E4 在 gHgL-gp42 复合物上的非重叠表位。结构和功能分析突出了三种 nAb 中的每一种的不同中和机制。总之，我们的研究结果为针对 EBV 感染的治疗方法或疫苗的合理设计提供了见解。
