Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Cell Rep. 2020 Oct 6;33(1):108226. doi: 10.1016/j.celrep.2020.108226.
Dengue virus (DENV) infects an estimated 390 million people each year worldwide. As tetravalent DENV vaccines have variable efficacy against DENV serotype 2 (DENV2), we evaluated the role of genetic diversity within the pre-membrane (prM) and envelope (E) proteins of DENV2 on vaccine performance. We generated a recombinant DENV2 genotype variant panel with contemporary prM and E isolates that are representative of global genetic diversity. The DENV2 genotype variants differ in growth kinetics, morphology, and virion stability. Importantly, the DENV2 genotypic variants are differentially neutralized by monoclonal antibodies, polyclonal serum neutralizing antibodies from DENV2-infected human subjects, and vaccine-elicited antibody responses from the TV003 NIH DENV2 monovalent and DENV tetravalent vaccines. We conclude that DENV2 prM and E genetic diversity significantly modulates antibody neutralization activity. These findings have important implications for dengue vaccines, which are being developed under the assumption that intraserotype variation has minimal impact on neutralizing antibodies.
登革热病毒（DENV）每年在全球估计感染 3.9 亿人。由于四价登革热疫苗对登革热血清型 2（DENV2）的功效存在差异，我们评估了 DENV2 前膜（prM）和包膜（E）蛋白内遗传多样性对疫苗性能的作用。我们生成了一个具有当代 prM 和 E 分离株的重组 DENV2 基因型变异面板，这些分离株代表了全球遗传多样性。DENV2 基因型变异在生长动力学、形态和病毒粒子稳定性方面存在差异。重要的是，DENV2 基因型变异体被单克隆抗体、来自感染 DENV2 的人类受试者的多克隆血清中和抗体以及 TV003 NIH DENV2 单价和四价疫苗诱导的抗体反应不同程度地中和。我们得出结论，DENV2 prM 和 E 遗传多样性显著调节抗体中和活性。这些发现对正在开发的登革热疫苗具有重要意义，因为人们假设同型内变异对中和抗体的影响最小。
