Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill.
Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill.
J Infect Dis. 2018 May 25;217(12):1932-1941. doi: 10.1093/infdis/jiy063.
Dengue virus serotypes 1-4 (DENV-1-4) are the most common vector-borne viral pathogens of humans and the etiological agents of dengue fever and dengue hemorrhagic syndrome. A live-attenuated tetravalent dengue vaccine (TDV) developed by Takeda Vaccines has recently progressed to phase 3 safety and efficacy evaluation.
We analyzed the qualitative features of the neutralizing antibody (nAb) response induced in naive and DENV-immune individuals after TDV administration. Using DENV-specific human monoclonal antibodies (mAbs) and recombinant DENV displaying different serotype-specific Ab epitopes, we mapped the specificity of TDV-induced nAbs against DENV-1-3.
Nearly all subjects had high levels of DENV-2-specific nAbs directed to epitopes centered on domain III of the envelope protein. In some individuals, the vaccine induced nAbs that tracked with a DENV-1-specific neutralizing epitope centered on domain I of the envelope protein. The vaccine induced binding Abs directed to a DENV-3 type-specific neutralizing epitope, but findings of mapping of DENV-3 type-specific nAbs were inconclusive.
Here we provide qualitative measures of the magnitude and epitope specificity of the nAb responses to TDV. This information will be useful for understanding the performance of TDV in clinical trials and for identifying correlates of protective immunity.
登革病毒血清型 1-4（DENV-1-4）是最常见的人类虫媒病毒病原体，也是登革热和登革出血热综合征的病原体。武田疫苗公司开发的一种减毒四价登革热疫苗（TDV）最近已进入 3 期安全性和疗效评估阶段。
我们分析了 TDV 给药后在无免疫力和 DENV 免疫个体中诱导的中和抗体（nAb）反应的定性特征。使用针对 DENV 的人源单克隆抗体（mAbs）和展示不同血清型特异性 Ab 表位的重组 DENV，我们对 TDV 诱导的 nAb 针对 DENV-1-3 的特异性进行了定位。
几乎所有受试者均具有高水平的针对登革病毒 2 型特异性 nAb，这些 nAb 针对包膜蛋白的 III 结构域中的表位。在某些个体中，疫苗诱导的 nAb 与包膜蛋白 I 结构域中的 DENV-1 特异性中和表位相关。疫苗诱导了针对 DENV-3 型特异性中和表位的结合 Ab，但 DENV-3 型特异性 nAb 的定位结果尚无定论。
在此，我们提供了针对 TDV 的 nAb 反应的幅度和表位特异性的定性衡量标准。这些信息将有助于了解 TDV 在临床试验中的表现，并确定保护性免疫的相关因素。
