Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, United States of America.
Department of Epidemiology, The University of North Carolina at Chapel Hill School of Public Health, Chapel Hill, NC, United States of America.
PLoS Negl Trop Dis. 2021 Mar 12;15(3):e0009258. doi: 10.1371/journal.pntd.0009258. eCollection 2021 Mar.
The four dengue virus serotypes (DENV1-4) infect several hundred million people each year living in tropical and sub-tropical regions. Clinical development of DENV vaccines is difficult because immunity to a single serotype increases risk of severe disease during a second infection with a new serotype. Leading vaccines are based on tetravalent formulations to induce simultaneous and balanced protective immunity to all 4 serotypes. TAK-003 is a tetravalent live attenuated dengue vaccine candidate developed by Takeda Vaccines Inc, which is currently being evaluated in phase 3 efficacy trials. Here, we use antibody depletion methods and chimeric, epitope transplant DENVs to characterize the specificity of neutralizing antibodies in dengue-naïve adults and non-human primates immunized with TAK-003. Our results demonstrate that TAK-003 induced high levels of DENV2 neutralizing antibodies that recognized unique (type-specific) epitopes on DENV2. In contrast, most vaccinated subjects developed lower levels of DENV1, DENV3 and DENV4 neutralizing antibodies that mainly targeted epitopes that were conserved (cross-reactive) between serotypes. Trial Registration: ClinicalTrials.gov NCT02425098.
四种登革热病毒血清型（DENV1-4）每年感染居住在热带和亚热带地区的数亿人。由于对单一血清型的免疫会增加对新血清型第二次感染的严重疾病风险，因此开发登革热疫苗具有挑战性。领先的疫苗基于四价配方，可诱导对所有 4 种血清型的同时和平衡的保护性免疫。TAK-003 是由武田疫苗公司开发的一种四价减毒活登革热疫苗候选物，目前正在进行 3 期疗效试验。在这里，我们使用抗体耗竭方法和嵌合、表位移植 DENVs 来描述 TAK-003 免疫的登革热初治成人和非人类灵长类动物中中和抗体的特异性。我们的结果表明，TAK-003 诱导了高水平的 DENV2 中和抗体，这些抗体识别 DENV2 上独特的（血清型特异性）表位。相比之下，大多数接种疫苗的受试者产生的 DENV1、DENV3 和 DENV4 中和抗体水平较低，这些抗体主要针对血清型之间保守（交叉反应）的表位。试验注册：ClinicalTrials.gov NCT02425098。
