PRECLINICAL ASSAYS TO PREDICT TETRAVALENT DENGUE VACCINE EFFICACY

节目概要 登革热是人类最常见的由节肢动物传播的病毒性疾病。迫切需要疫苗， 然而，由于存在四种登革病毒（DENV）， 血清型和免疫增强登革热病的可能性。主要候选疫苗含有4 减毒活病毒，以覆盖4种血清型。最先进的候选疫苗，一种嵌合的黄色 由赛诺菲巴斯德（SanofiPasteur）开发的登革热四价活病毒疫苗（CYD-TDV）最近进行了评价 在亚洲和拉丁美洲进行的人体功效研究中。总体而言，CYD-TDV有效降低了 登革热在接种疫苗人群中的负担。然而，该疫苗出乎意料地低 与暴露于登革热的受试者相比，对DENV血清型2（DENV 2）和登革热初治受试者的有效性 接种疫苗的受试者这些组中的较低疗效是出乎意料的，因为疫苗 在这些受试者中诱导中和抗体（Abs）。这一建议的核心假设是， 细胞培养中和抗体的质量（抗体表位特异性）而不是总量是更好的预测因子。 DENV疫苗在人群中的性能。此外，由于DENV复合物具有4种血清型， 疫苗将用于初治和部分免疫个体混合的人群，免疫测定 基于单一表位的结果不太可能预测对4种血清型的功效。 该项目是基于我们实验室的研究，以了解保护性和致病性抗体 暴露于自然DENV感染的人的反应。我们发现了新的四级结构Ab 与保护相关的表位和开发的试剂（人单克隆抗体，重组DENV）， 精确测量人血清中Ab表位特异性反应的测定。与赛诺菲合作 此外，我们将使用来自CYD-TDV疗效试验的样品，包括来自 经历过疫苗突破性感染的人，以确定基于Ab表位的保护性 免疫力目前，我们是唯一能够进行这项研究的小组，因为没有其他登革热疫苗 在功效研究中进行了测试。 由于DENV疫苗具有4种减毒复制病毒，因此难以获得平衡的DENV疫苗。 对所有4种血清型的复制和免疫力。目前还没有可靠的模型来优化配方 多组分活登革热疫苗制剂。赛诺菲巴斯德VaxDesign园区的研究人员 开发了一种全自动的人类外周组织等效（PTE）仿生模型，用于临床前 疫苗的评价。由于DENV最初在蚊子传播后在外周组织中复制， 疫苗接种后，我们将测试PTE仿生模型是否可用于预测和优化 单一和多组分减毒活登革热疫苗。 在本研究的时间范围内，我们将建立新的标准化检测方法，以支持全球范围内的 努力研制登革热疫苗。

Program Summary Dengue is the most common arthropod borne viral disease of humans. Vaccines are urgently needed to prevent dengue yet vaccine development is complicated by the presence of four dengue virus (DENV) serotypes and the possibility of immune enhanced dengue disease. The leading vaccine candidates contain 4 live attenuated viruses to cover the 4 serotypes. The most advanced vaccine candidate, a chimeric Yellow Fever-Dengue tetravalent live virus vaccine (CYD-TDV) developed by Sanofi Pasteur, was recently evaluated in human efficacy studies conducted in Asia and Latin America. Overall, CYD-TDV was efficacious at reducing the burden of dengue disease in the vaccinated populations. However, the vaccine had unexpectedly low efficacy against DENV serotype 2 (DENV2) and in dengue naïve subjects compared to dengue exposed subjects who were vaccinated. The lower efficacy in these groups was unexpected because the vaccine induced neutralizing antibodies (Abs) in these subjects. The central hypothesis of this proposal is that the quality (Ab epitope specificity) rather than total quantity of cell-culture neutralizing Abs is a better predictor of DENV vaccine performance in human populations. Moreover, as the DENV complex has 4 serotypes and vaccines will be used in populations with a mix of naïve and partially immune individuals, immune assays based on a single epitope are unlikely to predict efficacy against the 4 serotypes. This project is grounded on studies in our laboratories to understand protective and pathogenic Ab responses in people exposed to natural DENV infections. We have discovered new quaternary structure Ab epitopes linked to protection and developed reagents (human monoclonal Abs, recombinant DENVs) and assays that precisely measure Ab epitope-specific responses in human sera. In collaboration with Sanofi Pasture, we will use samples from the CYD-TDV efficacy trials, including several hundred samples from people who experienced vaccine breakthrough infections, to identify Ab epitope based correlates of protective immunity. Currently we are the only group capable of doing this study because no other dengue vaccine has been tested in efficacy studies. As DENV vaccines have 4 attenuated replicating viruses, it has been difficult to obtain balanced replication and immunity to all 4 serotypes. Currently there are no reliable models to optimize the formulation of multi-component live dengue vaccine formulations. Investigators at Sanofi Pasteur's VaxDesign campus have developed a fully automated human Peripheral Tissue Equivalent (PTE) biomimetic model for preclinical evaluation of vaccines. As DENVs initially replicate in peripheral tissues after mosquito transmission or vaccination, we will test if the PTE biomimetic model has utility for predicting and optimizing the replication of single and multicomponent live-attenuated dengue vaccines. Within the time frame of this study, we will establish novel standardized assays for supporting global efforts to develop dengue vaccines.