PRECLINICAL ASSAYS TO PREDICT TETRAVALENT DENGUE VACCINE EFFICACY

预测四价登革热疫苗功效的临床前测定

• 批准号: 9153244
• 负责人: Aravinda M. DeSilva
• 金额: $ 140.1万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-04 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9153244
• 关键词: 3-Dimensional; Antibodies; Antibody Formation; Antibody Response; Archives; Arthropods; Asia; Attenuated; Biological Assay; Biomimetics; Blocking Antibodies; Cell Culture Techniques; Clinical Trials; Collaborations; Complex; Culicidae; Dengue; Dengue Infection; Dengue Virus; Development; Disease; Epitopes; Equilibrium; Evaluation; Formulation; Goals; Human; Immune; Immunity; Individual; Infection; Laboratories; Latin America; Life; Link; Measures; Modeling; North Carolina; Performance; Peripheral; Phase; Population; Positioning Attribute; Property; Reagent; Recombinants; Reporting; Research; Research Personnel; Sampling; Serotyping; Serum; Site; Specificity; Structure; Testing; Time; Tissues; Universities; Vaccinated; Vaccination; Vaccines; Viral Antibodies; Virion; Virus; Virus Diseases; Yellow Fever; base; diagnostic assay; efficacy trial; experience; human monoclonal antibodies; in vivo; neutralizing antibody; novel; pre-clinical; preclinical evaluation; prevent; programs; research clinical testing; response; transmission process; vaccine candidate; vaccine development; vaccine efficacy

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.

程序摘要 登革热是人类最常见的节肢动物传播病毒病。迫切需要疫苗 防止登革热但疫苗的发育变得复杂，存在四种登革热病毒（DENV） 血清型和免疫增强的风扇疾病的可能性。领先的候选疫苗包含4个 活病毒覆盖4种血清型。最先进的疫苗候选者，一种嵌合黄色 最近评估了由Sanofi Pasteur开发的Fever-Dengue四位无活化病毒疫苗（CYD-TDV），最近评估了 在亚洲和拉丁美洲进行的人类效率研究中。总体而言，CYD-TDV有效地降低 接种疫苗的人群中的登革热病。但是，疫苗意外低 与登革热相比 接种疫苗的受试者。这些组的效率较低是出乎意料的，因为疫苗 在这些受试者中诱导中和抗体（ABS）。该提议的核心假设是 质量（AB表位特异性）而不是中和细胞培养的ABS的总数是更好的预测指标 人口中的DENV疫苗性能。此外，由于DENV综合体有4种血清型，并且 疫苗将用于与幼稚和部分免疫学个人混合的种群中，免疫学分析 基于单个表位，不太可能预测4种血清型的效率。 该项目基于我们实验室的研究，以了解受保护和致病性AB 暴露于自然DENV感染的人的反应。我们发现了新的第四纪结构AB 与保护和开发试剂（人类单克隆ABS，重组DENVS）和开发试剂有关的表位和 在人血清中精确测量AB表位特异性反应的测定。与赛诺菲合作 牧场，我们将使用来自CYD-TDV效率试验的样本，包括来自 经历了疫苗突破感染的人，以识别受保护的基于AB表位的相关性 免疫。目前，我们是唯一能够进行这项研究的小组，因为没有其他粉丝 我们在效率研究中进行了测试。 由于DENV疫苗的复制病毒已减弱，因此很难获得平衡 对所有4种血清型的复制和免疫学。当前没有可靠的模型来优化公式 多组件的现场粉丝公式。 Sanofi Pasteur VaxDesign校园的调查人员 为临床前开发了完全自动化的人外周组织当量（PTE）仿生模型 评估疫苗。作为DENV最初在蚊子传播后的外围时间复制或 疫苗接种，我们将测试PTE仿生模型是否具有预测和优化复制的实用性 单一和多组分的实时粉丝。 在本研究的时间范围内，我们将建立新颖的标准化评估，以支持全球 培养粉丝的努力。