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.

计划摘要 登革热是最常见的节肢动物传播的人类病毒性疾病。迫切需要疫苗来 预防登革热然而，由于存在四种登革热病毒(DENV)，疫苗的开发变得复杂 血清型和免疫增强型登革热的可能性。领先的候选疫苗包括4个 减毒活病毒覆盖4个血清型。最先进的候选疫苗，嵌合体黄色 赛诺菲巴斯德开发的登革热四价活病毒疫苗(CyD-TDV)最近进行了评估 在亚洲和拉丁美洲进行的人类功效研究中。总体而言，CyD-TDV在减少 登革热在接种人群中的负担。然而，疫苗的接种量出人意料地低 登革2型病毒(DENV2)和登革热幼稚人群与登革热暴露者的疗效比较 接种疫苗的受试者。这些组的低疗效是意想不到的，因为疫苗 在这些受试者中诱导中和抗体(Abs)。这项提议的中心假设是 细胞培养中和抗体的质量(抗体表位特异性)比总量更能预测 DENV疫苗在人类人群中的表现。此外，由于DENV复合体有4个血清型和 疫苗将用于混合了幼稚和部分免疫个体的人群，免疫分析 基于单一表位不太可能预测对4种血清型的疗效。 该项目基于我们实验室了解保护性抗体和致病性抗体的研究 接触自然DENV感染的人的反应。我们发现了新的四元结构 与保护性和已开发试剂(人源单抗、重组DENV)和 精确测量人类血清中抗体表位特异性反应的检测方法。与赛诺菲合作 草场，我们将使用来自CyD-TDV效力试验的样本，包括来自 经历疫苗突破性感染的人，找出基于抗体表位的保护性相关因素 豁免权。目前，我们是唯一有能力进行这项研究的小组，因为没有其他登革热疫苗 已经在疗效研究中进行了测试。 由于DENV疫苗有4个弱复制病毒，因此很难达到平衡 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 多组分的登革热活疫苗配方。赛诺菲巴斯德VaxDesign园区的调查人员 开发了一种全自动人体外周组织当量(PTE)仿生模型，用于临床前 疫苗的评估。由于DENV最初在蚊子传播或感染后在周围组织中复制 疫苗接种后，我们将测试PTE仿生模型是否对预测和优化复制具有实用价值 单组分和多组分减毒登革热疫苗。 在这项研究的时间框架内，我们将建立新的标准化分析方法，以支持全球 努力开发登革热疫苗。