A multi-tiered approach to develop validated assays to predict efficacy of a tetravalent live attenuated Dengue Virus vaccine in Phase II and Phase III clinical trials

采用多层方法开发经过验证的检测方法，以预测四价登革热病毒减毒活疫苗在 II 期和 III 期临床试验中的功效

• 批准号: 9153368
• 负责人: Rafick Pierre Sekaly
• 金额: $ 126.47万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-13 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9153368
• 关键词: Advocate; Antibodies; Arthropods; Attenuated; Biological Assay; Brazil; Cells; Cellular Assay; Clinical; Clinical Data; Clinical Research; Clinical Trials; Communicable Diseases; Country; Data; Data Analyses; Decision Making; Dengue Infection; Dengue Virus; Development; Disease; Dose; Economic Burden; Effector Cell; Epidemic; Equilibrium; Far East; Flavivirus; Genes; Guidelines; Human; Humoral Immunities; Immune; Immune response; Incidence; Individual; Infection; Infectious Agent; Life; Measures; Mediating; Natural Immunity; Peripheral Blood Mononuclear Cell; Phase; Phase III Clinical Trials; Placebos; Plasma; Predictive Value; Recruitment Activity; Reporting; Running; Sampling; Schedule; Serological; Serotyping; South America; Southeastern Asia; Statistical Data Interpretation; Structural Genes; T-Lymphocyte; Testing; Training; Trees; Vaccinated; Vaccines; Validation; Viral; Virus; Virus Diseases; Work; Yellow fever virus; adaptive immunity; assay development; burden of illness; case control; cohort; experience; genome-wide; high throughput screening; immunogenicity; in vitro Assay; member; novel; phase 1 study; phase III trial; predict clinical outcome; programs; seropositive; vaccine development; vaccine efficacy; vaccine response; vaccine trial; vaccine-induced immunity; virology

Dengue virus (DENV) infection has reached epidemic proportions in many countries in South America and Southeast Asia, with most experts advocating for a safe and efficacious vaccine to stop dissemination and reduce viral economic and disease burden. Advanced clinical trials of the Sanofi-Pasteur chimeric DENV- yellow fever virus (YFV) vaccine reported only partial protection and did not show efficacy against all DENV serotypes or in DENV-naive subjects. Most concerning, recent data has indicated that the Sanofi vaccine might enhance symptomatic disease in naive subjects, which has raised questions as to its eventual deployment. The lack of established immune correlates of vaccine-induced protection has hampered the development of a safe efficacious vaccine to DENV and to several other infectious diseases. Recent conceptual and technological advances in our understanding of effector mechanisms of cell and humoral immunity pave the way forward for implementing new assays that identify mechanisms and correlates of vaccine efficacy. A new live-attenuated DENV vaccine currently is being tested in Brazil, one of the countries where DENV has reached epidemic proportions. This TV003 vaccine formulation includes three attenuated strains corresponding to different DENV serotypes (DENV-1, DENV-3, and DENV-4) and a fourth chimeric strain (DENV-2/DENV-4), which contains the DENV-2 structural genes and the DENV-4 non-structural genes. One of the major advantages of the TV003 vaccine relative to the Sanofi DENV-YFV vaccine is that all of its components are from DENV strains. A Phase II trial of this vaccine has been completed and a Phase III trial has been initiated and will include over 17,000 subjects. Both phase II and III trials have been powered to include enough subjects to have training and test/validation cohorts. Peripheral blood mononuclear cells, serum and plasma have been collected on all subjects included in these two landmark studies. The major objective of our study will be to compare, prioritize and select the best assay that predicts the immunogenicity and the efficacy of this vaccine. We will test the hypothesis that several components (cellular, humoral and innate) are required to trigger the protection induced by this vaccine. The assays that will be tested here encompass a wide array of effector mechanisms of the cellular and humoral immune responses as well as novel genome-wide unbiased assessment of innate and adaptive immunity. A rigorous decision making tree will allow us in Aim 1 to identify and validate assays that predict a vaccine triggered broad immune response that targets all four DENV strains included in this vaccine. In Aim 2 we will identify the best in class assay(s) that predicts the efficacy of the vaccine in protecting recipients from infection. Efficacy will involve comparison of cases and controls if the vaccine's efficacy is below 80%; alternatively we will compare vaccinees and naturally infected placebos if the vaccine is highly efficacious (>85%). In Aim 3 our corporate partner Caprion, who has long standing experience in developing predictors of clinical outcome, will further optimize and scale the assay(s) identified in Aim 1 (immunogenicity) and in Aim 2 (efficacy) for robustness, accuracy, and throughput required for widespread clinical use in vaccine trials of DENV, and possibly other viruses.

登革热病毒（DENV）感染已在南美许多国家和 东南亚，大多数专家提倡采用安全有效的疫苗来停止传播和 减轻病毒经济和疾病负担。 Sanofi-Pasteur嵌合Denv-的高级临床试验 黄热病病毒（YFV）疫苗仅报告部分保护，并且没有显示出所有DENV的功效 血清型或DENV-NOIVE受试者。最令人担忧的是，最近的数据表明，赛诺菲疫苗可能 增强幼稚受试者的症状性疾病，这引发了有关其最终部署的问题。 疫苗诱导的保护缺乏已建立的免疫相关性，阻碍了A的发展 安全的有效疫苗可用于DENV和其他几种传染病。最近的概念和 我们对细胞和体液免疫效应机制的理解方面的技术进步铺平了 实施识别疫苗功效机制和相关性的新测定方法的前进方向。一个新 目前正在巴西进行了实时衰减疫苗，这是DENV拥有的国家之一 达到流行比例。该TV003疫苗配方包括三个相应的衰减菌株 对于不同的DENV血清型（DENV-1，DENV-3和DENV-4）和第四个嵌合菌株（DENV-2/DENV-4）， 其中包含DENV-2结构基因和DENV-4非结构基因。专业之一 TV003疫苗相对于SANOFI DENV-YFV疫苗的优势是其所有组件均为 来自DENV菌株。该疫苗的II期试验已经完成，已经开始了III期试验 并将包括17,000多名主题。第二阶段和III期试验均已投入到足够 受试者接受培训和测试/验证队列。外周血单核细胞，血清和血浆 已收集了这两个具有里程碑意义的研究中的所有受试者。我们研究的主要目标 将是比较，优先级和选择预测免疫原性和功效的最佳测定法 疫苗。我们将测试需要几个组成部分（细胞，体液和先天）的假设 触发该疫苗引起的保护。将在这里测试的测定法包括 细胞和体液免疫反应的效应机制阵列以及全基因组的新型 对先天和适应性免疫的无偏评估。严格的决策树将使我们进入目标1 识别和验证预测疫苗触发广泛免疫反应的测定法 该疫苗中包括DENV菌株。在AIM 2中，我们将确定班级测定中最好的预测 疫苗在保护受体免受感染的功效。功效将涉及案件和 控制疫苗的功效是否低于80％；或者，我们将比较疫苗并自然感染 安慰剂如果疫苗高效（> 85％）。在AIM 3中，我们的公司合作伙伴Caprion长期很长 在开发临床结果预测指标方面的常规经验，将进一步优化和扩展测定法 在AIM 1（免疫原性）和AIM 2（功效）中鉴定出鲁棒性，准确性和吞吐量 在DENV和其他病毒的疫苗试验中广泛使用。