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

登革热病毒（DENV）感染在南美洲的许多国家已经达到流行病的程度， 东南亚，大多数专家主张使用安全有效的疫苗来阻止传播， 减少病毒经济和疾病负担。赛诺菲-巴斯德嵌合DENV的高级临床试验- 黄热病病毒（YFV）疫苗仅报告了部分保护，并没有显示出对所有DENV的有效性 血清型或未感染DENV的受试者。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，这引发了人们对其最终部署的质疑。 缺乏疫苗诱导保护的既定免疫相关性阻碍了疫苗的发展。 对DENV和其他几种传染病安全有效的疫苗。最近的概念和 我们对细胞和体液免疫效应机制的理解的技术进步， 实施新的检测方法，以确定疫苗效力的机制和相关因素。一个新 减毒活登革病毒疫苗目前正在巴西进行测试，巴西是登革病毒感染的国家之一。 达到了流行病的程度。该TV 003疫苗制剂包括三种减毒株， 针对不同的DENV血清型（DENV-1、DENV-3和DENV-4）和第四嵌合株（DENV-2/DENV-4）， 其含有DENV-2结构基因和DENV-4非结构基因。的一个主要 TV 003疫苗相对于Sanofi DENV-YFV疫苗的优势在于其所有组分均 DENV菌株。这种疫苗的二期试验已经完成，三期试验已经启动 将包括超过17,000名受试者II期和III期试验都有足够的动力， 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 已收集了这两项里程碑式研究中所有受试者的数据。我们研究的主要目的 将比较，优先考虑和选择预测免疫原性和有效性的最佳试验， 疫苗我们将测试的假设，几个组成部分（细胞，体液和先天）是必需的 来触发疫苗的保护作用这里将要测试的检测试剂盒包括广泛的 细胞和体液免疫应答的一系列效应机制以及新的全基因组免疫应答， 先天性和适应性免疫的无偏见评估。一个严格的决策树将使我们在目标1 鉴定和验证预测疫苗引发的广泛免疫反应的检测方法， 本疫苗中包含的DENV毒株。在目标2中，我们将确定最佳的同类检测方法， 疫苗在保护接受者免受感染方面的效力。疗效将涉及病例比较， 如果疫苗的效力低于80%，我们将进行对照;或者，我们将比较接种疫苗者和自然感染者 安慰剂，如果疫苗是高度有效的（>85%）。在Aim 3中，我们的企业合作伙伴Caprion， 在开发临床结局预测因子方面的长期经验，将进一步优化和扩展检测试剂盒 在目标1（免疫原性）和目标2（有效性）中确定了所需的耐用性、准确度和通量 用于DENV和可能的其他病毒的疫苗试验中的广泛临床使用。

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.