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)感染已在南美洲和许多国家达到流行程度 东南亚，大多数专家倡导安全有效的疫苗，以阻止传播和 减少病毒式经济和疾病负担。赛诺菲-巴斯德嵌合DENV的高级临床试验 黄热病病毒(YFV)疫苗仅报道了部分保护作用，并未显示出对所有DENV的疗效 血清型或在DENV幼稚受试者中。最令人担忧的是，最近的数据表明赛诺菲疫苗可能会 在幼稚的受试者中加强症状性疾病，这对其最终部署提出了问题。 缺乏已建立的疫苗诱导保护的免疫相关性，阻碍了一种 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了解的技术进步为 实施新的检测方法以确定疫苗效力的机制和相关性的前进方向。一种新的 DENV减毒活疫苗目前正在巴西进行测试，巴西是DENV 达到了流行的程度。该TV003疫苗配方包括三个相应的减毒株 对不同的DENV血清型(DENV-1、DENV-3和DENV-4)和第四个嵌合株(DENV-2/DENV-4)， 它包含DENV-2结构基因和DENV-4非结构基因。其中一个主要的 TV003疫苗相对于赛诺菲DENV-YFV疫苗的优点是其所有成分都是 来自DENV毒株。该疫苗的第二阶段试验已经完成，第三阶段试验已经启动。 将包括超过17,000个主题。第二阶段和第三阶段试验都已获得动力，以包括足够的 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 已经收集了这两项里程碑式研究中包括的所有主题的信息。我们研究的主要目标是 将是比较、排序和选择预测免疫原性和有效性的最佳检测方法 疫苗。我们将检验这一假设，即需要几种成分(细胞成分、体液成分和固有成分) 以触发该疫苗诱导的保护作用。将在这里测试的化验方法涵盖了广泛的 细胞和体液免疫反应的效应机制阵列以及新的全基因组 对先天免疫和获得性免疫的公正评估。一棵严谨的决策树将允许我们进入目标1 识别和验证预测疫苗引发针对所有四种疫苗的广泛免疫反应的分析 该疫苗中包括的DENV毒株。在目标2中，我们将确定同类中最好的分析方法(S)，它可以预测 疫苗在保护接受者免受感染方面的效力。疗效将包括病例和 控制疫苗的有效率是否低于80%；或者，我们将比较接种疫苗的人和自然感染的人 如果疫苗高效，则使用安慰剂(&gt；85%)。在Aim 3中，我们的企业合作伙伴Caprion 在开发临床结果预测指标方面的长期经验，将进一步优化和扩大检测方法(S) 在目标1(免疫原性)和目标2(有效性)中确定所需的稳健性、准确性和吞吐量 用于DENV疫苗试验的广泛临床应用，可能还有其他病毒。

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.