PROJECT 2: Linking Vaccine-Induced Antibody Responses to Protective or Disease Enhancing Immunity

项目 2：将疫苗诱导的抗体反应与保护性或疾病增强免疫力联系起来

• 批准号: 10458129
• 负责人: Aravinda M. DeSilva
• 金额: $ 37.68万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-29 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10458129
• 关键词: Antibodies; Antibody Affinity; Antibody Response; Antigenic Variation; Antigens; Attenuated; Attenuated Vaccines; Avidity; Child; Clinical; Clinical Research; Clinical Trials; Collaborations; Culicidae; Data; Dengue; Dengue Infection; Dengue Vaccine; Dengue Virus; Dengvaxia; Development; Disease; Epitopes; Exposure to; Failure; Flavivirus; Formulation; Genetic Variation; Genotype; Grant; Human; Immune; Immune response; Immunity; Individual; Infection; Lead; Link; Memory B-Lymphocyte; Methods; Modeling; Molecular; Monitor; North Carolina; Outcome; Pediatric cohort; Performance; Persons; Phase I Clinical Trials; Phase II Clinical Trials; Philippines; Population; Prevention; Problem Solving; Property; Reagent; Recombinants; Research Personnel; Risk; Safety; Sampling; Serotyping; Specificity; Specimen; Structure; T cell response; Testing; Transplantation; United States National Institutes of Health; Universities; Vaccinated; Vaccination; Vaccine Research; Vaccinee; Vaccines; Variant; Virus Diseases; base; breakthrough infection; clinical development; cohort; cost effective; cross reactivity; efficacy study; efficacy trial; experience; immunological status; improved; neutralizing antibody; pandemic disease; programs; response; severe dengue; vaccine development; vaccine efficacy; vaccine failure; vaccine immunogenicity; vaccine response; vaccine safety; vaccine-induced antibodies

PROJECT 2: Linking Vaccine Induced Antibody Responses to Protective or Disease Enhancing Immunity (University of North Carolina, Chapel Hill). SUMMARY Vaccination is the most promising and cost-effective strategy for controlling the global pandemic caused by the four dengue virus (DENV) serotypes. DENV vaccines based on tetravalent live attenuated (TV-DLAV) formulations are at different stages of clinical development. Recently, DENV vaccines have faced major setbacks in clinical studies, such as poorly balanced immune responses across the four DENV serotypes, variable vaccine efficacy depending on the baseline immune status of children, vaccine responses that are more effective against strains that closely match the vaccine strain and, most significantly, vaccine-primed severe dengue disease upon exposure to wild-type DENVs. It has been challenging to understand and solve these problems because we still lack robust immune correlates that predict DENV vaccine efficacy and safety. The overall approach of Project 2 is to characterize antibody (Ab) responses in people who receive TV-DLAV. To link vaccine-induced Ab responses to specific outcomes such as protection, vaccine failure and vaccine-primed severe disease, our studies utilize samples from vaccinated people with known outcomes upon exposure to wild- type DENVs. We will test the hypothesis that in people with no prior immunity to DENVs who are vaccinated, durable protection will require the induction of Abs to type-specific (TS) tertiary and quaternary structure epitopes on each DENV serotype (Specific Aim 1.1). In children who are seronegative at baseline, we will test if low- avidity cross-reactive (XR) Abs induced by vaccination increase the risk of severe dengue disease (Specific Aim 1.2). In people with pre-existing immunity to DENV, we will explore if vaccine efficacy is linked to the activation of DENV-specific memory B cells and the induction of cross-protective Ab responses, similar to protective responses in natural 2° DENV infections (Specific Aim 2). We will also conduct studies to define the impact of genotypic variation within each DENV serotype on vaccine efficacy (Specific Aim 3). This project will define immune correlates and mechanisms of vaccine efficacy and safety in people with different levels of baseline immunity to DENV. Project 2 is highly synergistic with the other Projects and Cores in this P01. We will generate reagents (chimeric epitope transplant flaviviruses and recombinant antigens) for use by other Projects (Projects 1 & 4), share clinical samples (Core C, Projects 1 & 3), compare Ab responses to vaccines and natural DENV infections (Projects 1 and 4) and integrate the analysis (Core B) of the Ab and T cell response to DENV vaccines (Project 3).

项目 2：将疫苗诱导的抗体反应与保护性或疾病增强免疫力联系起来 （北卡罗来纳大学教堂山分校）。 概括 疫苗接种是控制由新冠病毒引起的全球大流行的最有前途和最具成本效益的策略 基于四价减毒活疫苗（TV-DLAV）的四种登革热病毒（DENV）血清型。 制剂正处于临床开发的不同阶段，最近，DENV 疫苗面临重大挑战。 临床研究中的挫折，例如四种 DENV 血清型之间的免疫反应不平衡， 不同的疫苗功效取决于儿童的基线免疫状态，疫苗反应更 对与疫苗株非常匹配的菌株有效，最重要的是，对疫苗引发的严重病毒株有效 接触野生型登革热病毒后发生登革热疾病 理解和解决这些问题一直具有挑战性。 问题是因为我们仍然缺乏预测登革热病毒疫苗功效和安全性的强大免疫相关因素。 项目 2 的总体方法是表征接受 TV-DLAV 的人的抗体 (Ab) 反应。 疫苗诱导的抗体对特定结果的反应，例如保护、疫苗失败和疫苗引发 严重的疾病，我们的研究利用了肺炎患者的样本，这些患者在接触野生病毒后具有已知的结果 我们将检验以下假设：对于既往对 DENV 没有免疫力的肺炎患者， 持久的保护需要将抗体诱导至类型特异性 (TS) 三级和四级结构表位 对于每种 DENV 血清型（具体目标 1.1），我们将测试基线血清阴性的儿童是否呈低水平。 疫苗接种诱导的亲和力交叉反应 (XR) 抗体会增加患严重登革热疾病的风险（具体 目标 1.2)。对于预先存在 DENV 免疫力的人，我们将探讨疫苗功效是否与 DENV 相关。 激活 DENV 特异性记忆 B 细胞并诱导交叉保护性抗体反应，类似于 自然 2° DENV 感染中的保护性反应（具体目标 2）。 每种 DENV 血清型内的基因型变异对疫苗功效的影响（具体目标 3）。 定义不同水平人群的免疫相关性以及疫苗功效和安全性的机制 项目 2 与本 P01 中的其他项目和核心具有高度协同性。 将生成试剂（嵌合表位移植黄病毒和重组抗原）供其他人使用 项目（项目 1 和 4），共享临床样本（核心 C，项目 1 和 3），比较抗体对疫苗的反应 和自然 DENV 感染（项目 1 和 4），并整合 Ab 和 T 细胞反应的分析（核心 B） DENV 疫苗（项目 3）。