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: 10244877
• 负责人: Aravinda M. DeSilva
• 金额: $ 40.7万
• 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/10244877
• 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; 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; Vaccines; Variant; Virus Diseases; base; clinical development; cohort; cost effective; cross reactivity; efficacy study; efficacy trial; experience; immunogenicity; immunological status; improved; neutralizing antibody; pandemic disease; programs; response; severe dengue; vaccine development; vaccine efficacy; 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：将疫苗诱导的抗体应答与保护性或疾病增强免疫联系起来 （北卡罗来纳州，查佩尔山）。 总结 疫苗接种是控制由流感病毒引起的全球大流行的最有希望和最具成本效益的战略。 四种登革病毒（DENV）血清型。基于四价减毒活疫苗（TV-DLAV）的DENV疫苗 这些制剂处于不同的临床开发阶段。最近，DENV疫苗面临重大挑战， 临床研究中的挫折，例如四种DENV血清型之间的免疫应答不平衡， 根据儿童的基线免疫状态，疫苗的有效性是可变的， 有效对抗与疫苗株紧密匹配的菌株，最重要的是， 在暴露于野生型DENV后，理解和解决这些问题一直是一个挑战。 这是因为我们仍然缺乏强有力的免疫相关性来预测DENV疫苗的有效性和安全性。的 项目2的总体方法是表征接受TV-DLAV的人中的抗体（Ab）应答。链接 疫苗诱导的抗体应答特定结果，如保护，疫苗失败和疫苗引发 严重的疾病，我们的研究利用了接种疫苗的人的样本，这些人在暴露于野生 DENV类型。我们将检验这一假设，即在没有对DENV免疫的人中接种疫苗， 持久的保护需要将Ab诱导至类型特异性（TS）三级和四级结构表位 每种DENV血清型（特异性目标1.1）。在基线血清阴性的儿童中，我们将检测是否低- 疫苗接种诱导的亲合力交叉反应（XR）抗体增加了严重登革热病的风险（特异性 目标1.2）。在对DENV已有免疫力的人群中，我们将探索疫苗有效性是否与 激活DENV特异性记忆B细胞和诱导交叉保护性Ab应答，类似于 在自然2° DENV感染中的保护性应答（具体目标2）。我们亦会进行研究， 每种DENV血清型内基因型变异对疫苗效力的影响（具体目标3）。该项目将 确定免疫相关性和疫苗在不同水平人群中的有效性和安全性机制， 对DENV的基线免疫力。项目2与本P01中的其他项目和核心具有高度协同作用。我们 将产生试剂（嵌合表位移植黄病毒和重组抗原）供其他 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 和天然DENV感染（项目1和4），并整合Ab和T细胞应答的分析（核心B DENV疫苗（项目3）。