Evaluation of Antibody Responses Elicited by Zika Vaccination in Flavivirus-naïve and -experienced Individuals

评估寨卡疫苗接种在未接触过黄病毒和有黄病毒病毒经历的个体中引起的抗体反应

• 批准号: 10595067
• 负责人: Shelly J Krebs
• 金额: $ 30万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-13 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595067
• 关键词: Adenovirus Vector; Adenoviruses; Affinity; Animal Model; Antibodies; Antibody Repertoire; Antibody Response; Antibody-Dependent Enhancement; Antigens; Area; B cell repertoire; B-Cell Antigen Receptor; B-Lymphocytes; Binding; Biological Assay; Cell Lineage; Cells; Communicable Diseases; Data; Defect; Dengue; Dengue Infection; Dengue Virus; Development; Disease; Dose; Epidemiology; Epitopes; Evaluation; Evolution; Exposure to; Flavivirus; Flavivirus Infections; Flow Cytometry; Genes; Goals; Human; Humoral Immunities; Immunity; Immunization; Immunodominant Epitopes; Immunoglobulin Somatic Hypermutation; In Vitro; Inactivated Vaccines; Individual; Infection; Japanese encephalitis virus; Lateral; Length; Longevity; Maps; Memory B-Lymphocyte; Methodology; Methods; Monoclonal Antibodies; Mus; Neurologic; Phase; Plasma; Population; Prevalence; Publishing; Puerto Rico; Reporting; Research; Research Personnel; Role; Sampling; Serotyping; Shapes; Sorting; Specificity; Technology; Tissues; Translating; Travel; Vaccinated; Vaccination; Vaccine Clinical Trial; Vaccinee; Vaccines; Virus; Virus Replication; Yellow fever virus; ZIKA; Zika Virus; Zika virus vaccine; comparative; cross reactivity; design; experience; insight; member; memory recall; mouse model; neurological pathology; neutralizing antibody; next generation sequencing; permissiveness; response; single-cell RNA sequencing; tool; transcriptome sequencing; vaccination strategy; vaccine candidate; vaccine development; vaccine response; vaccine strategy; vector

Project Title: Evaluation of Antibody Responses Elicited by Zika Vaccination in Flavivirus-naïve and - experienced Individuals Project Summary Zika virus (ZIKV) is a member of the flavivirus genus that recently precipitated widespread cases of neurological pathology and congenital neurologic defects. In response, a multilateral coalition of investigators designed and developed multiple vaccine candidates that elicited potent ZIKV-neutralizing antibodies, which were shown to correlate with disease protection in animal models. Despite these advances, it remains unclear how the ZIKV immunization antibody response is shaped in humans with and without prior exposure to other flaviviruses, such as dengue virus (DENV), Japanese encephalitis (JEV) or yellow fever virus (YFV); particularly as these viruses all have significant epidemiologic overlap with ZIKV. Our long-term goal is to understand the underlying humoral mechanisms generated by flavivirus vaccination, which can provide long-term protection in flavivirus-naïve and/or -experienced populations. Such information would guide vaccination strategies in flavivirus-endemic areas or among flavivirus-naïve individuals traveling to endemic areas. The overall objective of this proposed research is to evaluate the specificity and function of the B cell repertoire elicited by ZIKV vaccination in flavivirus- naïve and -experienced individuals. To achieve these goals, this research will utilize leading-edge technologies to sequence B cell receptors (BCRs) from flavivirus-specific, single B cells using RNAseq and Next Generation Sequencing (NGS). BCRs will be compared between Zika vaccinated individuals, and to previously published monoclonal antibodies, to determine the prevalence of B cell lineages, gene assignment, degree of somatic hypermutation (SHM), and lengths of heavy chain complementary-determining region 3 (HCDR3). Common B cell lineages will be expressed as monoclonal antibodies and evaluated for their specificity, function, structural, and ability to protect against flavivirus challenges in mouse models. A total of 40 samples will be evaluated from individuals representing 5 groups in 3 different Phase I Zika vaccine clinical trials: a) Flavivirus-naïve individuals who were vaccinated using a Zika purified inactivated whole virus vaccine (ZPIV) b) Flavivirus-naïve individuals who were vaccinated with an adeno-vectored Zika M-E (Ad26.ZIKV.M-Env) c) Individuals living in Puerto Rico with prior dengue infection who were ZPIV vaccinated d) JEV (IXIARO®) vaccinated individuals who were ZPIV vaccinated and e) YFV (YV-VAX®) vaccinated individuals who were ZPIV vaccinated. Flavivirus-naïve, Zika vaccinated individuals (Groups a-b) will be explored in Aim 1 and Flavivirus-experienced individuals, either by prior infection (Group c) or by prior vaccination (Groups d-e), will be explored in Aim 2. Aim 3 will examine a late timepoint (6 months) following the last ZPIV vaccination to determine the longevity of the circulating B cell lineages characterized in Aims 1 and 2. Evaluating prevalent B cell lineages responding to Zika vaccination will reveal the specificity, function and durability of the humoral response among individuals living in different regions. These studies will provide insights into the potency and durability of ZIKV vaccine responses in both flavivirus- naïve and -experienced individuals and may translate into vaccine strategies that yield long-lived protection.

项目名称：在黄病毒初治和未感染者中评估寨卡疫苗接种引起的抗体应答 经验丰富的个人 项目摘要 寨卡病毒（ZIKV）是黄病毒属的一种，最近引发了广泛的神经系统疾病病例。 病理学和先天性神经缺陷。作为回应，一个多边调查人员联盟设计并 开发了多种候选疫苗，这些候选疫苗可引发有效的ZIKV中和抗体， 与动物模型中的疾病保护相关。尽管取得了这些进展，但尚不清楚ZIKV如何 免疫抗体应答在先前暴露于或未暴露于其他黄病毒的人中形成， 如登革热病毒（DENV）、日本脑炎病毒（JEV）或黄热病病毒（YFV）;特别是这些病毒 都与ZIKV有显著的流行病学重叠。我们的长期目标是了解潜在的体液 黄病毒疫苗接种产生的机制，可为黄病毒初治患者提供长期保护。 和/或有经验的人群。这些信息将指导黄病毒流行的疫苗接种策略。 地区或黄病毒初治个体前往流行地区。拟议的总体目标 研究的目的是评估黄病毒中ZIKV疫苗接种引起的B细胞库的特异性和功能。 天真和经验丰富的人。为了实现这些目标，这项研究将利用领先的技术 使用RNAseq和Next Generation对来自黄病毒特异性单个B细胞的B细胞受体（BCR）进行测序 测序（NGS）。BCR将在寨卡疫苗接种个体之间进行比较，并与先前发表的 单克隆抗体，以确定B细胞谱系的患病率，基因分配，体细胞分化程度， 超突变（SHM）和重链互补决定区3（HCDR 3）的长度。普通B 将细胞谱系表达为单克隆抗体，并评价它们的特异性、功能、结构 以及在小鼠模型中保护免受黄病毒攻击的能力。总共将评价40个样本， 在3个不同的I期寨卡疫苗临床试验中代表5个组的个体： B）未感染过黄病毒的个体 c）居住在波多黎各的个人 d）ZPIV疫苗接种的JEV（IXIARO®）疫苗接种个体， e）接种ZPIV的YFV（YV-VAX®）接种个体。黄病毒初治、寨卡 将在Aim 1和黄病毒感染个体中探索接种疫苗的个体（a-b组）， 先前感染（c组）或先前接种（d-e组）的情况将在目的2中进行探讨。目标3将检查一个晚 末次ZPIV疫苗接种后的时间点（6个月），以确定循环B细胞的寿命 目标1和目标2中所描述的血统。评估对寨卡疫苗接种有反应的流行B细胞谱系将 揭示了生活在不同地区的个人之间的体液反应的特异性，功能和持久性。 这些研究将提供对ZIKV疫苗应答在黄病毒-巨噬细胞两种中的效力和持久性的见解。 这可能会转化为疫苗策略，产生长期的保护。