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: 10392318
• 负责人: Shelly J Krebs
• 金额: $ 85.91万
• 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 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10392318
• 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; Length; Longevity; 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 - Cell Movement; 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; 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：评估寨卡疫苗接种在未接触过黄病毒的人和 - 中引起的抗体反应 有经验的人 项目概要 寨卡病毒 (ZIKV) 是黄病毒属的一员，最近引发了广泛的神经系统病例 作为回应，一个由研究人员组成的多边联盟设计并进行了研究。 开发了多种候选疫苗，可引发有效的 ZIKV 中和抗体，这些抗体被证明可以 尽管取得了这些进展，但 ZIKV 与疾病保护的相关性仍不清楚。 免疫抗体反应是在人类之前接触过或未接触过其他黄病毒的情况下形成的，例如 例如登革热病毒(DENV)、日本脑炎病毒(JEV)或黄热病病毒(YFV)，特别是这些病毒； 所有这些都与 ZIKV 具有显着的流行病学重叠。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，可以为未接触过黄病毒的人提供长期保护 和/或 - 有经验的人群将指导黄病毒流行的疫苗接种策略。 地区或前往流行地区的未感染黄病毒的个体中 本提议的总体目标。 研究目的是评估黄病毒中 ZIKV 疫苗接种所引发的 B 细胞库的特异性和功能。 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) 将在寨卡疫苗接种个体之间进行比较，并与之前发布的结果进行比较。 单克隆抗体，确定 B 细胞谱系的流行程度、基因分配、体细胞程度 超突变 (SHM) 和重链互补决定区 3 (HCDR3) 的长度。 细胞谱系将被表达为单克隆抗体，并对其特异性、功能、结构、 以及在小鼠模型中抵御黄病毒挑战的能力 将评估总共 40 个样本。 代表 3 个不同 I 期寨卡疫苗临床试验中 5 个组的个体：a) 未接触过黄病毒的个体 使用寨卡纯化灭活全病毒疫苗 (ZPIV) 进行疫苗接种 b) 未接触过黄病毒的个体 接种了腺载体 Zika M-E (Ad26.ZIKV.M-Env) 疫苗的人 c) 居住在波多黎各的个人 既往感染登革热并接种过 ZPIV 疫苗的人 d) 接种过 ZPIV 疫苗的 JEV (IXIARO®) 个体 e) 属于 ZPIV 流感病毒的 YFV (YV-VAX®) 流感病毒个体。 将在目标 1 中探索受感染个体（a-b 组）和经历过黄病毒的个体，方法是 目标 2 将探讨先前感染（c 组）或先前接种疫苗（d-e 组）。目标 3 将检查晚期感染 最后一次 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 2 中描述的谱系。评估对寨卡疫苗接种做出反应的流行 B 细胞谱系将 揭示生活在不同地区的个体体液反应的特异性、功能和持久性。 这些研究将深入了解 ZIKV 疫苗在黄病毒和病毒中的反应效力和持久性。 天真的和有经验的个人，可能会转化为产生长期保护的疫苗策略。