Mechanisms of Protection and Durability for a Live Attenuated Tetravalent Dengue Vaccine

四价登革热减毒活疫苗的保护和持久性机制

• 批准号: 10334565
• 负责人: Jason W. Botten
• 金额: $ 60.9万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10334565
• 关键词: Antibodies; Antibody Response; Antibody-Dependent Enhancement; Attenuated; B-Lymphocytes; Biological Specimen Banks; CD8-Positive T-Lymphocytes; CD8B1 gene; Clinical Research; Clinical Trials; Clinical Trials Design; Communicable Diseases; Data; Dengue; Dengue Infection; Dengue Vaccine; Dengue Virus; Dengvaxia; Development; Disease; Epitopes; Evaluation; Exhibits; Exposure to; Flavivirus; Goals; Heterophile Antibodies; Human; Immune; Immunity; Immunologics; Individual; Infection; Lead; Link; Mediating; Modeling; Nonstructural Protein; Outcome; Pathway interactions; Plasmablast; Population; Research Personnel; Risk; Role; Safety; Serotyping; Specimen; Surface; T cell response; T-Lymphocyte; Testing; Time; United States National Institutes of Health; Vaccination; Vaccine Design; Vaccinee; Vaccines; Viral; Virus; Work; cytotoxic; experience; memory CD4 T lymphocyte; neutralizing antibody; response; severe dengue; vaccine development; vaccine efficacy; vaccine trial; vaccinology

PROJECT SUMMARY Approximately 40% of the world's population is at risk for illness caused by the four serotypes of dengue virus. Development of durable, safe, and efficacious tetravalent dengue vaccines is a global priority. Since incomplete immunity may predispose individuals to more severe disease via antibody-dependent enhancement, the goal of dengue vaccines is long-term simultaneous protection against all four serotypes. Given the weaknesses and risks observed following use of the only currently licensed dengue vaccine, it is critical to clarify components and mechanisms of durable four-serotype protection following vaccination. This proposal leverages the work of long- standing collaborative investigators involved in the development of the NIH live-attenuated tetravalent dengue vaccine. It builds on preliminary data from our monovalent and tetravalent vaccine studies, as well use of the human dengue virus challenge model for early indications of vaccine efficacy. Preliminary work suggests that protected vaccinees exhibit dengue-specific plasmablasts soon after vaccination, followed by neutralizing antibody responses targeted to all serotypes and cellular responses-including CD8+ T cell responses targeting dengue non-structural proteins. This proposal plans to evaluate data and specimens via four aims corresponding to specifically-designed vaccine and/or human viral challenge trials to iteratively expand and refine these observations for the immunologic characterization of durable protection. These trials include tetravalent vaccinations followed by short term (30d) or long term (>3 years) viral challenge; an incompletely protective tri- valent vaccine followed by missing-serotype challenge; and an endemic setting vaccine trial of naïve and previous dengue-experienced subjects followed for several years post-vaccination. We hypothesize that if homotypic antibodies all serotypes are not present, defined mechanisms may compensate for the missing serotype and to maintain protection from illness. We hope to demonstrate that in settings of incomplete or waning immunity, these mechanisms, such as cellular responses (CD8+ non-structural protein and CD4+ cytotoxic) or heterotypic antibodies to conserved epitopes, are necessary and effective even in the presence of enhancing antibodies. Overall, these immunologic evaluations will help answer critical and persistent questions about dengue vaccine risk and efficacy. Leveraged with highly controlled clinical studies these data should be broadly generalizable to the understanding of safe and durable immunity following tetravalent dengue vaccines.

项目概要 Approximately 40% of the world's population is at risk for illness caused by the four serotypes of dengue virus. 开发持久、安全、有效的四价登革热疫苗是全球的首要任务。由于不完整 免疫力可能通过抗体依赖性增强使个体易患更严重的疾病，这是免疫治疗的目标 登革热疫苗可针对所有四种血清型提供长期同时保护。鉴于弱点和 使用目前唯一获得许可的登革热疫苗后观察到的风险，澄清其成分和成分至关重要 疫苗接种后持久的四血清型保护机制。该提案利用了长期的工作 参与 NIH 减毒活四价登革热开发的常设合作研究人员 疫苗。它建立在我们单价和四价疫苗研究的初步数据以及使用 人类登革热病毒攻击模型用于疫苗功效的早期指示。初步工作表明 受保护的疫苗接种者在接种疫苗后不久就会表现出登革热特异性浆母细胞，然后进行中和 针对所有血清型的抗体反应和细胞反应 - 包括针对 CD8+ T 细胞的反应 登革热非结构蛋白。该提案计划通过四个目标来评估数据和样本 专门设计的疫苗和/或人类病毒挑战试验，以迭代扩展和完善这些 持久保护的免疫学特征的观察。这些试验包括四价 接种疫苗后进行短期（30 天）或长期（> 3 年）病毒攻击；不完全保护三 价疫苗，然后是缺失血清型挑战；以及一项地方性疫苗试验 以前患有登革热的受试者在接种疫苗后进行了数年的追踪。我们假设如果 同型抗体并非所有血清型都存在，明确的机制可能会弥补缺失 血清型并保持对疾病的保护。我们希望证明，在不完整或衰弱的情况下 免疫，这些机制，例如细胞反应（CD8+非结构蛋白和CD4+细胞毒性）或 即使存在增强的情况下，针对保守表位的异型抗体也是必要且有效的 抗体。总体而言，这些免疫学评估将有助于回答以下关键和持续存在的问题： 登革热疫苗的风险和功效。通过高度对照的临床研究，这些数据应该被广泛利用 可推广到四价登革热疫苗后安全且持久的免疫力的理解。