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: 10089397
• 负责人: Jason W. Botten
• 金额: $ 61.16万
• 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/10089397
• 关键词: Antibodies; Antibody Response; Antibody-Dependent Enhancement; Antiviral Agents; 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; 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.

项目摘要 大约40％的世界人口受到登革热病毒四种血清型引起的疾病的风险。 耐用，安全和高效的四载粉丝的发展是全球优先事项。由于不完整 免疫力可能会通过抗体依赖性增强使个体诱发更严重的疾病，这是 登革热疫苗是针对所有四种血清型的长期简单保护。考虑到弱点和 使用当前唯一许可的粉丝后观察到的风险，澄清组件和 疫苗接种后耐用的四型保护的机制。该提议利用了长期的工作 参与NIH实时攻击的四龙登革热的常规协作调查员 疫苗。它建立在我们单价和四价疫苗研究中的初步数据基础上 人类登革热病毒挑战模型，以提早疫苗效率。初步工作表明 疫苗后不久，受保护的疫苗暴露于特异性浆液中，然后中和 针对所有血清型和细胞反应的抗体反应，包括CD8+ T细胞反应的靶向 风扇非结构性蛋白质。该建议计划通过四个目标评估数据和标本 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试验 耐用保护的免疫特征的观察。这些试验包括四价 接种疫苗，然后进行短期（30d）或长期（> 3年）病毒挑战；不完全保护的三 Valent疫苗，然后进行缺失的型挑战；以及幼稚和 疫苗接种后几年后，先前经验丰富的受试者随后受试者。我们假设如果 同型抗体所有血清型都不存在，定义的机制可能会补偿缺失 血清型并维持免受疾病的保护。我们希望在不完整或减弱的环境中证明这一点 免疫力，这些机制，例如细胞反应（CD8+非结构蛋白和CD4+细胞毒性）或 构成表位的异型抗体，即使在有增强的情况下也是必要和有效的 抗体。总体而言，这些免疫学评估将有助于回答有关的关键和持续问题 登革热疫苗风险和有效性。使用高度控制的临床研究杠杆作用，这些数据应广泛 可以在四伏粉丝后了解安全和耐用的免疫力。