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

项目总结 世界上约40%的人口面临由四种血清型登革热病毒引起的疾病的风险。 开发持久、安全和有效的四价登革热疫苗是全球的优先事项。由于不完整 免疫可能通过抗体依赖的增强使个人更容易患上更严重的疾病，其目标是 登革热疫苗是对所有四种血清型的长期同时保护。鉴于这些弱点和 在使用目前唯一获得许可的登革热疫苗后观察到的风险，关键是澄清成分和 疫苗接种后持久的四种血清型保护机制。这项建议充分利用了Long- 参与NIH减毒活四价登革热发展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基础上，以及使用 人类登革热病毒挑战模型用于疫苗效力的早期指标。初步工作表明， 受保护的接种者在接种后不久就会出现登革热特异的成浆细胞，然后进行中和 针对所有血清型和细胞反应的抗体反应--包括针对CD8+T细胞反应 登革热非结构蛋白。该提案计划通过以下四个目标对数据和样本进行评估 专门设计的疫苗和/或人类病毒挑战试验，以迭代地扩展和改进这些 观察持久保护的免疫学特征。这些试验包括四价 疫苗接种后短期(30天)或长期(3年)病毒挑战；一个不完全保护的三个 价疫苗，然后是缺失血清型挑战；以及天真和地方性背景疫苗试验 之前有登革热经验的受试者在接种疫苗后跟踪了几年。我们假设如果 同型抗体所有血清型都不存在，已定义的机制可能会弥补缺失 血清型和保持对疾病的保护。我们希望在不完整或衰落的情况下证明这一点 免疫，这些机制，如细胞反应(CD8+非结构蛋白和CD4+细胞毒性)或 针对保守表位的异型抗体，即使在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关键和长期存在的问题 登革热疫苗的风险和效力。利用高度受控的临床研究，这些数据应该广泛应用 可概括为理解四价登革热疫苗后的安全和持久免疫。

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.