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

项目摘要 大约40%的世界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优先事项。由于不完整 免疫可能通过抗体依赖性增强使个体易患更严重的疾病， 登革热疫苗是针对所有四种血清型的长期同时保护。鉴于这些弱点和 使用目前唯一获得许可的登革热疫苗后观察到的风险，关键是要澄清成分， 疫苗接种后持久的四种血清型保护机制。这项提案利用了长期以来的工作- 参与NIH四价登革热减毒活疫苗开发的长期合作研究者 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， 用于疫苗效力早期指示的人登革病毒攻击模型。初步工作表明， 受保护的疫苗接种者在接种疫苗后不久就表现出登革热特异性浆母细胞， 针对所有血清型的抗体应答和细胞应答-包括针对 登革热非结构蛋白。该方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/或人类病毒攻击试验，以反复扩大和完善这些 观察持久保护的免疫学表征。这些试验包括四价 疫苗接种后进行短期（30天）或长期（>3年）病毒攻击;不完全保护性的三- 价疫苗，然后缺失血清型攻击;以及一项地方性疫苗试验， 接种疫苗后对先前经历登革热的受试者进行了数年的随访。我们假设如果 如果所有血清型均不存在同型抗体，则定义的机制可以弥补缺失的 血清型，并保持对疾病的保护。我们希望证明，在不完全或衰退的情况下， 免疫，这些机制，如细胞反应（CD 8+非结构蛋白和CD 4+细胞毒性）或 针对保守表位的异型抗体，即使在存在增强型抗体的情况下也是必要和有效的。 抗体的总的来说，这些免疫学评价将有助于回答关键和持续的问题， 登革热疫苗的风险和效力。利用高度对照的临床研究，这些数据应广泛 可推广到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.