Flavivirus immunity in endemic and non-endemic human cohorts

项目总结 节肢动物传播的黄病毒登革热(DENV1-4)和寨卡病毒(ZIKV)是全球传播的主要病毒 全球公共卫生挑战。世界卫生组织呼吁科学界对 这一新出现的威胁来自疫苗、治疗和诊断。然而，在根本上存在的差距 关于DENV和ZIKV免疫的知识，特别是对每个血清型的类型特异性免疫是如何形成的 而且是可持续的，这使得合理的疫苗开发变得特别困难。显性免疫模式出现了 从人类对新城疫病毒的挑战研究(1910年的S-1940年的S)，并提出首次感染诱导中和 对相同(同型)血清型病毒的重复感染提供终身灭菌免疫力的抗体， 并且在没有严格评估的情况下，将该模型推广到ZIKV。然而，来自DENV的最新研究 流行区提供了同型再感染和自然免疫增强的证据，随着时间的推移和我们的 来自俄勒冈州波特兰的非流行DENV和ZIKV免疫队列的初步数据显示- 随着时间的推移，特定的抗体会腐烂，失去效力和广度，使人对杀菌免疫力和 这导致我们假设天然黄病毒(ZIKV和DENV)的保护性免疫依赖于上下文： 地方性传播环境间歇性无症状增强保持病毒的效力和广度 特异性免疫以及在非地方性或极低传播环境中黄病毒的效力和广度 免疫力明显减弱。为了检验这一假设，我们建议前瞻性地描述和比较 在波多黎各庞塞定期再次暴露的地方性队列中的DENV和ZIKV免疫，其中 波特兰未加强免疫的非地方性新城疫疫苗队列。这是一个有争议的新奇假设。 这将需要大量的支持证据，因此我们将比较和对比三个高度相关的和 两个队列之间增强的相关标志物：中和血清DENV和 ZIKV特异性抗体(AIM 1)、DENV和ZIKV非结构蛋白1(NS1)的频率和效力 特异性抗体(目标2)以及DENV和ZIKV特异性记忆B细胞(MBCs)的频率和特异性 (目标3)。我们预计会发现，在来自非老年人的个体中，Abs和MBCs的下降速度明显更快 地方性环境与地方性环境的比较支持了加强在 这些病毒的自然免疫力，对未来疫苗开发的影响。因为MBCS是 在功能上与抗体相关联，量化病毒特异性的MBCs测试重复之间的机械联系 感染和抗体滴度升高。我们建议的工作将全面评估角色传递的背景 使用两个高度相关和机械连接的决定簇(抗体和MBC)在黄病毒免疫中发挥作用。 无论具体结果如何，从拟议工作中获得的知识将对DENV疫苗至关重要。 黄病毒抗体免疫机制的研究进展

PROJECT SUMMARY The global spread of the arthropod borne flaviviruses dengue (DENV1-4) and Zika (ZIKV) viruses are major global public health challenges. World health organizations are calling for scientific communities to respond to this emerging threat with vaccines, therapeutics and diagnostics. However, existing gaps in fundamental knowledge about DENV and ZIKV immunity, specifically how type-specific immunity to each serotype develops and is sustained, makes rational vaccine development particularly difficult. The dominant immunity model comes from human challenge studies on DENV (1910’s-1940’s) and posits that first infection induces neutralizing antibodies that provide life-long sterilizing immunity to repeat infections by the same (homotypic) serotype virus, and this model has been extended to ZIKV without rigorous evaluation. However, recent studies from DENV endemic regions provide evidence of homotypic re-infection and natural immune boosting over time and our preliminary data from a non-endemic, Portland, Oregon resident DENV and ZIKV immune cohort show type- specific Abs decay – lose both potency and breadth - over time, calling into question sterilizing immunity and leading us to hypothesize that natural flavivirus (ZIKV and DENV) protective immunity is context dependent: in endemic transmission settings intermittent asymptomatic boosting maintains potency and breadth of virus specific immunity and in non-endemic or very low transmission settings potency and breadth of flavivirus immunity significantly wanes. To test this hypothesis, we propose to prospectively characterize and compare DENV and ZIKV immunity in a regularly re-exposed endemic cohort in Ponce, Puerto Rico with immunity in an un-boosted, non-endemic cohort of DENV immunes in Portland. This is a controversial and novel hypothesis that will call for substantial supporting evidence, hence we will compare and contrast three highly relevant and related markers of boosting between the two cohorts: The potency and breadth of neutralizing serum DENV and ZIKV specific Abs (Aim 1), the frequency of and potency of DENV and ZIKV non-structural protein 1 (NS1) specific antibodies (Aim 2), and the frequency and specificity of DENV and ZIKV specific memory B-cells (MBCs) (Aim 3). We expect to find that Abs and MBCs decline at a significantly greater rate in individuals from the non- endemic setting compared to the endemic setting supporting the hypothesis that boosting plays a critical role in natural immunity for these viruses, with implications for future vaccine development. Because MBCs are functionally linked to Abs, quantifying virus specific MBCs tests a mechanistic connection between repeat infection and Ab titer boosting. Our proposed work will comprehensively assess the role transmission context plays in flavivirus immunity using two highly relevant and mechanistically linked determinants (Ab and MBC). Irrespective of specific results, the knowledge obtained from the proposed work will be essential to DENV vaccine development and mechanistic understanding of flavivirus Ab mediated immunity.