Flavivirus immunity in endemic and non-endemic human cohorts

地方性和非地方性人群中的黄病毒免疫力

• 批准号: 10353435
• 负责人: William Messer
• 金额: $ 38.4万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-16 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10353435
• 关键词: Antibodies; Antibody titer measurement; Antibody-mediated protection; Biological Assay; Cells; Cohort Studies; Collaborations; Communities; Complex; Data; Dengue; Dengue Vaccine; Dengue Virus; Dependence; Diagnostic; Disease; Disease Surveillance; Epidemic; Evaluation; Flavivirus; Fluorescence-Activated Cell Sorting; Fostering; Frequencies; Future; Gold; Human; Immune; Immunity; Immunologic Memory; Individual; Infection; Knowledge; Label; Life; Link; Maintenance; Memory; Memory B-Lymphocyte; Methods; Mission; Modeling; Natural Immunity; Nicaragua; Nonstructural Protein; Observational Study; Oregon; Pathogenicity; Peripheral Blood Mononuclear Cell; Peru; Play; Primary Infection; Property; Public Health; Puerto Rico; Research; Role; Sentinel; Serotyping; Serum; Specificity; Surveillance Modeling; System; Testing; Therapeutic; Time; United States National Institutes of Health; Vaccine Design; Vaccines; Variant; Viral Proteins; Virus; Work; World Health Organization; Zika Virus; arthropod-borne; burden of illness; cohort; immunogenic; innovation; mosquito-borne; neutralizing antibody; novel; prospective; response; transmission process; vaccine development; vaccine evaluation

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.

项目概要 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做出回应 通过疫苗、治疗方法和诊断方法来应对这一新出现的威胁。然而，在基本面方面仍存在差距 有关 DENV 和 ZIKV 免疫的知识，特别是针对每种血清型的类型特异性免疫如何发展 并且持续存在，使得合理的疫苗开发变得尤其困难。主导免疫模型来了 来自对 DENV 的人类挑战研究（1910 年代至 1940 年代），并假设首次感染会诱导中和 提供终生灭菌免疫力的抗体，以防止同一（同型）血清型病毒的重复感染， 并且这个模型在没有经过严格评估的情况下就被推广到了ZIKV。然而，DENV 最近的研究 流行地区提供了同型再感染和随着时间的推移自然免疫增强的证据，我们的 来自俄勒冈州波特兰市非地方性居民 DENV 和 ZIKV 免疫队列的初步数据显示， 随着时间的推移，特定的 Abs 衰减 - 失去效力和广度，从而引发对灭菌免疫力和 让我们假设天然黄病毒（ZIKV 和 DENV）的保护性免疫是依赖于环境的： 地方性传播环境间歇性无症状加强维持病毒的效力和广度 特异性免疫以及在非地方性或传播率极低的环境中黄病毒的效力和广度 免疫力明显下降。为了检验这一假设，我们建议前瞻性地描述和比较 波多黎各庞塞定期重新暴露的流行人群中的 DENV 和 ZIKV 免疫力 波特兰未增强、非流行的 DENV 免疫群体。这是一个有争议且新颖的假设 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且 两个队列之间增强的相关标志物：中和血清 DENV 的效力和广度以及 ZIKV 特异性抗体（目标 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 (MBC) 的频率和特异性 （目标 3）。我们预计会发现非正常人的 Abs 和 MBC 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这样的假设：增强在 对这些病毒的天然免疫力，对未来疫苗的开发具有影响。因为 MBC 是 与 Abs 功能相关，量化病毒特异性 MBC 测试重复之间的机械联系 感染和抗体滴度升高。我们提出的工作将全面评估角色传递背景 使用两个高度相关且机械关联的决定簇（Ab 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对于 DENV 疫苗至关重要 黄病毒抗体介导的免疫的发展和机制理解。