Long Term Immunity Following Yellow Fever Vaccination

黄热病疫苗接种后的长期免疫力

• 批准号: 10355419
• 负责人: William Messer
• 金额: $ 43.74万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-05 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10355419
• 关键词: Acute; Address; Adult; Aedes; Africa; African; Antibodies; Antibody titer measurement; Antibody-mediated protection; Antigens; Attenuated; Attenuated Live Virus Vaccine; Attenuated Vaccines; Brazil; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Country; Cross-Sectional Studies; Culicidae; Data; Dengue; Disease; Disease Outbreaks; Dose; Enrollment; Evaluation; Flavivirus; Fostering; Foundations; Frequencies; Future; Heterogeneity; Human; Immune; Immune response; Immunity; Immunologic Markers; Individual; Infection; Kinetics; Knowledge; Life; Long-Term Effects; Mass Vaccinations; Memory B-Lymphocyte; Mission; Modeling; Nail plate; Phase I/II Clinical Trial; Policies; Prospective Studies; Public Health; Recommendation; Recording of previous events; Research; Safety; South Africa; South America; Surveys; Symptoms; Testing; Time; United States National Institutes of Health; Vaccinated; Vaccination; Vaccine Antigen; Vaccinee; Vaccines; Viral Antibodies; Viral Load result; Viral Vaccines; Viremia; Virus; Yellow Fever; Yellow Fever Vaccine; Yellow fever virus; ZIKA; Zika Virus; adaptive immune response; antibody detection; arthropod-borne; base; burden of illness; cohort; critical period; falls; health organization; human pathogen; immune activation; immunogenicity; innovation; mortality; neutralizing antibody; nonhuman primate; pathogenic virus; pressure; prospective; prototype; recruit; response; secondary analysis; seroconversion; seropositive; serosurvey

PROJECT SUMMARY Yellow fever virus (YFV) is the prototype flavivirus and is historically the most important arthropod-borne viral pathogen of humans worldwide with ~200,000 infections annually and a mortality of ~50% in those who develop severe symptoms. YFV is endemic throughout Africa and South America and had been largely controlled through mass vaccination. The YFV vaccine 17D is considered one of the most effective live-attenuated virus (LAV) vaccines ever developed. Even so, every 10-year boosts have been recommended to maintain immunity. However, falling vaccination rates have led to a dramatic resurgence of disease in both Africa and South America, and subsequent vaccination campaigns have depleted the global supply of 17D. In response to these vaccine shortages, the WHO and CDC revised the 10-year boost to a once-in-a-lifetime vaccination recommendation, despite limited supporting data: although serosurveys find that ~90% of vaccinees have detectable neutralizing antibodies to YFV, careful review of these surveys finds that among individuals living in YFV non-endemic settings, at least 20% of YFV vaccinees lack detectable neutralizing antibodies at >10 years post-vaccination. While this finding must be critically evaluated in the context of ongoing outbreaks and vaccine shortages, it also represents a unique opportunity to study how 17D induces and maintains neutralizing antibodies in some vaccinees but not in others. Our central premise is that long-term YFV immunity is established by host immune activation in response to vaccine viremia at the time of vaccination: downstream effects of detectable differences in duration and magnitude of vaccine viremia at vaccination determine whether or not a vaccinee develops life-long immunity. We propose to evaluate this premise and its broader implications in three separate Aims: Aim 1 tests the hypothesis that vaccine viremia correlates with the long-term durability of of YFV neutralizing antibodies. We will enroll YFV pre-vaccinees and prospectively characterize acute vaccine viremia, acute innate immune and adaptive immune responses, and neutralizing antibody titers up to 5 years thereafter. Aim 2 tests the hypothesis that at least 20% of 17D vaccinated subjects will lose YFV immunity between 3- and 7-years post vaccination. We will recruit and prospectively follow a cohort of 17D vaccinees vaccinated 2-3 years prior to enrollment, comparing changes in YFV neutralizing antibodies and other immune markers over time and characterizing individual and cohort antibody decay kinetics. In Aim 3 we use 17D revaccination as a live-virus challenge to test the hypothesis that neutralizing antibody titers correlate with YFV protection. We will prospectively characterize pre-boost antibodies titers, vaccine viremia, acute immune responses and post-boost titers in vaccinees receiving boost 17D vaccinations. We expect to identify neutralizing antibody titers above which sterilizing immunity is conferred and titers below which it is not. These Aims will set a foundation for future studies to further dissect determinants of 17D and other LAV induced immunity and establish metrics that could allow efficient prioritization of 17D vaccination and optimize 17D use in the face of current and future outbreaks.

项目摘要 黄热病病毒（YFV）是原型黄病毒，历史上是最重要的节肢动物传播病毒 全世界的人类病原体每年约有200,000种感染，死亡率约为50％ 严重的症状。 YFV在整个非洲和南美都是地方性的，并在很大程度上通过 大规模疫苗接种。 YFV疫苗17D被认为是最有效的活衰减病毒之一（LAV） 疫苗曾经开发过。即便如此，建议每10年提升一次以维持免疫力。 但是，疫苗接种率下降导致非洲和南方的疾病急剧复兴 美国以及随后的疫苗接种运动已经耗尽了17d的全球供应。回应这些 疫苗短缺，WHO和CDC修改了10年的增强剂到一生的疫苗接种 建议，尽管支持数据有限：尽管血清武器发现约90％的疫苗有 对YFV的可检测中和抗体，对这些调查的仔细审查发现，在生活中的个人中 YFV非流行环境，至少20％的YFV疫苗在> 10年时缺乏可检测的中和抗体 疫苗接种后。虽然必须在持续暴发和疫苗的背景下进行严格评估这一发现 短缺，它也代表了研究17D如何诱导和保持中和的独特机会 某些疫苗中的抗体，但在其他疫苗中没有。我们的中心前提是建立了长期的YFV豁免权 通过疫苗接种时疫苗病毒血症的宿主免疫激活：下游影响 疫苗接种时疫苗病毒血症的持续时间和幅度可检测到的差异确定是否是否 疫苗会发展终身免疫力。我们建议评估这一前提及其在三个中的广泛含义 单独目的：目标1检验了疫苗病毒血症与YFV的长期耐用性相关的假设 中和抗体。我们将注册YFV前疫苗感，并前瞻性地表征急性疫苗病毒血症， 急性先天免疫和适应性免疫反应，并在此后5年中和抗体滴度中和。 AIM 2检验以下假设：17D接种受试者中至少有20％在3-和 疫苗接种后7年。我们将招募并前瞻性地跟随17D疫苗接种2 - 3年的队列 在入学之前，比较YFV中和抗体和其他免疫标记的变化，并且 表征个体和队列抗体衰减动力学。在AIM 3中，我们使用17D Revaccination作为活病毒 测试中和抗体滴度与YFV保护相关的假设的挑战。我们将 前瞻性地表征前增强抗体滴度，疫苗病毒血症，急性免疫反应和增强后 接种17D疫苗接种的疫苗中的滴度。我们希望在上面识别中和抗体滴度 赋予哪种灭菌免疫力，而滴度则低于它。这些目标将为未来树立基础 研究进一步剖析17d和其他LAV诱导免疫力的决定因素的研究，并建立可能 在面对当前和将来的暴发时，允许有效的17D疫苗接种并优化17D使用。