Long Term Immunity Following Yellow Fever Vaccination

黄热病疫苗接种后的长期免疫力

• 批准号: 10558592
• 负责人: William Messer
• 金额: $ 52.46万
• 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/10558592
• 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; Cessation of life; Country; Cross-Sectional Studies; Culicidae; Data; Dengue Virus; Disease; Disease Outbreaks; Dose; Enrollment; Evaluation; Flavivirus; Fostering; Foundations; Frequencies; Future; Heterogeneity; Human; Immune; Immune response; Immunity; Immunologic Markers; Individual; Infection; Innate Immune Response; Kinetics; Knowledge; 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 Virus; adaptive immune response; antibody detection; arthropod-borne; burden of illness; cohort; critical period; falls; future outbreak; health organization; human pathogen; immune activation; immunogenicity; improved; innovation; mortality; neutralizing antibody; nonhuman primate; pathogenic virus; pressure; prospective; prototype; recruit; response; secondary analysis; seroconversion; seropositive; serosurvey; transmission process

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（Yellow Fever Virus，YFV）是黄病毒的原型，是历史上最重要的节肢动物传播病毒 每年约有200，000例感染，发生感染者的死亡率约为50%。 严重的症状。YFV在整个非洲和南美洲流行， 大规模接种疫苗YFV疫苗17 D被认为是最有效的减毒活病毒（LAV）之一。 曾经研制的疫苗。即便如此，建议每10年加强一次以保持免疫力。 然而，疫苗接种率的下降导致非洲和南苏丹的疾病急剧死灰复燃， 美国，以及随后的疫苗接种运动耗尽了全球17 D的供应。针对这些 由于疫苗短缺，世卫组织和疾病预防控制中心将10年的疫苗接种改为一生一次的疫苗接种 建议，尽管支持数据有限：尽管血清调查发现约90%的疫苗接种者 可检测到的YFV中和抗体，仔细审查这些调查发现，在生活在 在YFV非流行性环境中，至少20%的YFV疫苗接种者在>10年时缺乏可检测的中和抗体 接种疫苗后。虽然这一发现必须在正在发生的疫情和疫苗的背景下进行批判性评估， 短缺，它也代表了一个独特的机会，研究如何17 D诱导和维持中和 一些疫苗接种者体内有抗体，而另一些则没有。我们的中心前提是建立长期的YFV免疫力 通过接种疫苗时疫苗病毒血症引起的宿主免疫激活： 疫苗接种时疫苗病毒血症的持续时间和程度的可检测差异决定了是否存在免疫缺陷。 接种疫苗可产生终身免疫力。我们建议从三个方面来评估这一前提及其更广泛的含义。 单独的目的：目的1检验疫苗病毒血症与YFV的长期持久性相关的假设 中和抗体我们将招募YFV疫苗接种前受试者，并前瞻性地描述急性疫苗病毒血症， 急性先天性免疫和适应性免疫应答，以及此后长达5年的中和抗体效价。 目的2检验以下假设：至少20%的17 D疫苗接种受试者将在3- 15岁之间丧失YFV免疫力。 7-接种疫苗后几年。我们将招募并前瞻性随访一组17 D疫苗接种者2-3年 入组前，比较YFV中和抗体和其他免疫标志物随时间的变化， 表征个体和群组抗体衰减动力学。在目标3中，我们使用17 D再接种作为活病毒 挑战测试中和抗体滴度与YFV保护相关的假设。我们将 前瞻性表征加强前抗体滴度、疫苗病毒血症、急性免疫应答和加强后 接受加强17 D疫苗接种的疫苗接种者的滴度。我们希望能够确定上述中和抗体滴度 其杀菌免疫被赋予，而低于其则不被赋予。这些目标将为未来奠定基础。 研究进一步剖析17 D和其他LAV诱导免疫的决定因素，并建立可以 允许17 D疫苗接种的有效优先级，并在当前和未来的疫情中优化17 D的使用。