Long Term Immunity Following Yellow Fever Vaccination

项目总结 黄热病病毒(YFV)是黄病毒的原型，是历史上最重要的节肢动物传播病毒 全世界人类的病原体，每年约有20万人感染，患此病的人死亡率约为50% 严重的症状。YFV在整个非洲和南美洲都是地方病，主要通过 大规模接种疫苗。YFV疫苗17d被认为是最有效的减毒活病毒之一。 最新研发的疫苗。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非疾病的戏剧性死灰复燃 美国，以及随后的疫苗接种运动耗尽了全球17D的供应。在回应这些问题时 疫苗短缺，世卫组织和疾控中心将10年强化接种修订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%的疫苗接种者有 可检测到的YFV中和抗体，仔细审查这些调查发现，在居住在 在YFV非流行环境下，至少20%的YFV疫苗接种者在10年内缺乏可检测到的中和抗体 疫苗接种后。虽然这一发现必须在持续爆发和疫苗接种的背景下进行批判性评估 不足，这也是一个独特的机会来研究17D如何诱导和维持中和 一些接种疫苗的人体内有抗体，而另一些人则没有。我们的中心前提是建立长期的YFV免疫力 在接种疫苗时通过宿主免疫激活对疫苗病毒血症的反应： 疫苗接种时疫苗病毒血症持续时间和程度的可检测差异决定了 接种疫苗的人会产生终身免疫。我们建议在三个阶段评估这一前提及其更广泛的影响 不同的目标：目标1测试疫苗病毒血症与YFV的长期持久性相关的假设 中和抗体。我们将招募接种前YFV的人，并前瞻性地描述急性疫苗病毒血症的特征， 急性先天免疫和获得性免疫反应，中和抗体效价长达5年。 Aim 2验证了这样的假设，即至少20%的17D疫苗接种对象将在3-5岁之间失去YFV免疫力 接种后7年。我们将招募并前瞻性地跟踪接种2-3年的17D疫苗接种者队列 在登记之前，比较YFV中和抗体和其他免疫标志物随时间和 描述个体和队列抗体衰变的动力学。在目标3中，我们使用17D复种作为活病毒 挑战检验中和抗体效价与YFV保护相关的假设。我们会 前瞻性地描述加强免疫前抗体效价、疫苗病毒血症、急性免疫反应和加强免疫后 接受加强17D疫苗接种的接种者中的效价。我们希望鉴定出中和抗体效价高于 被授予的消毒免疫力和不低于的滴度。这些目标将为未来奠定基础 进一步研究17D和其他LAV诱导的免疫决定因素，并建立能够 允许有效地优先接种17D疫苗，并优化17D使用，以应对当前和未来的疫情。

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.