Early and long term immunity following SARS-CoV-2 infection in humans

人类感染 SARS-CoV-2 后的早期和长期免疫力

• 批准号: 10265655
• 负责人: William Messer
• 金额: $ 19.17万
• 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: 2020-06-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265655
• 关键词: Acute; Africa; Antibodies; Antibody titer measurement; Attenuated; Attenuated Live Virus Vaccine; Centers for Disease Control and Prevention (U.S.); Data; Disease; Disease Outbreaks; Enrollment; Evaluation; Flavivirus; Fostering; Foundations; Future; Human; Immune; Immune response; Immunity; Immunologic Markers; Individual; Infection; Kinetics; Knowledge; Life; Mass Vaccinations; Mission; Recommendation; Research; SARS-CoV-2 infection; South America; Surveys; Symptoms; Testing; Time; United States National Institutes of Health; Vaccinated; Vaccination; Vaccines; Viremia; Virus; Yellow Fever Vaccine; Yellow fever virus; adaptive immune response; arthropod-borne; burden of illness; cohort; falls; human pathogen; immune activation; innovation; mortality; neutralizing antibody; pathogenic virus; prospective; prototype; recruit; response; 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.

项目概要 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 200,000 例感染，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，并在很大程度上通过以下方式得到控制： 大规模疫苗接种。 YFV 疫苗 17D 被认为是最有效的减毒活病毒 (LAV) 之一 曾经研制出疫苗。即便如此，仍建议每 10 年加强一次以维持免疫力。 然而，疫苗接种率下降导致非洲和南非疾病急剧卷土重来。 美国和随后的疫苗接种运动已经耗尽了 17D 的全球供应。针对这些 疫苗短缺，世界卫生组织和疾控中心将10年加强疫苗接种改为一生一次 尽管支持数据有限，但仍建议：尽管血清调查发现约 90% 的疫苗接种者已接种疫苗 可检测到 YFV 中和抗体，仔细审查这些调查发现，生活在 在 YFV 非流行环境中，至少 20% 的 YFV 疫苗接种者在 10 年以上时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严格评估 短缺，它也提供了一个独特的机会来研究 17D 如何诱导和维持中和 一些疫苗接种者体内有抗体，但另一些疫苗接种者则没有。我们的核心前提是建立长期的 YFV 免疫力 通过宿主免疫激活来响应疫苗接种时的疫苗病毒血症：下游效应 接种疫苗时疫苗病毒血症持续时间和程度的可检测差异决定了是否 接种疫苗者会产生终生免疫力。我们建议从三个方面评估这一前提及其更广泛的含义 单独的目标：目标 1 检验疫苗病毒血症与 YFV 的长期耐久性相关的假设 中和抗体。我们将招募 YFV 预疫苗接种者并前瞻性地描述急性疫苗病毒血症的特征， 急性先天免疫和适应性免疫反应，以及此后长达 5 年的中和抗体滴度。 目标 2 检验以下假设：至少 20% 的 17D 疫苗接种对象将在 3 至 3 年间失去 YFV 免疫力。 接种疫苗后 7 年。我们将招募并前瞻性跟踪一组已接种 2-3 年的 17D 疫苗接种者 在入组之前，比较 YFV 中和抗体和其他免疫标志物随时间的变化， 表征个体和群体抗体衰减动力学。在目标 3 中，我们使用 17D 重新接种作为活病毒 挑战检验中和抗体滴度与 YFV 保护相关的假设。我们将 前瞻性地表征加强前抗体滴度、疫苗病毒血症、急性免疫反应和加强后 接受加强 17D 疫苗接种的疫苗接种者的滴度。我们期望鉴定出上述中和抗体滴度 具有哪种灭菌免疫力，低于哪种滴度则不具有灭菌免疫力。这些目标将为未来奠定基础 研究进一步剖析 17D 和其他 LAV 诱导免疫的决定因素，并建立可以 允许有效优先考虑 17D 疫苗接种，并在当前和未来的疫情爆发时优化 17D 使用。