Molecular analysis of antibody repertoire elicited after yellow fever vaccination

黄热病疫苗免疫后抗体库的分子生物学分析 尽管针对黄热病病毒（YFV）的有效疫苗存在高频率的 全球YFV爆发对人类健康构成迫在眉睫的威胁。卫生当局已 在过去的两年里，仅在巴西就有500多人死亡， 在过去的30年里，有26个非洲国家向世界卫生组织报告了YFV疫情。YFV 感染引起发热性流感样疾病，约10-25%的患者发生出血性疾病 临床表现，肾脏和肝脏损伤，可导致死亡。YFV显示相似性 与登革热病毒（DENV）和寨卡病毒（ZIKV）等其他医学上重要的黄病毒相比。 这项工作的核心假设是，在YFV存在的地理区域， 与DENV和ZIKV地方性黄病毒共循环，接种YFV的队列将表现出 DENV和ZIKV感染的发生率具有统计学上的不同模式（显著较低或 与未接种对照组相比，由于疫苗引起血清IgG抗体， YFV和DENV和/或ZIKV之间的交叉反应性。有鉴于此，本次活动的目的 合作项目是：（i）告知抗体的复杂性和分子特征 由YFV疫苗接种引起的对YFV特异的库和与YFV交叉反应的库 DENV-2和/或ZIKV，（ii）分离具有治疗性的YFV特异性单克隆抗体（mAb）， （iii）评估这些mAb保护免受YFV、DENV和ZIKV的能力 感染或通过抗体依赖性增强（ADE）增加感染，和（iv） 鉴定中和和交叉反应性mAb靶向的表位。我们的多学科 该方法将包括一套用于分析适应性免疫反应的原始工具- 由两项已颁发的美国专利开发、出版和保护，目前仅在 UT Austin-以高通量、高亲和力全面鉴定人类交叉反应性 血清抗体，并描绘交叉反应性抗体产生的分子性质。 总的来说，这项工作将是重要的，以确定是否存在的ADE诱导的YFV 疫苗接种，并开辟前景，制定疫苗接种战略， YFV、ZIKV和DENV之间的ADE应答以及有效mAb的开发 黄热病的治疗方法

Molecular analysis of antibody repertoire elicited after yellow fever vaccination Even though an effective vaccine against the yellow fever virus (YFV) exist a high frequency of global YFV outbreaks represent an imminent threat to human health. Health authorities have confirmed more than 500 deaths just in Brazil in the last two years, and more than 150 incidents of YFV outbreaks in 26 African countries were reported to the WHO in the last 30 years. YFV infection causes a febrile flu-like illness, and about 10-25% of patients develop hemorrhagic manifestations, kidney and liver damage that can result in death. YFV show similarities compared to other medical important flavivirus as dengue virus (DENV) and zika virus (ZIKV). The central hypothesis underlying the proposed work is that in geographic regions where YFV co-circulates with DENV and ZIKV endemic flaviviruses, cohorts vaccinated for YFV will exhibit a statistically different pattern of incidence of DENV and ZIKV infections (significantly lower or greater) compared to unvaccinated controls, due to vaccine elicitation of serum IgG antibodies cross-reactive between YFV and DENV and/or ZIKV. In view of this, the aims of this collaborative project are to: (i) inform on the complexity and molecular features of the antibody repertoire elicited by YFV vaccination that are specific to YFV and those that cross-react with DENV-2 and/or ZIKV, (ii) isolate YFV-specific monoclonal antibodies (mAbs) with therapeutic potential, (iii) evaluate the ability of these mAbs to protect against YFV, DENV and ZIKV infections or to increase the infection through antibody dependent enhancement (ADE), and (iv) identify the epitopes targeted by the neutralizing and cross-reactive mAbs. Our multidisciplinary approach will include a set of original tools for analyzing adaptive immune responses— developed, published, and protected by two issued US patents and currently available only at UT Austin—to comprehensively identify, at high throughput, high-affinity human cross-reactive serum antibodies and delineate the molecular nature of cross-reactive antibody generation. Collectively, this work will be important to determine the existence of ADE-induced by YFV vaccination and to open up the perspectives to develop vaccination strategies that minimize ADE responses between YFV, ZIKV and DENV and also the development of effective mAb therapeutics against Yellow Fever.