Molecular analysis of antibody repertoire elicited after yellow fever vaccination

黄热病疫苗免疫后抗体谱的分子分析 尽管黄热病病毒(YFV)的有效疫苗存在很高的频率 全球YFV疫情对人类健康构成迫在眉睫的威胁。卫生当局已经 过去两年仅在巴西就确认了500多人死亡，150多起事件 在过去的30年里，26个非洲国家爆发的YFV疫情被报告给了世界卫生组织。YFV 感染会导致一种类似流感的发烧疾病，大约10%-25%的患者会出现出血性 可能导致死亡的症状、肾脏和肝脏损害。YFV表现出相似性 与其他医学上重要的黄病毒如登革热病毒(DENV)和寨卡病毒(ZIKV)相比。 支持这项拟议工作的中心假设是，在YFV 与DENV和ZIKV地方性黄病毒共同传播，接种YFV疫苗的队列将展示 DENV和ZIKV感染的发病率模式在统计学上不同(显著低于或 与未接种疫苗的对照组相比，由于疫苗诱导血清免疫球蛋白抗体， YFV与DENV和/或ZIKV之间的交叉反应。有鉴于此，这一行动的目的是 合作项目是：(I)告知抗体的复杂性和分子特征 对YFV特异的YFV疫苗和与YFV发生交叉反应的疫苗所产生的特异谱 DENV-2和/或ZIKV，(Ii)用治疗性方法分离YFV特异性单抗 潜力，(Iii)评估这些单抗对YFV、DENV和ZIKV的保护能力 感染或通过抗体依赖增强(ADE)增加感染，以及(Iv) 确定中和和交叉反应单抗所针对的表位。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创工具- 由两项已颁发的美国专利开发、发布和保护，目前仅在 德克萨斯大学奥斯汀分校--以高吞吐量、高亲和力的人类交叉反应全面识别 并描述交叉反应抗体产生的分子本质。 总之，这项工作将对确定YFV诱导的ADE的存在具有重要意义 疫苗接种和开拓前景，以制定疫苗接种战略，尽量减少 YFV、ZIKV和DENV的ADE反应及有效单抗的研制 治疗黄热病。

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.